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Live Conference Coverage @Medcitynews Converge 2018 Philadelphia: The Davids vs. the Cancer Goliath Part 2

8:40 – 9:25 AM The Davids vs. the Cancer Goliath Part 2

Startups from diagnostics, biopharma, medtech, digital health and emerging tech will have 8 minutes to articulate their visions on how they aim to tame the beast.

Start Time End Time Company
8:40 8:48 3Derm
8:49 8:57 CNS Pharmaceuticals
8:58 9:06 Cubismi
9:07 9:15 CytoSavvy
9:16 9:24 PotentiaMetrics

Speakers:
Liz Asai, CEO & Co-Founder, 3Derm Systems, Inc. @liz_asai
John M. Climaco, CEO, CNS Pharmaceuticals @cns_pharma 

John Freyhof, CEO, CytoSavvy
Robert Palmer, President & CEO, PotentiaMetrics @robertdpalmer 
Moira Schieke M.D., Founder, Cubismi, Adjunct Assistant Prof UW Madison @cubismi_inc

 

3Derm Systems

3Derm Systems is an image analysis firm for dermatologic malignancies.  They use a tele-medicine platform to accurately triage out benign malignancies observed from the primary care physician, expediate those pathology cases if urgent to the dermatologist and rapidly consults with you over home or portable device (HIPAA compliant).  Their suite also includes a digital dermatology teaching resource including digital training for students and documentation services.

 

CNS Pharmaceuticals

developing drugs against CNS malignancies, spun out of research at MD Anderson.  They are focusing on glioblastoma and Berubicin, an anthracycline antiobiotic (TOPOII inhibitor) that can cross the blood brain barrier.  Berubicin has good activity in a number of animal models.  Phase I results were very positive and Phase II is scheduled for later in the year.  They hope that the cardiotoxicity profile is less severe than other anthracyclines.  The market opportunity will be in temazolamide resistant glioblastoma.

Cubismi

They are using machine learning and biomarker based imaging to visualize tumor heterogeneity. “Data is the new oil” (Intel CEO). We need prediction machines so they developed a “my body one file” system, a cloud based data rich file of a 3D map of human body.

CUBISMI IS ON A MISSION TO HELP DELIVER THE FUTURE PROMISE OF PRECISION MEDICINE TO CURE DISEASE AND ASSURE YOUR OPTIMAL HEALTH.  WE ARE BUILDING A PATIENT-DOCTOR HEALTH DATA EXCHANGE PLATFORM THAT WILL LEVERAGE REVOLUTIONARY MEDICAL IMAGING TECHNOLOGY AND PUT THE POWER OF HEALTH DATA INTO THE HANDS OF YOU AND YOUR DOCTORS.

 

CytoSavvy

CytoSavvy is a digital pathology company.  They feel AI has a fatal flaw in that no way to tell how a decision was made. Use a Shape Based Model Segmentation algorithm which uses automated image analysis to provide objective personalized pathology data.  They are partnering with three academic centers (OSU, UM, UPMC) and pool data and automate the rule base for image analysis.

CytoSavvy’s patented diagnostic dashboards are intuitive, easy–to-use and HIPAA compliant. Our patented Shape-Based Modeling Segmentation (SBMS) algorithms combine shape and color analysis capabilities to increase reliability, save time, and improve decisions. Specifications and capabilities for our web-based delivery system follow.

link to their white paper: https://www.cytosavvy.com/resources/healthcare-ai-value-proposition.pdf

PotentialMetrics

They were developing a diagnostic software for cardiology epidemiology measuring outcomes however when a family member got a cancer diagnosis felt there was a need for outcomes based models for cancer treatment/care.  They deliver real world outcomes for persoanlized patient care to help patients make decisions on there care by using a socioeconomic modeling integrated with real time clinical data.

Featured in the Wall Street Journal, using the informed treatment decisions they have generated achieve a 20% cost savings on average.  There research was spun out of Washington University St. Louis.

They have concentrated on urban markets however the CEO had mentioned his desire to move into more rural areas of the country as there models work well for patients in the rural setting as well.

Please follow on Twitter using the following #hash tags and @pharma_BI 

#MCConverge

#cancertreatment

#healthIT

#innovation

#precisionmedicine

#healthcaremodels

#personalizedmedicine

#healthcaredata

And at the following handles:

@pharma_BI

@medcitynews

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

A heart-healthy diet has been the basis of atherosclerotic cardiovascular disease (ASCVD) prevention and treatment for decades. The potential cardiovascular (CV) benefits of specific individual components of the “food-ome” (defined as the vast array of foods and their constituents) are still incompletely understood, and nutritional science continues to evolve.

 

The scientific evidence base in nutrition is still to be established properly. It is because of the complex interplay between nutrients and other healthy lifestyle behaviours associated with changes in dietary habits. However, several controversial dietary patterns, foods, and nutrients have received significant media exposure and are stuck by hype.

 

Decades of research have significantly advanced our understanding of the role of diet in the prevention and treatment of ASCVD. The totality of evidence includes randomized controlled trials (RCTs), cohort studies, case-control studies, and case series / reports as well as systematic reviews and meta-analyses. Although a robust body of evidence from RCTs testing nutritional hypotheses is available, it is not feasible to obtain meaningful RCT data for all diet and health relationships.

 

Studying preventive diet effects on ASCVD outcomes requires many years because atherosclerosis develops over decades and may be cost-prohibitive for RCTs. Most RCTs are of relatively short duration and have limited sample sizes. Dietary RCTs are also limited by frequent lack of blinding to the intervention and confounding resulting from imperfect diet control (replacing 1 nutrient or food with another affects other aspects of the diet).

 

In addition, some diet and health relationships cannot be ethically evaluated. For example, it would be unethical to study the effects of certain nutrients (e.g., sodium, trans fat) on cardiovascular disease (CVD) morbidity and mortality because they increase major risk factors for CVD. Epidemiological studies have suggested associations among diet, ASCVD risk factors, and ASCVD events. Prospective cohort studies yield the strongest observational evidence because the measurement of dietary exposure precedes the development of the disease.

 

However, limitations of prospective observational studies include: imprecise exposure quantification; co-linearity among dietary exposures (e.g., dietary fiber tracks with magnesium and B vitamins); consumer bias, whereby consumption of a food or food category may be associated with non-dietary practices that are difficult to control (e.g., stress, sleep quality); residual confounding (some non-dietary risk factors are not measured); and effect modification (the dietary exposure varies according to individual/genetic characteristics).

 

It is important to highlight that many healthy nutrition behaviours occur with other healthy lifestyle behaviours (regular physical activity, adequate sleep, no smoking, among others), which may further confound results. Case-control studies are inexpensive, relatively easy to do, and can provide important insight about an association between an exposure and an outcome. However, the major limitation is how the study population is selected or how retrospective data are collected.

 

In nutrition studies that involve keeping a food diary or collecting food frequency information (i.e., recall or record), accurate memory and recording of food and nutrient intake over prolonged periods can be problematic and subject to error, especially before the diagnosis of disease.

 

The advent of mobile technology and food diaries may provide opportunities to improve accuracy of recording dietary intake and may lead to more robust evidence. Finally, nutrition science has been further complicated by the influences of funding from the private sector, which may have an influence on nutrition policies and practices.

 

So, the future health of the global population largely depends on a shift to healthier dietary patterns. Green leafy vegetables and antioxidant suppliments have significant cardio-protective properties when consumed daily. Plant-based proteins are significantly more heart-healthy compared to animal proteins.

 

However, in the search for the perfect dietary pattern and foods that provide miraculous benefits, consumers are vulnerable to unsubstantiated health benefit claims. As clinicians, it is important to stay abreast of the current scientific evidence to provide meaningful and effective nutrition guidance to patients for ASCVD risk reduction.

 

Available evidence supports CV benefits of nuts, olive oil and other liquid vegetable oils, plant-based diets and plant-based proteins, green leafy vegetables, and antioxidant-rich foods. Although juicing may be of benefit for individuals who would otherwise not consume adequate amounts of fresh fruits and vegetables, caution must be exercised to avoid excessive calorie intake. Juicing of fruits / vegetables with pulp removal increases calorie intake. Portion control is necessary to avoid weight gain and thus cardiovascular health.

 

There is currently no evidence to supplement regular intake of antioxidant dietary supplements. Gluten is an issue for those with gluten-related disorders, and it is important to be mindful of this in routine clinical practice; however, there is no evidence for CV or weight loss benefits, apart from the potential caloric restriction associated with a gluten free diet.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/28254181

 

https://www.sciencedirect.com/science/article/pii/S0735109713060294?via%3Dihub

 

http://circ.ahajournals.org/content/119/8/1161

 

http://refhub.elsevier.com/S0735-1097(17)30036-0/sref6

 

https://www.scopus.com/record/display.uri?eid=2-s2.0-0031709841&origin=inward&txGid=af40773f7926694c7f319d91efdcd40c

 

https://www.magonlinelibrary.com/doi/10.12968/hosp.2000.61.4.1875

 

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2548255

 

https://pharmaceuticalintelligence.com/2018/05/31/supplements-offer-little-cv-benefit-and-some-are-linked-to-harm-in-j-am-coll-cardiol/

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Treatment of Lymphomas [2.4.4C]

Larry H. Bernstein, MD, FCAP, Author, Curator, Editor

http://pharmaceuticalinnovation.com/2015/8/11/larryhbern/Treatment-of-Lymphomas-[2.4.4C]

 

Lymphoma treatment

Overview

http://www.emedicinehealth.com/lymphoma/page8_em.htm#lymphoma_treatment

The most widely used therapies are combinations of chemotherapyand radiation therapy.

  • Biological therapy, which targets key features of the lymphoma cells, is used in many cases nowadays.

The goal of medical therapy in lymphoma is complete remission. This means that all signs of the disease have disappeared after treatment. Remission is not the same as cure. In remission, one may still have lymphoma cells in the body, but they are undetectable and cause no symptoms.

  • When in remission, the lymphoma may come back. This is called recurrence.
  • The duration of remission depends on the type, stage, and grade of the lymphoma. A remission may last a few months, a few years, or may continue throughout one’s life.
  • Remission that lasts a long time is called durable remission, and this is the goal of therapy.
  • The duration of remission is a good indicator of the aggressiveness of the lymphoma and of the prognosis. A longer remission generally indicates a better prognosis.

Remission can also be partial. This means that the tumor shrinks after treatment to less than half its size before treatment.

The following terms are used to describe the lymphoma’s response to treatment:

  • Improvement: The lymphoma shrinks but is still greater than half its original size.
  • Stable disease: The lymphoma stays the same.
  • Progression: The lymphoma worsens during treatment.
  • Refractory disease: The lymphoma is resistant to treatment.

The following terms to refer to therapy:

  • Induction therapy is designed to induce a remission.
  • If this treatment does not induce a complete remission, new or different therapy will be initiated. This is usually referred to as salvage therapy.
  • Once in remission, one may be given yet another treatment to prevent recurrence. This is called maintenance therapy.

Chemotherapy

Many different types of chemotherapy may be used for Hodgkin lymphoma. The most commonly used combination of drugs in the United States is called ABVD. Another combination of drugs, known as BEACOPP, is now widely used in Europe and is being used more often in the United States. There are other combinations that are less commonly used and not listed here. The drugs that make up these two more common combinations of chemotherapy are listed below.

ABVD: Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban, Velsar), and dacarbazine (DTIC-Dome). ABVD chemotherapy is usually given every two weeks for two to eight months.

BEACOPP: Bleomycin, etoposide (Toposar, VePesid), doxorubicin, cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS, Oncovin), procarbazine (Matulane), and prednisone (multiple brand names). There are several different treatment schedules, but different drugs are usually given every two weeks.

The type of chemotherapy, number of cycles of chemotherapy, and the additional use of radiation therapy are based on the stage of the Hodgkin lymphoma and the type and number of prognostic factors.

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/Patient/page1

Key Points for This Section

Adult non-Hodgkin lymphoma is a disease in which malignant (cancer) cells form in the lymph system.

Because lymph tissue is found throughout the body, adult non-Hodgkin lymphoma can begin in almost any part of the body. Cancer can spread to the liver and many other organs and tissues.

Non-Hodgkin lymphoma in pregnant women is the same as the disease in nonpregnant women of childbearing age. However, treatment is different for pregnant women. This summary includes information on the treatment of non-Hodgkin lymphoma during pregnancy

Non-Hodgkin lymphoma can occur in both adults and children. Treatment for children, however, is different than treatment for adults. (See the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information.)

There are many different types of lymphoma.

Lymphomas are divided into two general types: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of adult non-Hodgkin lymphoma. For information about other types of lymphoma, see the following PDQ summaries:

Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin lymphoma.

If cancer is found, the following tests may be done to study the cancer cells:

  • Immunohistochemistry : A test that uses antibodies to check for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the tissue to light up under a microscope. This type of test may be used to tell the difference between different types of cancer.
  • Cytogenetic analysis : A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
  • Immunophenotyping : A process used to identify cells, based on the types of antigens ormarkers on the surface of the cell. This process is used to diagnose specific types of leukemia and lymphoma by comparing the cancer cells to normal cells of the immune system.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer.
  • The type of non-Hodgkin lymphoma.
  • The amount of lactate dehydrogenase (LDH) in the blood.
  • The amount of beta-2-microglobulin in the blood (for Waldenström macroglobulinemia).
  • The patient’s age and general health.
  • Whether the lymphoma has just been diagnosed or has recurred (come back).

Stages of adult non-Hodgkin lymphoma may include E and S.

Adult non-Hodgkin lymphoma may be described as follows:

E: “E” stands for extranodal and means the cancer is found in an area or organ other than the lymph nodes or has spread to tissues beyond, but near, the major lymphatic areas.

S: “S” stands for spleen and means the cancer is found in the spleen.

Stage I adult non-Hodgkin lymphoma is divided into stage I and stage IE.

  • Stage I: Cancer is found in one lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen).
  • Stage IE: Cancer is found in one organ or area outside the lymph nodes.

Stage II adult non-Hodgkin lymphoma is divided into stage II and stage IIE.

  • Stage II: Cancer is found in two or more lymph node groups either above or below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIE: Cancer is found in one or more lymph node groups either above or below the diaphragm. Cancer is also found outside the lymph nodes in one organ or area on the same side of the diaphragm as the affected lymph nodes.

Stage III adult non-Hodgkin lymphoma is divided into stage III, stage IIIE, stage IIIS, and stage IIIE+S.

  • Stage III: Cancer is found in lymph node groups above and below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIIE: Cancer is found in lymph node groups above and below the diaphragm and outside the lymph nodes in a nearby organ or area.
  • Stage IIIS: Cancer is found in lymph node groups above and below the diaphragm, and in the spleen.
  • Stage IIIE+S: Cancer is found in lymph node groups above and below the diaphragm, outside the lymph nodes in a nearby organ or area, and in the spleen.

In stage IV adult non-Hodgkin lymphoma, the cancer:

  • is found throughout one or more organs that are not part of a lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen), and may be in lymph nodes near those organs; or
  • is found in one organ that is not part of a lymphatic area and has spread to organs or lymph nodes far away from that organ; or
  • is found in the liver, bone marrow, cerebrospinal fluid (CSF), or lungs (other than cancer that has spread to the lungs from nearby areas).

Adult non-Hodgkin lymphomas are also described based on how fast they grow and where the affected lymph nodes are in the body.  Indolent & aggressive.

The treatment plan depends mainly on the following:

  • The type of non-Hodgkin’s lymphoma
  • Its stage (where the lymphoma is found)
  • How quickly the cancer is growing
  • The patient’s age
  • Whether the patient has other health problems
  • If there are symptoms present such as fever and night sweats (see above)

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Treatments for Lymphomas and Leukemias

Curator and Editor: Larry H. Bernstein, MD, FCAP

 

2.4.4 Treatments for leukemia by type

2.4.4.1 Acute Lymphocytic Leukemias

Treatment of Acute Lymphoblastic Leukemia

Ching-Hon Pu, and William E. Evans
N Engl J Med Jan 12, 2006; 354:166-178
http://dx.doi.org:/10.1056/NEJMra052603

Although the overall cure rate of acute lymphoblastic leukemia (ALL) in children is about 80 percent, affected adults fare less well. This review considers recent advances in the treatment of ALL, emphasizing issues that need to be addressed if treatment outcome is to improve further.

Acute Lymphoblastic Leukemia

Ching-Hon Pui, Mary V. Relling, and James R. Downing
N Engl J Med Apr 8, 2004; 350:1535-1548
http://dx.doi.org:/10.1056/NEJMra023001

This comprehensive survey emphasizes how recent advances in the knowledge of molecular mechanisms involved in acute lymphoblastic leukemia have influenced diagnosis, prognosis, and treatment.

Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment

Amy Holleman, Meyling H. Cheok, Monique L. den Boer, et al.
N Engl J Med 2004; 351:533-42

Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown.

Methods We tested leukemia cells from 173 children for sensitivity in vitro to prednisolone, vincristine, asparaginase, and daunorubicin. The cells were then subjected to an assessment of gene expression with the use of 14,500 probe sets to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Gene-expression patterns that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome in the original 173 patients and an independent cohort of 98 children treated with the same drugs at another institution.

Results We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes). A combined gene-expression score of resistance to the four drugs, as compared with sensitivity to the four, was significantly and independently related to treatment outcome in a multivariate analysis (hazard ratio for relapse, 3.0; P=0.027). Results were confirmed in an independent population of patients treated with the same medications (hazard ratio for relapse, 11.85; P=0.019). Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs we tested.

Conclusions  Differential expression of a relatively small number of genes is associated with drug resistance and treatment outcome in childhood ALL.

Leukemias Treatment & Management

Author: Lihteh Wu, MD; Chief Editor: Hampton Roy Sr
http://emedicine.medscape.com/article/1201870-treatment

The treatment of leukemia is in constant flux, evolving and changing rapidly over the past few years. Most treatment protocols use systemic chemotherapy with or without radiotherapy. The basic strategy is to eliminate all detectable disease by using cytotoxic agents. To attain this goal, 3 phases are typically used, as follows: remission induction phase, consolidation phase, and maintenance therapy phase.

Chemotherapeutic agents are chosen that interfere with cell division. Tumor cells usually divide more rapidly than host cells, making them more vulnerable to the effects of chemotherapy. Primary treatment will be under the direction of a medical oncologist, radiation oncologist, and primary care physician. Although a general treatment plan will be outlined, the ophthalmologist does not prescribe or manage such treatment.

  • The initial treatment of ALL uses various combinations of vincristine, prednisone, and L-asparaginase until a complete remission is obtained.
  • Maintenance therapy with mercaptopurine is continued for 2-3 years following remission.
  • Use of intrathecal methotrexate with or without cranial irradiation to cover the CNS varies from facility to facility.
  • Daunorubicin, cytarabine, and thioguanine currently are used to obtain induction and remission of AML.
  • Maintenance therapy for 8 months may lengthen remission. Once relapse has occurred, AML generally is curable only by bone marrow transplantation.
  • Presently, treatment of CLL is palliative.
  • CML is characterized by a leukocytosis greater than 100,000 cells. Emergent treatment with leukopheresis sometimes is necessary when leukostastic complications are present. Otherwise, busulfan or hydroxyurea may control WBC counts. During the chronic phase, treatment is palliative.
  • When CML converts to the blastic phase, approximately one third of cases behave as ALL and respond to treatment with vincristine and prednisone. The remaining two thirds resemble AML but respond poorly to AML therapy.
  • Allogeneic bone marrow transplant is the only curative therapy for CML. However, it carries a high early mortality rate.
  • Leukemic retinopathy usually is not treated directly. As the hematological parameters normalize with systemic treatment, many of the ophthalmic signs resolve. There are reports that leukopheresis for hyperviscosity also may alleviate intraocular manifestations.
  • When definite intraocular leukemic infiltrates fail to respond to systemic chemotherapy, direct radiation therapy is recommended.
  • Relapse, manifested by anterior segment involvement, should be treated by radiation. In certain cases, subconjunctival chemotherapeutic agents have been injected.
  • Optic nerve head infiltration in patients with ALL is an emergency and requires prompt radiation therapy to try to salvage some vision.

Treatments and drugs

http://www.mayoclinic.org/diseases-conditions/leukemia/basics/
treatment/con-20024914

Common treatments used to fight leukemia include:

  • Chemotherapy. Chemotherapy is the major form of treatment for leukemia. This drug treatment uses chemicals to kill leukemia cells.

Depending on the type of leukemia you have, you may receive a single drug or a combination of drugs. These drugs may come in a pill form, or they may be injected directly into a vein.

  • Biological therapy. Biological therapy works by using treatments that help your immune system recognize and attack leukemia cells.
  • Targeted therapy. Targeted therapy uses drugs that attack specific vulnerabilities within your cancer cells.

For example, the drug imatinib (Gleevec) stops the action of a protein within the leukemia cells of people with chronic myelogenous leukemia. This can help control the disease.

  • Radiation therapy. Radiation therapy uses X-rays or other high-energy beams to damage leukemia cells and stop their growth. During radiation therapy, you lie on a table while a large machine moves around you, directing the radiation to precise points on your body.

You may receive radiation in one specific area of your body where there is a collection of leukemia cells, or you may receive radiation over your whole body. Radiation therapy may be used to prepare for a stem cell transplant.

  • Stem cell transplant. A stem cell transplant is a procedure to replace your diseased bone marrow with healthy bone marrow.

Before a stem cell transplant, you receive high doses of chemotherapy or radiation therapy to destroy your diseased bone marrow. Then you receive an infusion of blood-forming stem cells that help to rebuild your bone marrow.

You may receive stem cells from a donor, or in some cases you may be able to use your own stem cells. A stem cell transplant is very similar to a bone marrow transplant.

2.4.4.2 Acute Myeloid Leukemia

New treatment approaches in acute myeloid leukemia: review of recent clinical studies.

Norsworthy K1Luznik LGojo I.
Rev Recent Clin Trials. 2012 Aug; 7(3):224-37.
http://www.ncbi.nlm.nih.gov/pubmed/22540908

Standard chemotherapy can cure only a fraction (30-40%) of younger and very few older patients with acute myeloid leukemia (AML). While conventional allografting can extend the cure rates, its application remains limited mostly to younger patients and those in remission. Limited efficacy of current therapies and improved understanding of the disease biology provided a spur for clinical trials examining novel agents and therapeutic strategies in AML. Clinical studies with novel chemotherapeutics, antibodies, different signal transduction inhibitors, and epigenetic modulators demonstrated their clinical activity; however, it remains unclear how to successfully integrate novel agents either alone or in combination with chemotherapy into the overall therapeutic schema for AML. Further studies are needed to examine their role in relation to standard chemotherapy and their applicability to select patient populations based on recognition of unique disease and patient characteristics, including the development of predictive biomarkers of response. With increasing use of nonmyeloablative or reduced intensity conditioning and alternative graft sources such as haploidentical donors and cord blood transplants, the benefits of allografting may extend to a broader patient population, including older AML patients and those lacking a HLA-matched donor. We will review here recent clinical studies that examined novel pharmacologic and immunologic approaches to AML therapy.

Novel approaches to the treatment of acute myeloid leukemia.

Roboz GJ1
Hematology Am Soc Hematol Educ Program. 2011:43-50.
http://dx.doi.org:/10.1182/asheducation-2011.1.43.

Approximately 12 000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, the majority of whom die from their disease. The mainstay of initial treatment, cytosine arabinoside (ara-C) combined with an anthracycline, was developed nearly 40 years ago and remains the worldwide standard of care. Advances in genomics technologies have identified AML as a genetically heterogeneous disease, and many patients can now be categorized into clinicopathologic subgroups on the basis of their underlying molecular genetic defects. It is hoped that enhanced specificity of diagnostic classification will result in more effective application of targeted agents and the ability to create individualized treatment strategies. This review describes the current treatment standards for induction, consolidation, and stem cell transplantation; special considerations in the management of older AML patients; novel agents; emerging data on the detection and management of minimal residual disease (MRD); and strategies to improve the design and implementation of AML clinical trials.

Age ≥ 60 years has consistently been identified as an independent adverse prognostic factor in AML, and there are very few long-term survivors in this age group.5 Poor outcomes in elderly AML patients have been attributed to both host- and disease-related factors, including medical comorbidities, physical frailty, increased incidence of antecedent myelodysplastic syndrome and myeloproliferative disorders, and higher frequency of adverse cytogenetics.28 Older patients with multiple poor-risk factors have a high probability of early death and little chance of long-term disease-free survival with standard chemotherapy. In a retrospective analysis of 998 older patients treated with intensive induction at the M.D. Anderson Cancer Center, multivariate analysis identified age ≥ 75 years, unfavorable karyotype, poor performance status, creatinine > 1.3 mg/dL, duration of antecedent hematologic disorder > 6 months, and treatment outside a laminar airflow room as adverse prognostic indicators.29 Patients with 3 or more of these factors had expected complete remission rates of < 20%, 8-week mortality > 50%, and 1-year survival < 10%. The Medical Research Council (MRC) identified cytogenetics, WBC count at diagnosis, age, and de novo versus secondary disease as critical factors influencing survival in > 2000 older patients with AML, but cautioned in their conclusions that less objective factors, such as clinical assessment of “fitness” for chemotherapy, may be equally important in making treatment decisions in this patient population.30 It is hoped that data from comprehensive geriatric assessments of functional status, cognition, mood, quality of life, and other measures obtained during ongoing cooperative group trials will improve our ability to predict how older patients will tolerate treatment.

Current treatment of acute myeloid leukemia.

Roboz GJ1.
Curr Opin Oncol. 2012 Nov; 24(6):711-9.
http://dx.doi.org:/10.1097/CCO.0b013e328358f62d.

The objectives of this review are to discuss standard and investigational nontransplant treatment strategies for acute myeloid leukemia (AML), excluding acute promyelocytic leukemia.

RECENT FINDINGS: Most adults with AML die from their disease. The standard treatment paradigm for AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or allogeneic stem cell transplantation, depending on the patient’s ability to tolerate intensive treatment and the likelihood of cure with chemotherapy alone. Although this approach has changed little in the last three decades, increased understanding of the pathogenesis of AML and improvements in molecular genomic technologies are leading to novel drug targets and the development of personalized, risk-adapted treatment strategies. Recent findings related to prognostically relevant and potentially ‘druggable’ molecular targets are reviewed.

SUMMARY: At the present time, AML remains a devastating and mostly incurable disease, but the combination of optimized chemotherapeutics and molecularly targeted agents holds significant promise for the future.

Adult Acute Myeloid Leukemia Treatment (PDQ®)
http://www.cancer.gov/cancertopics/pdq/treatment/adultAML/healthprofessional/page9

About This PDQ Summary

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Treatment Option Overview for AML

Successful treatment of acute myeloid leukemia (AML) requires the control of bone marrow and systemic disease and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% of patients with AML develop CNS disease, prophylactic treatment is not indicated.[13]

Treatment is divided into two phases: remission induction (to attain remission) and postremission (to maintain remission). Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States, other than for acute promyelocytic leukemia. (Refer to the Adult Acute Myeloid Leukemia in Remission section of this summary for more information.) Other studies have used more intensive postremission therapy administered for a shorter duration of time after which treatment is discontinued.[4] Postremission therapy appears to be effective when given immediately after remission is achieved.[4]

Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions including platelet transfusions and for the treatment of related infectious complications.[5] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than 20,000/mm3.[6] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[7] Colony-stimulating factors, for example, granulocyte colony–stimulating factor (G-CSF) and granulocyte-macrophage colony–stimulating factor (GM-CSF), have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[8] If used, these agents are administered after completion of induction therapy. GM-CSF was shown to improve survival in a randomized trial of AML in patients aged 55 to 70 years (median survival was 10.6 months vs. 4.8 months). In this Eastern Cooperative Oncology Group (ECOG) (EST-1490) trial, patients were randomly assigned to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow;[9] however, GM-CSF did not show benefit in a separate similar randomized trial in patients older than 60 years.[10] In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a Southwest Oncology Group (NCT00023777) randomized trial of G-CSF given following induction therapy to patients older than 65 years, complete response was higher in patients who received G-CSF because of a decreased incidence of primary leukemic resistance. Growth factor administration did not impact on mortality or on survival.[11,12] Because the majority of randomized clinical trials have not shown an impact of growth factors on survival, their use is not routinely recommended in the remission induction setting.

The administration of GM-CSF or other myeloid growth factors before and during induction therapy, to augment the effects of cytotoxic therapy through the recruitment of leukemic blasts into cell cycle (growth factor priming), has been an area of active clinical research. Evidence from randomized studies of GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF priming during conventional induction and postremission therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[13,14][Level of evidence: 1iiA] In contrast, a similar randomized placebo-controlled study of GM-CSF priming in patients with AML aged 55 to 75 years showed improved disease-free survival (DFS) in the group receiving GM-CSF (median DFS for patients who achieved complete remission was 23 months vs. 11 months; 2-year DFS was 48% vs. 21%), with a trend towards improvement in overall survival (2-year survival was 39% vs. 27%, = .082) for patients aged 55 to 64 years.[15][Level of evidence: 1iiDii]

References

  1. Kebriaei P, Champlin R, deLima M, et al.: Management of acute leukemias. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1928-54.
  2. Wiernik PH: Diagnosis and treatment of acute nonlymphocytic leukemia. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 283-302.
  3. Morrison FS, Kopecky KJ, Head DR, et al.: Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia–results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia 6 (7): 708-14, 1992. [PUBMED Abstract]
  4. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992. [PUBMED Abstract]
  5. Supportive Care. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 779-967.
  6. Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto. N Engl J Med 337 (26): 1870-5, 1997. [PUBMED Abstract]
  7. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997. [PUBMED Abstract]
  8. Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 14 (4): 1371-82, 1996. [PUBMED Abstract]
  9. Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86 (2): 457-62, 1995. [PUBMED Abstract]
  10. Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 332 (25): 1671-7, 1995. [PUBMED Abstract]
  11. Dombret H, Chastang C, Fenaux P, et al.: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 332 (25): 1678-83, 1995. [PUBMED Abstract]
  12. Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 91 (10): 3607-15, 1998. [PUBMED Abstract]
  13. Buchner T, Hiddemann W, Wormann B, et al.: GM-CSF multiple course priming and long-term administration in newly diagnosed AML: hematologic and therapeutic effects. [Abstract] Blood 84 (10 Suppl 1): A-95, 27a, 1994.
  14. Löwenberg B, Boogaerts MA, Daenen SM, et al.: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15 (12): 3496-506, 1997. [PUBMED Abstract]
  15. Witz F, Sadoun A, Perrin MC, et al.: A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 91 (8): 2722-30, 1998. [PUBMED Abstract]

2.4.4.3 Treatment for CML

Chronic Myelogenous Leukemia Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/CML/Patient/page4

Treatment Option Overview

Key Points for This Section

There are different types of treatment for patients with chronic myelogenous leukemia.

Six types of standard treatment are used:

  1. Targeted therapy
  2. Chemotherapy
  3. Biologic therapy
  4. High-dose chemotherapy with stem cell transplant
  5. Donor lymphocyte infusion (DLI)
  6. Surgery

New types of treatment are being tested in clinical trials.

Patients may want to think about taking part in a clinical trial.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Follow-up tests may be needed.

There are different types of treatment for patients with chronic myelogenous leukemia.

Different types of treatment are available for patients with chronic myelogenous leukemia (CML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information about new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Six types of standard treatment are used:

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Tyrosine kinase inhibitors are targeted therapy drugs used to treat chronic myelogenous leukemia.

Imatinib mesylate, nilotinib, dasatinib, and ponatinib are tyrosine kinase inhibitors that are used to treat CML.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Biologic therapy

Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

High-dose chemotherapy with stem cell transplant

High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Donor lymphocyte infusion (DLI)

Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant.Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.

Surgery

Splenectomy

What`s new in chronic myeloid leukemia research and treatment?

http://www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-new-research

Combining the targeted drugs with other treatments

Imatinib and other drugs that target the BCR-ABL protein have proven to be very effective, but by themselves these drugs don’t help everyone. Studies are now in progress to see if combining these drugs with other treatments, such as chemotherapy, interferon, or cancer vaccines (see below) might be better than either one alone. One study showed that giving interferon with imatinib worked better than giving imatinib alone. The 2 drugs together had more side effects, though. It is also not clear if this combination is better than treatment with other tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib. A study going on now is looking at combing interferon with nilotinib.

Other studies are looking at combining other drugs, such as cyclosporine or hydroxychloroquine, with a TKI.

New drugs for CML

Because researchers now know the main cause of CML (the BCR-ABL gene and its protein), they have been able to develop many new drugs that might work against it.

In some cases, CML cells develop a change in the BCR-ABL oncogene known as a T315I mutation, which makes them resistant to many of the current targeted therapies (imatinib, dasatinib, and nilotinib). Ponatinib is the only TKI that can work against T315I mutant cells. More drugs aimed at this mutation are now being tested.

Other drugs called farnesyl transferase inhibitors, such as lonafarnib and tipifarnib, seem to have some activity against CML and patients may respond when these drugs are combined with imatinib. These drugs are being studied further.

Other drugs being studied in CML include the histone deacetylase inhibitor panobinostat and the proteasome inhibitor bortezomib (Velcade).

Several vaccines are now being studied for use against CML.

2.4.4.4. Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Treatment (PDQ®)

General Information About Chronic Lymphocytic Leukemia

Key Points for This Section

  1. Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
  2. Leukemia may affect red blood cells, white blood cells, and platelets.
  3. Older age can affect the risk of developing chronic lymphocytic leukemia.
  4. Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.
  5. Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.
  6. Certain factors affect treatment options and prognosis (chance of recovery).
  7. Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).

Chronic lymphocytic leukemia (also called CLL) is a blood and bone marrow disease that usually gets worse slowly. CLL is one of the most common types of leukemia in adults. It often occurs during or after middle age; it rarely occurs in children.

http://www.cancer.gov/images/cdr/live/CDR755927-750.jpg

Anatomy of the bone; drawing shows spongy bone, red marrow, and yellow marrow. A cross section of the bone shows compact bone and blood vessels in the bone marrow. Also shown are red blood cells, white blood cells, platelets, and a blood stem cell.

Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

Leukemia may affect red blood cells, white blood cells, and platelets.

Normally, the body makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A myeloid stem cell becomes one of three types of mature blood cells:

  1. Red blood cells that carry oxygen and other substances to all tissues of the body.
  2. White blood cells that fight infection and disease.
  3. Platelets that form blood clots to stop bleeding.

A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

  1. B lymphocytes that make antibodies to help fight infection.
  2. T lymphocytes that help B lymphocytes make antibodies to fight infection.
  3. Natural killer cells that attack cancer cells and viruses.
Blood cell development. CDR526538-750

Blood cell development. CDR526538-750

http://www.cancer.gov/images/cdr/live/CDR526538-750.jpg

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.

Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

In CLL, too many blood stem cells become abnormal lymphocytes and do not become healthy white blood cells. The abnormal lymphocytes may also be called leukemia cells. The lymphocytes are not able to fight infection very well. Also, as the number of lymphocytes increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding.

This summary is about chronic lymphocytic leukemia. See the following PDQ summaries for more information about leukemia:

  • Adult Acute Lymphoblastic Leukemia Treatment.
  • Childhood Acute Lymphoblastic Leukemia Treatment.
  • Adult Acute Myeloid Leukemia Treatment.
  • Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
  • Chronic Myelogenous Leukemia Treatment.
  • Hairy Cell Leukemia Treatment

Older age can affect the risk of developing chronic lymphocytic leukemia.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for CLL include the following:

  • Being middle-aged or older, male, or white.
  • A family history of CLL or cancer of the lymph system.
  • Having relatives who are Russian Jews or Eastern European Jews.

Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.

Usually CLL does not cause any signs or symptoms and is found during a routine blood test. Signs and symptoms may be caused by CLL or by other conditions. Check with your doctor if you have any of the following:

  • Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
  • Feeling very tired.
  • Pain or fullness below the ribs.
  • Fever and infection.
  • Weight loss for no known reason.

Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.

The following tests and procedures may be used:

Physical exam and history : An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.

  • Complete blood count (CBC) with differential : A procedure in which a sample of blood is drawn and checked for the following:
  • The number of red blood cells and platelets.
  • The number and type of white blood cells.
  • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
  • The portion of the blood sample made up of red blood cells.

Results from the Phase 3 Resonate™ Trial

Significantly improved progression free survival (PFS) vs ofatumumab in patients with previously treated CLL

  • Patients taking IMBRUVICA® had a 78% statistically significant reduction in the risk of disease progression or death compared with patients who received ofatumumab1
  • In patients with previously treated del 17p CLL, median PFS was not yet reached with IMBRUVICA® vs 5.8 months with ofatumumab (HR 0.25; 95% CI: 0.14, 0.45)1

Significantly prolonged overall survival (OS) with IMBRUVICA® vs ofatumumab in patients with previously treated CLL

  • In patients with previously treated CLL, those taking IMBRUVICA® had a 57% statistically significant reduction in the risk of death compared with those who received ofatumumab (HR 0.43; 95% CI: 0.24, 0.79; P<0.05)1

Typical treatment of chronic lymphocytic leukemia

http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-treating-treatment-by-risk-group

Treatment options for chronic lymphocytic leukemia (CLL) vary greatly, depending on the person’s age, the disease risk group, and the reason for treating (for example, which symptoms it is causing). Many people live a long time with CLL, but in general it is very difficult to cure, and early treatment hasn’t been shown to help people live longer. Because of this and because treatment can cause side effects, doctors often advise waiting until the disease is progressing or bothersome symptoms appear, before starting treatment.

If treatment is needed, factors that should be taken into account include the patient’s age, general health, and prognostic factors such as the presence of chromosome 17 or chromosome 11 deletions or high levels of ZAP-70 and CD38.

Initial treatment

Patients who might not be able to tolerate the side effects of strong chemotherapy (chemo), are often treated with chlorambucil alone or with a monoclonal antibody targeting CD20 like rituximab (Rituxan) or obinutuzumab (Gazyva). Other options include rituximab alone or a corticosteroid like prednisione.

In stronger and healthier patients, there are many options for treatment. Commonly used treatments include:

  • FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab
  • Bendamustine (sometimes with rituximab)
  • FR: fludarabine and rituximab
  • CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab)
  • CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone
  • Chlorambucil combined with prednisone, rituximab, obinutuzumab, or ofatumumab
  • PCR: pentostatin (Nipent), cyclophosphamide, and rituximab
  • Alemtuzumab (Campath)
  • Fludarabine (alone)

Other drugs or combinations of drugs may also be also used.

If the only problem is an enlarged spleen or swollen lymph nodes in one region of the body, localized treatment with low-dose radiation therapy may be used. Splenectomy (surgery to remove the spleen) is another option if the enlarged spleen is causing symptoms.

Sometimes very high numbers of leukemia cells in the blood cause problems with normal circulation. This is calledleukostasis. Chemo may not lower the number of cells until a few days after the first dose, so before the chemo is given, some of the cells may be removed from the blood with a procedure called leukapheresis. This treatment lowers blood counts right away. The effect lasts only for a short time, but it may help until the chemo has a chance to work. Leukapheresis is also sometimes used before chemo if there are very high numbers of leukemia cells (even when they aren’t causing problems) to prevent tumor lysis syndrome (this was discussed in the chemotherapy section).

Some people who have very high-risk disease (based on prognostic factors) may be referred for possible stem cell transplant (SCT) early in treatment.

Second-line treatment of CLL

If the initial treatment is no longer working or the disease comes back, another type of treatment may help. If the initial response to the treatment lasted a long time (usually at least a few years), the same treatment can often be used again. If the initial response wasn’t long-lasting, using the same treatment again isn’t as likely to be helpful. The options will depend on what the first-line treatment was and how well it worked, as well as the person’s health.

Many of the drugs and combinations listed above may be options as second-line treatments. For many people who have already had fludarabine, alemtuzumab seems to be helpful as second-line treatment, but it carries an increased risk of infections. Other purine analog drugs, such as pentostatin or cladribine (2-CdA), may also be tried. Newer drugs such as ofatumumab, ibrutinib (Imbruvica), and idelalisib (Zydelig) may be other options.

If the leukemia responds, stem cell transplant may be an option for some patients.

Some people may have a good response to first-line treatment (such as fludarabine) but may still have some evidence of a small number of leukemia cells in the blood, bone marrow, or lymph nodes. This is known as minimal residual disease. CLL can’t be cured, so doctors aren’t sure if further treatment right away will be helpful. Some small studies have shown that alemtuzumab can sometimes help get rid of these remaining cells, but it’s not yet clear if this improves survival.

Treating complications of CLL

One of the most serious complications of CLL is a change (transformation) of the leukemia to a high-grade or aggressive type of non-Hodgkin lymphoma called diffuse large cell lymphoma. This happens in about 5% of CLL cases, and is known as Richter syndrome. Treatment is often the same as it would be for lymphoma (see our document called Non-Hodgkin Lymphoma for more information), and may include stem cell transplant, as these cases are often hard to treat.

Less often, CLL may transform to prolymphocytic leukemia. As with Richter syndrome, these cases can be hard to treat. Some studies have suggested that certain drugs such as cladribine (2-CdA) and alemtuzumab may be helpful.

In rare cases, patients with CLL may have their leukemia transform into acute lymphocytic leukemia (ALL). If this happens, treatment is likely to be similar to that used for patients with ALL (see our document called Leukemia: Acute Lymphocytic).

Acute myeloid leukemia (AML) is another rare complication in patients who have been treated for CLL. Drugs such as chlorambucil and cyclophosphamide can damage the DNA of blood-forming cells. These damaged cells may go on to become cancerous, leading to AML, which is very aggressive and often hard to treat (see our document calledLeukemia: Acute Myeloid).

CLL can cause problems with low blood counts and infections. Treatment of these problems were discussed in the section “Supportive care in chronic lymphocytic leukemia.”

2.4.4.5  Lymphoma treatment

Overview

http://www.emedicinehealth.com/lymphoma/page8_em.htm#lymphoma_treatment

The most widely used therapies are combinations of chemotherapy and radiation therapy.

  • Biological therapy, which targets key features of the lymphoma cells, is used in many cases nowadays.

The goal of medical therapy in lymphoma is complete remission. This means that all signs of the disease have disappeared after treatment. Remission is not the same as cure. In remission, one may still have lymphoma cells in the body, but they are undetectable and cause no symptoms.

  • When in remission, the lymphoma may come back. This is called recurrence.
  • The duration of remission depends on the type, stage, and grade of the lymphoma. A remission may last a few months, a few years, or may continue throughout one’s life.
  • Remission that lasts a long time is called durable remission, and this is the goal of therapy.
  • The duration of remission is a good indicator of the aggressiveness of the lymphoma and of the prognosis. A longer remission generally indicates a better prognosis.

Remission can also be partial. This means that the tumor shrinks after treatment to less than half its size before treatment.

The following terms are used to describe the lymphoma’s response to treatment:

  • Improvement: The lymphoma shrinks but is still greater than half its original size.
  • Stable disease: The lymphoma stays the same.
  • Progression: The lymphoma worsens during treatment.
  • Refractory disease: The lymphoma is resistant to treatment.

The following terms to refer to therapy:

  • Induction therapy is designed to induce a remission.
  • If this treatment does not induce a complete remission, new or different therapy will be initiated. This is usually referred to as salvage therapy.
  • Once in remission, one may be given yet another treatment to prevent recurrence. This is called maintenance therapy.

Chemotherapy

Many different types of chemotherapy may be used for Hodgkin lymphoma. The most commonly used combination of drugs in the United States is called ABVD. Another combination of drugs, known as BEACOPP, is now widely used in Europe and is being used more often in the United States. There are other combinations that are less commonly used and not listed here. The drugs that make up these two more common combinations of chemotherapy are listed below.

ABVD: Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban, Velsar), and dacarbazine (DTIC-Dome). ABVD chemotherapy is usually given every two weeks for two to eight months.

BEACOPP: Bleomycin, etoposide (Toposar, VePesid), doxorubicin, cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS, Oncovin), procarbazine (Matulane), and prednisone (multiple brand names). There are several different treatment schedules, but different drugs are usually given every two weeks.

The type of chemotherapy, number of cycles of chemotherapy, and the additional use of radiation therapy are based on the stage of the Hodgkin lymphoma and the type and number of prognostic factors.

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/Patient/page1

Key Points for This Section

Adult non-Hodgkin Lymphoma is a disease in which malignant (cancer) cells form in the lymph system.

Because lymph tissue is found throughout the body, adult non-Hodgkin lymphoma can begin in almost any part of the body. Cancer can spread to the liver and many other organs and tissues.

Non-Hodgkin lymphoma in pregnant women is the same as the disease in nonpregnant women of childbearing age. However, treatment is different for pregnant women. This summary includes information on the treatment of non-Hodgkin lymphoma during pregnancy

Non-Hodgkin lymphoma can occur in both adults and children. Treatment for children, however, is different than treatment for adults. (See the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information.)

There are many different types of lymphoma.

Lymphomas are divided into two general types: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of adult non-Hodgkin lymphoma. For information about other types of lymphoma, see the following PDQ summaries:

Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin lymphoma.

If cancer is found, the following tests may be done to study the cancer cells:

  • Immunohistochemistry : A test that uses antibodies to check for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the tissue to light up under a microscope. This type of test may be used to tell the difference between different types of cancer.
  • Cytogenetic analysis : A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
  • Immunophenotyping : A process used to identify cells, based on the types of antigens ormarkers on the surface of the cell. This process is used to diagnose specific types of leukemia and lymphoma by comparing the cancer cells to normal cells of the immune system.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer.
  • The type of non-Hodgkin lymphoma.
  • The amount of lactate dehydrogenase (LDH) in the blood.
  • The amount of beta-2-microglobulin in the blood (for Waldenström macroglobulinemia).
  • The patient’s age and general health.
  • Whether the lymphoma has just been diagnosed or has recurred (come back).

Stages of adult non-Hodgkin lymphoma may include E and S.

Adult non-Hodgkin lymphoma may be described as follows:

E: “E” stands for extranodal and means the cancer is found in an area or organ other than the lymph nodes or has spread to tissues beyond, but near, the major lymphatic areas.

S: “S” stands for spleen and means the cancer is found in the spleen.

Stage I adult non-Hodgkin lymphoma is divided into stage I and stage IE.

  • Stage I: Cancer is found in one lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen).
  • Stage IE: Cancer is found in one organ or area outside the lymph nodes.

Stage II adult non-Hodgkin lymphoma is divided into stage II and stage IIE.

  • Stage II: Cancer is found in two or more lymph node groups either above or below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIE: Cancer is found in one or more lymph node groups either above or below the diaphragm. Cancer is also found outside the lymph nodes in one organ or area on the same side of the diaphragm as the affected lymph nodes.

Stage III adult non-Hodgkin lymphoma is divided into stage III, stage IIIE, stage IIIS, and stage IIIE+S.

  • Stage III: Cancer is found in lymph node groups above and below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIIE: Cancer is found in lymph node groups above and below the diaphragm and outside the lymph nodes in a nearby organ or area.
  • Stage IIIS: Cancer is found in lymph node groups above and below the diaphragm, and in the spleen.
  • Stage IIIE+S: Cancer is found in lymph node groups above and below the diaphragm, outside the lymph nodes in a nearby organ or area, and in the spleen.

In stage IV adult non-Hodgkin lymphoma, the cancer:

  • is found throughout one or more organs that are not part of a lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen), and may be in lymph nodes near those organs; or
  • is found in one organ that is not part of a lymphatic area and has spread to organs or lymph nodes far away from that organ; or
  • is found in the liver, bone marrow, cerebrospinal fluid (CSF), or lungs (other than cancer that has spread to the lungs from nearby areas).

Adult non-Hodgkin lymphomas are also described based on how fast they grow and where the affected lymph nodes are in the body.  Indolent & aggressive.

The treatment plan depends mainly on the following:

  • The type of non-Hodgkin’s lymphoma
  • Its stage (where the lymphoma is found)
  • How quickly the cancer is growing
  • The patient’s age
  • Whether the patient has other health problems
  • If there are symptoms present such as fever and night sweats (see above)

Read Full Post »


Liposomal encapsulated drug

Writer and Curator: Larry H. Bernstein, MD, FCAP 

7.2  Liposomal encapsulated drug

7.2.1 Curcumin-containing liposomes stabilized by thin layers of chitosan derivatives

7.2.2 Colloids and Surfaces B: Biointerfaces 1 Sep 2013; 109:307–316

7.2.3 Increasing the stability of curcumin in serum with liposomes or hybrid drug-in-cyclodextrin-in-liposome systems

7.2.4 Influence of curcumin-loaded cationic liposome on anticancer activity for cervical cancer therapy

7.2.5 Liposome encapsulation of curcumin

7.2.6 Gemcitabine and γ-cyclodextrin-docetaxel inclusion complex-loaded liposome for highly effective combinational therapy of osteosarcoma

7.2.7 Self-organized thermo-responsive hydroxypropyl cellulose nanoparticles for curcumin delivery

7.2.8 The enhancement of gene silencing efficiency with chitosan-coated liposome formulations of siRNAs targeting HIF-1α and VEGF

7.2.9 Interactions of nanomaterials and biological systems. Implications to personalized nanomedicine

7.2.1 Curcumin-containing liposomes stabilized by thin layers of chitosan derivatives

Anna Karewicz, Dorota Bielska, Agnieszka Loboda, Barbara Gzyl-Malcher, Jan Bednar, Alicja Jozkowicz, Jozef Dulak, Maria Nowakowska

Highlights

    • Cationic, hydrophobic and cationic–hydrophobic derivatives of chitosan were obtained and characterized.• Curcumin-containing liposomes were successfully stabilized by effective coating with these derivatives.• Liposomes coated with cationic–hydrophobic chitosan are most promising for curcumin delivery.• Such coated liposomes easily penetrate cell membrane and release curcumin in a controlled manner.• These curcumin-loaded liposomal systems are non-toxic for normal cells, but toxic for murine melanoma.

Abstract

Stable vesicles for efficient curcumin encapsulation, delivery and controlled release have been obtained by coating of liposomes with thin layer of newly synthesized chitosan derivatives. Three different derivatives of chitosan were obtained and studied: the cationic (by introduction of the stable, quaternary ammonium groups), the hydrophobic (by attachment of N-dodecyl groups) and cationic–hydrophobic one (containing both quaternary ammonium and N-dodecyl groups). Zeta potential measurements confirmed effective coating of liposomes with all these chitosan derivatives. The liposomes coated with cationic–hydrophobic chitosan derivative are the most promising curcumin carriers; they can easily penetrate cell membrane and release curcumin in a controlled manner. Biological studies indicated that such systems are non-toxic for murine fibroblasts (NIH3T3) while toxic toward murine melanoma (B16F10) cell line.


Graphical abstract

Full-size image (30 K)

http://ars.els-cdn.com/content/image/1-s2.0-S0927776513002518-fx1.jpg

7.2.2 Colloids and Surfaces B: Biointerfaces 1 Sep 2013; 109:307–316
http://dx.doi.org:/10.1016/j.colsurfb.2013.03.059

Highlights

  • Cationic, hydrophobic and cationic–hydrophobic derivatives of chitosan were obtained and characterized.
  • Curcumin-containing liposomes were successfully stabilized by effective coating with these derivatives.
  • Liposomes coated with cationic–hydrophobic chitosan are most promising for curcumin delivery.
  • Such coated liposomes easily penetrate cell membrane and release curcumin in a controlled manner.
  • These curcumin-loaded liposomal systems are non-toxic for normal cells, but toxic for murine melanoma.

Abstract

Stable vesicles for efficient curcumin encapsulation, delivery and controlled release have been obtained by coating of liposomes with thin layer of newly synthesized chitosan derivatives. Three different derivatives of chitosan were obtained and studied: the cationic (by introduction of the stable, quaternary ammonium groups), the hydrophobic (by attachment of N-dodecyl groups) and cationic–hydrophobic one (containing both quaternary ammonium and N-dodecyl groups). Zeta potential measurements confirmed effective coating of liposomes with all these chitosan derivatives. The liposomes coated with cationic–hydrophobic chitosan derivative are the most promising curcumin carriers; they can easily penetrate cell membrane and release curcumin in a controlled manner. Biological studies indicated that such systems are non-toxic for murine fibroblasts (NIH3T3) while toxic toward murine melanoma (B16F10) cell line.

http://ars.els-cdn.com/content/image/1-s2.0-S0927776513002518-fx1.jpg

7.2.3 Increasing the stability of curcumin in serum with liposomes or hybrid drug-in-cyclodextrin-in-liposome systems

Matloob AH1Mourtas S1Klepetsanis P2Antimisiaris SG3.
Int J Pharm. 2014 Dec 10; 476(1-2):108-15
http://dx.doi.org:/10.1016/j.ijpharm.2014.09.041

Curcumin (CURC) was incorporated in liposomes as free drug or after formation of hydropropyl-β- or hydroxypropyl-γ-cyclodextrin (HPβCD or HPγCD) complexes prepared by coprecipitation and characterized by X-ray diffractometry. Liposomes encapsulating CURC as free drug or CD-complexes (hybrid formulations) were prepared by the dehydration-rehydration vesicle (DRV) method followed by extrusion, and characterized for size, zeta-potential and CURC loading. CURC stability (at 0.01 and 0.05mg/mL) in 80% (v/v) fetal bovine serum (FBS) was evaluated at 37°C. Results demonstrate that HPβCD stabilizes CURC more than HPγCD, but liposome encapsulation provides substantially more protection, than CDs. CURC stabilization is similar, when encapsulated as free compound or CD-complex. However, the last method increases CURC loading by 23 times (depending on the lipid composition of liposomes and the CD used), resulting in higher solubility. The stability profile of CURC in serum depends on the composition of liposomes and CURC concentration, since at lower concentrations larger CURC fractions are protected due to protein binding. Compared to the corresponding CD complexes, hybrid formulations provide intermediate CURC solubility (comparable to HPβCD) but profoundly higher stabilization.

7.2.4 Influence of curcumin-loaded cationic liposome on anticancer activity for cervical cancer therapy

Saengkrit N1Saesoo S1Srinuanchai W1Phunpee S1Ruktanonchai UR2.
Colloids Surf B Biointerfaces. 2014 Feb 1; 114:349-56.
http://dx.doi.org:/10.1016/j.colsurfb.2013.10.005

Highlights

  • The delivery of curcumin using liposomes was explored in cervical cancer cell lines.
  • A critical role of DDAB in liposomes containing curcumin was investigated.
  • DDAB is a potent inducer of cell uptake, anticancer efficiency and cell death.
  • Anticancer efficiency of liposomal curcumin was more pronounced than free curcumin.

The delivery of curcumin has been explored in the form of liposomal nanoparticles to treat various cancer cells. Since curcumin is water insoluble and an effective delivery route is through encapsulation in liposomes, which were modified with three components of DDAB, cholesterol and non-ionic surfactant. The purpose of this study was to establish a critical role of DDAB in liposomes containing curcumin at cellular response against two types of cell lines (HeLa and SiHa). Here, we demonstrate that DDAB is a potent inducer of cell uptake and cell death in both cell lines. The enhanced cell uptake was found on DDAB-containing liposome, but not on DDAB-free liposome. However, the cytotoxicity of DDAB-containing liposomes was high and needs to be optimized. The cytotoxicity of liposomal curcumin was more pronounced than free curcumin in both cells, suggesting the benefits of using nanocarrier. In addition, the anticancer efficiency and apoptosis effect of the liposomal curcumin formulations with DDAB was higher than those of DDAB-free liposomes. Therefore curcumin loaded liposomes indicate significant potential as delivery vehicles for the treatment of cervical cancers.

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7.2.5 Liposome encapsulation of curcumin: physico-chemical characterizations and effects on MCF7 cancer cell proliferation.

Hasan M1Belhaj N1Benachour H2Barberi-Heyob M3Kahn CJ4Jabbari E5Linder M1Arab-Tehrany E6.
Int J Pharm. 2014 Jan 30; 461(1-2):519-28
http://dx.doi.org:/10.1016/j.ijpharm.2013.12.007

The role of curcumin (diferuloylmethane), for cancer treatment has been an area of growing interest. However, due to its low absorption, the poor bioavailability of curcumin limits its clinical use. In this study, we reported an approach of encapsulation a curcumin by nanoliposome to achieve an improved bioavailability of a poorly absorbed hydrophobic compound. We demonstrated that liposomal preparations to deliver curcumin increase its bioavailability. Liposomes composed of salmon’s lecithin also improved curcumin bioavailability compared to those constituted of rapeseed and soya lecithins. A real-time label-free cell analysis system based on real-time cell impedance monitoring was used to investigate the in vitro cytotoxicity of liposomal preparations.

Fig. 1. Chemical structure of curcuminoids (curcumin, demethoxycurcumin, bis
demethoxycurcumin).

Table 2 Membrane fluidity of nanoliposomes with and without curcumin.
Sample                                            Membrane fluidity
Salmon liposome                           3.19 ± 0.08a,b,*
Curcumin loaded
salmon liposome                           2.81 ± 0.05*
Rapeseed liposome                       3.53 ± 0.07a,*
Curcumin loaded
rapeseed liposome                        2.83 ± 0.04*
Soya liposome                                3.58 ± 0.10b,*
Curcumin loaded
soya liposome                                2.83 ± 0.02*
* Significant t-test                         (p < 0.05)
between salmon
and rapeseed
(a), salmon and soya
(b), curcumin loaded liposome
and liposome of the same lecithin.

Fig. 3. Transmission electron microscopic images of rapeseed
(a), soya
(b) and salmon
(c) nanoliposomes

Fig. 4. Cell index (CI) kinetics of the MCF-7 cells exposed to different concentrations of curcumin.
CI was monitored during 72 h after compounds exposure. Reported data are the means of three replicates.
Statistical differences were found after 24 h for 12 and 20 mM of curcumin vs. control cells (without curcumin)
and between 12 mM and 20 mM of curcumin.

http://ars.els-cdn.com/content/image/1-s2.0-S0378517313010752-fx1.jpg

7.2.6 Gemcitabine and γ-cyclodextrin-docetaxel inclusion complex-loaded liposome for highly effective combinational therapy of osteosarcoma

Int J Pharm. 2014 Nov 26; 478(1):308-317.
http://dx.doi.org:/10.1016/j.ijpharm.2014.11.052

Fig.1. Schematic illustration of DTX and GEM loaded nanocarriers. First, DTX was complexed with HP-g-cyclodextrin to form a DTX/CD inclusion complex.
In the second step, GEM and DTX/CD complex was incorporated in a PEGylated liposome.

In vitro release study
The release study of DTX/GEM-L was performed in phosphate buffered saline (pH 7.4) at 37C. As shown in Fig. 3, no initial burst release phenomenon was
observed with both the drugs indicating that none of the drugs were present in the surface of liposome. As expected, hydrophilic GEM released faster than
that of DTX. 50% of GEM released within 16 h of study period and almost 90% of drug released during the 48 h study period. The faster release of drug was
attributed to the free diffusion of drug from the core of liposomes to the release media. On the other hand, DTX relatively released slowly from the liposome
system. It could be due to the presence of inclusion complex which delayed the release rate of DTX. Nearly 40% of DTX released from the CD/liposome
system at the end of 48 h study period. For this system, various factors decide the drug release patterns including nature of drug, interaction between drug
and lipid, diffusion path length. Moreover, difference in the hydrophobicity of drugs decides the drug release pattern. GEM is a highly hydrophilic drug
while DTX is a hydrophobic drug.

Cytotoxic effect of GEM and DTX against MG63 cancer cells
The in vitro antitumor potential of GEM and DTX (individually and combined) was evaluated in MG63 bone tumor cells. The cells were exposed to increasing
concentration of single as well as combined drug in a time-dependent manner. As shown in Fig. 4, both DTX and GEM inhibited the growth of the cancer cell
in a dose-dependent and time-dependent manner. As seen, DTX was more effective in controlling the cell growth rate compared to that of GEM. However,
combined DTX/GEM showed better antitumor potential than that of individual drugs. Most importantly, DTX/GEM-L showed a more pronounced tumor inhibiting
effect than the free drug combination. For example, at a fixed concentration of 1 mg/mL, free DTX/GEM showed 55% cell viability compared to 40% cell viability
for DTX/GEM-L at the end of 24 h. Notably, cellular viabilities of combinational drug were significantly lower than that of individual GEM or DTX. IC50 value
was calculated to quantitatively estimate the inhibitory levels. The IC50 for free GEM and free DTX were >10 mg/mL and 5.4 mg/mL.

Fig. 2. Transmission electron microscope (TEM) image of nanocarriers (A) blank liposome (B) DTX/GEM-loaded CD/liposome.

Fig. 3. In vitro release kinetics of DTX and GEM from DTX/GEM-L. The release study was performed in phosphate buffered saline (pH 7.4) at 37C. The nanoparticle
dispersions were kept in dialysis tube placed in tube containing media. The release samples were collected at predetermined time intervals. *p < 0.05 is the
statistical difference between release rate of GEM and DTX.

Fig. 4. In vitro cytotoxicity evaluation of formulations on MG63 cancer cells. The cells were treated with DTX, GEM, DTX/GEM, and DTX/GEM-L and incubated
for 24 h (a) and 48 h (b), respectively. Untreated cells were considered as control. (c) Cytotoxicity of blank nanoparticles. The free DTX and free GEM was
treated in respective concentrations while a molar ratio of 1:1 (two drugs) was used for DTX/GEM combinational cocktail as well as nanocarriers. *p < 0.05
and **p < 0.01 are the statistical difference between cytotoxicity of DTX/GEM-L and free GEM/DTX.

7.2.7 Self-organized thermo-responsive hydroxypropyl cellulose nanoparticles for curcumin delivery

European Polymer Journal Sep 2013; 49(9)9:2485–2494
http://dx.doi.org:/10.1016/j.eurpolymj.2013.02.012

A tunable temperature-responsive nanoparticulate system based on the ionic modifications of hydroxypropyl cellulose (HPC) was obtained. Two derivatives of HPC were successfully obtained and characterized: cationic (modified with trimethylammonium groups) and anionic (modified with styrenesulfonate groups). Due to the polycation-polyanion interactions they spontaneously self-assemble into nanoparticles in water. The size and surface charge of the nanoparticles can be controlled by the polycation/polyanion ratio. The resulting structures are spherical with diameters in the range from 150 to 250 nm, as confirmed by AFM, SEM, and DLS measurements. The size of the nanospheres increases in elevated temperatures. A model compound, curcumin, known for its anti-cancer and anti-inflammatory properties, was effectively entrapped inside nanospheres. Its release profile was found to be temperature-dependent.


Graphical abstract

Full-size image (10 K)

Highlights

► Cationic and anionic derivatives of hydroxypropyl cellulose were synthesized. ► The polymers self-assemble forming spherical nanoparticles. ► The size of the nanoparticles is temperature-dependent. ► Curcumin could be efficiently entrapped within the nanospheres. ► No burst effect was observed for curcumin release.

7.2.8 The enhancement of gene silencing efficiency with chitosan-coated liposome formulations of siRNAs targeting HIF-1α and VEGF

Int J Pharm. 2014 Nov 13; 478(1):147-154.
http://dx.doi.org:/10.1016/j.ijpharm.2014.10.065

RNA interference (RNAi) holds considerable promise as a novel therapeutic strategy in the silencing of disease-causing genes. The development of effective delivery systems is important for the use of small interfering RNA (siRNA) as therapy. In the present study, we investigated the effect on breast cancer cell lines and the co-delivery of liposomes containing siHIF1-α and siVEGF. In order to achieve the co-delivery of siHIF1-α and siVEGF and to obtain lower cytotoxicity, higher transfection and silencing efficiency, in this study, we used chitosan-coated liposomal formulation as the siRNA delivery system. The obtained particle size and zeta potential values show that the chitosan coating process is an effective parameter for particle size and the zeta potential of liposomes. The liposome formulations loaded with siHIF1-α and siVEGF showed good stability and protected siRNA from serum degradation after 24-h of incubation. The expression level of VEGF mRNA was markedly suppressed in MCF-7 and MDA-MB435 cells transfected with chitosan-coated liposomes containing HIF1-α and VEGF siRNA, respectively (95% and 94%). In vitro co-delivery of siVEGF and siHIF1-α using chitosan-coated liposome significantly inhibited VEGF (89%) and the HIF1-α (62%) protein expression when compared to other liposome formulations in the MDA-MB435 cell. The co-delivery of siVEGF and siHIF1-α was greatly enhanced in the vitro gene silencing efficiency. In addition, chitosan-coated liposomes showed 96% cell viability. Considering the role of VEGF and HIF1-α in breast cancer, siRNA-based therapies with chitosan coated liposomes may have some promises in cancer therapy.

Fig. 2. TEM photographs of  cationic (a) and chitosan-coated (b) liposomes.

As shown in Table 1, the particle sizes of the liposome formulations fluctuated from 131.25 2.76 nm to 641.75 + 5.24 nm. The particle size of the chitosan-coated liposomes was significantly larger
than the non-coated liposome formulations (between 510.65 + 49.71 nm and 641.75 + 25.24 nm). In addition, the particle sizes of the liposome formulations containing siVEGF and siHIF were
smaller than those containing either siVEGF or siHIF  only (Table 1). According to the net surface charge values, the prepared liposome formulations which are suitable for the methods used,
are determined to have the expected electrical charge type (anionic liposome 23.10 + 0.71 mV; cationic liposome 39.05  1.63 mV). It was determined that siRNA which was added to the
formulation and coating with the chitosan of  the liposomes affected their net surface charge. The surface charge values changed into negative directions with the amount of siRNA added
to the formulation (anionic liposome 26.60 + 0.14 mV; cationic liposome 29.95 + 0.64 mV). It was determined that the surface charge values changed into positive directions during the
coating process of the negatively charged liposomes with a natural cationic polymer chitosan (chitosan coated anionic liposome 27.0 + 0.57). These  data suggest the liposome exerts
a protective effect on the siRNA.

7.2.9 Interactions of nanomaterials and biological systems. Implications to personalized nanomedicine

Adv Drug Deliv Rev. 2012 Oct; 64(13):1363-84.
http://dx.doi.org:/10.1016/j.addr.2012.08.005

The application of nanotechnology to personalized medicine provides an unprecedented opportunity to improve the treatment of many diseases. Nanomaterials offer several advantages as therapeutic and diagnostic tools due to design flexibility, small sizes, large surface-to-volume ratio, and ease of surface modification with multivalent ligands to increase avidity for target molecules. Nanomaterials can be engineered to interact with specific biological components, allowing them to benefit from the insights provided by personalized medicine techniques. To tailor these interactions, a comprehensive knowledge of how nanomaterials interact with biological systems is critical. Herein, we discuss how the interactions of nanomaterials with biological systems can guide their design for diagnostic, imaging and drug delivery purposes. A general overview of nanomaterials under investigation is provided with an emphasis on systems that have reached clinical trials. Finally, considerations for the development of personalized nanomedicines are summarized such as the potential toxicity, scientific and technical challenges in fabricating them, and regulatory and ethical issues raised by the utilization of nanomaterials.

The application of nanotechnology to medicine has created an interdisciplinary research field, often referred to as nanomedicine, which has the potential to significantly improve the way many diseases are treated [1]. Within the nascent but rapidly growing field of nanomedicine, personalized medicine applications are among the most promising and exciting innovations [2]. Personalized medicine consists of a healthcare strategy where specific therapeutics are prescribed to patients on the basis of genetic, phenotypic, and environmental factors that influence the response to therapy [3]. It has long been recognized that individual patients respond differently to the same drug in terms of efficacy and safety due to the complexity and heterogeneity of diseases and patients [4]. For example, some drugs and dosages cause adverse health effects within a particular patient population while a different patient population responds well to the drug treatment with minimal side effects. Similarly, there may be marked variability in efficacy as well. With an increased understanding of genomics and the emergence of novel technologies for the investigation of molecular profiling and genetic mapping of a patient, personalized medicine is poised to begin reaching its full potential.

The application of nanomaterials to medical problems has already demonstrated a clinical impact in terms of delivery strategies for a range of bioactive molecules, including therapeutic agents, nucleic acids and imaging contrast agents [5]. Nanotechnology enables a combinatorial library of nanoparticles to be synthesized with precise control over surface modifications (e.g., targeting moieties, charge modification, stealth), size, shape, and other particle characteristics that can be screened in order to find the best particle properties for patient-specific therapeutics [6]. There are already examples of nanomedicine in the clinic. Doxil®, a PEGylated liposomal doxorubicin formulation, was the first nanosized therapeutic on the market in 1995 and was used as an effective treatment for metastatic breast cancer and recurrent ovarian cancer [7]. Other systems are in various stages of preclinical and clinical advancements. For example, a targeted therapeutic nanoparticle, named BIND-014, that accumulates in tumors while avoiding uptake by the healthy cells have shown promising results in an ongoing clinical trial [6]. Another example is a lipid nanoparticulate delivery system (Oncoprex®) containing plasmid DNA encoding the TUSC2 tumor suppressor that is being studied in combination with erlotinib, a human epidermal growth factor receptor (EGFR) inhibitor, in lung cancer patients unresponsive to erlotinib or lacking the EGFR mutation [8]. Preclinical studies in animals showed that intravenous TUSC2 nanoparticles work synergistically with erlotinib to overcome drug-induced resistance by simultaneously inactivating the EGFR pathway and by inducing apoptosis in resistant cells. A phase II clinical trial evaluating intravenous TUSC2 nanoparticles in combination with erlotinib will begin in 2012. This will provide two possible therapeutic options depending on the tumor EGFR expression: EGFR inhibitor monotherapy or in combination with the nanoparticles. Progress has also been made in the development of versatile nanocarriers placing emphasis upon patient-specific treatments. For example, Zhang and colleagues recently proposed red blood cell (RBC) membrane-coated nanoparticles to evade the immune system and exhibit longer retention time in the blood [9]. This approach suggests an elegant yet hard to clinically-implement methodology: the patient’s RBCs are collected and emptied to leave only the membranes, the latter are then fused with pre-formed polymeric nanoparticles. The resultant RBC-membrane coated nanoparticles are therefore decorated with the patient’s own proteins and cell membranes to evade the host’s defense mechanisms.

While personalized medicine can guide the design and use of nanocarriers, nanotechnology can also aid in the collection of genomic and molecular data necessary for personalized medicine. Advances in personalized medicine occur through the development of novel nanomaterials as well as technologies for the early detection, imaging, and identification of molecular signatures of diseases. The field of pharmacogenetics and “omics” technologies (e.g., pharmacogenomics, pharmacoproteomics and pharmacometabonomics) have enabled the investigation of an individual patient’s genetic and molecular profiles. This information have provided insights into the mechanisms of disease and how to appropriately combine therapeutics with specific disease profiles. Nanoscale materials and technologies have the ability to greatly expand the molecular and genetic information gathered from patients. For example, the GeneChip® microarray allows nanoscale patterning of biological molecules on surfaces with exquisite control over their spatial placement to obtain DNA sequencing [1, 10]. With the ability to control molecular deposition now in the nanometer range, a million-fold increase in information density could be packed in “nanoarrays” for the detection of nucleic acids or proteomic profiles [1113]. Another example is gold nanoparticles modified with biorecognition molecules that are used for high-throughput genomic detection and are currently approved for use by the FDA [1416].

A research report of commercialization efforts of nanomedicine from the Business Communications Company indicated that the global nanomedicine sales are projected to grow to over $100 billion by 2014 [17]. There are increasingly growing partnerships between biopharmaceutical companies and nanomedicine startups pursuing nanomedicine R&D projects due to the enormous potential applications of nanotechnology to healthcare. One of the predominant focuses is drug delivery applications. The other nanomedicine products include in vivo imaging agents, in vitro diagnostics, biomaterials, and active implants [18]. As our fundamental understanding of diseases increases, implementations of nanotechnology will offer an expanding toolbox to improve point-of-care diagnostics, enable integration of diagnostics with therapeutics, and treat patients with a more personal approach.

While nanomedicine starts to show much promise to the field of personalized medicine, further research is required to expand its impact. In particular, a fundamental understanding of the interactions between nanomaterial surfaces and complex proteins in biological fluids needs to be achieved. This would influence both in vivo delivery of therapeutics and ex vivo diagnostics. Likewise, interactions between nanomaterials and cells, through non-specific contacts or ligand-receptor interactions, as well as the intracellular mechanisms responsible for trafficking of a nanomaterial in the cell, must be more thoroughly characterized. There is a complex relationship between a nanomaterial’s physicochemical properties (e.g., size, charge, surface properties), and its interaction within a biological system. Small changes in size, charge, surface functionalization and chemical composition can lead to radically different interactions with living systems [19]. These interactions then determine the biocompatibility, stability, biological performance and side effects of the nanomaterial. In this regard, understanding the nano-bio interactions and the relationships between the nanomaterial properties/structure and activity will provide a conceptual basis for the rational design and safe use of personalized nanomedicines.

In the first section of this review, we will address different areas in which better comprehension is required and propose examples showing how nanomaterials interact with their environment in complex and subtle manners. Each subject will be discussed from the perspective of its implications for personalized medicine. The second section will highlight some examples that demonstrate current trends and novel concepts in the field of nanomedicine and its impact on personalized medicine. These include nano-sized platforms for the targeted delivery of therapeutics, contrast agents for diagnostic imaging, and theranostic nanoparticles. The use of nanoparticles for the discovery of biomarkers and molecular diagnostic will also be evaluated. Finally, the third section will present the scientific and technical challenges associated with developing personalized nanomedicines, various safety, political and ethical issues raised in the field, as well as the obstacles and limitations associated with personalized nanomedicine.

Interactions of nanomaterials in biological systems

As the role of nanomaterials in biology and medicine continues to grow, the number of situations in which they will be in contact with biological systems will indisputably increase. In this domain where the complexities of nanotechnology and human physiology combine, fundamental understanding is essential before one can think about intricate applications. In the following section, three different aspects of the interactions between nanomaterials and proteins will be presented. Their relevance to personalized medicine will be highlighted in the last section.

Protein-binding

When nanoparticles are utilized for treatment, imaging a tumor, or aiding to establish a diagnosis upon systemic administration, the first tissue they encounter is the blood and all the proteins it contains within. Similarly, when diagnostic nanomaterials are used in vitro or ex vivo to analyze samples of biological fluids, they will come in contact with complex proteins mixtures. The adsorption of proteins on a substrate is a much more complex phenomenon when the surface possesses nanoscale dimensions as compared to that of larger proportions [20]. The relative surface area of nanomaterials is very large and their features are on the same order as proteins (1 to 20 nm) [21]. The interactions between proteins and materials of the nano- and meso- or macroscales are therefore both quantitatively and qualitatively different.

Upon contact with biological fluids (e.g., blood, interstitial fluid or mucosal secretions), nanoparticles are coated with proteins that may change their surface charge and properties. This biological coating can subsequently lead to the loss of performance due to an increase in hydrodynamic size or aggregation. The protein that binds most strongly to polymeric nanoparticles, liposomes, iron oxide nanoparticles and carbon nanotubes are albumin, immunoglobulins, fibrinogen, apolipoproteins and proteins from the complement cascade [20].

Decreasing the nonspecific protein interaction

When nanoparticles are administered systemically, the proteins that adhere to their surface will greatly affect their circulation and biodistribution [22, 23]. Complement and immunoglobulin binding promotes particle opsonization, leading to recognition by the mononuclear phagocyte system (MPS) and rapid clearance from the bloodstream [22]. MPS capture is dictated by macrophage phagocytosis (mostly in the sinusoids of the liver) and splenic filtration [23, 24]. Aggregation of nanoparticles in the blood can also lead to retention and embolism in the lung capillaries [25].

Short circulation half-life, low efficacy, and toxicity caused by accumulation of foreign materials in the liver and spleen are the primary limitation for the systemic administration of nanoparticles. These issues have led to the development of strategies aimed at increasing blood residence time. Among these, the use of poly(ethylene glycol) (PEG) for surface functionalization has been shown to dramatically reduce protein absorption, particularly apolipoprotein J and complement protein C3, through hydrophilicity and steric repulsion effects, therefore extending residence time in blood [2628]. This has allowed the “stealth” nanoparticle carriers to be present in the bloodstream long enough to reach or recognize their therapeutic site of action [29].

Examples of “stealth” nanocarriers include PEGylated liposomal doxorubicin (Doxil®) and the PLA-PEG micelle form of paclitaxel (Genexol-PM®, marketed in Korea in 2007). Encapsulating doxorubicin within PEGylated nanoparticles allows for extended circulation half-life in blood and higher tumor concentration of doxorubicin. The homing to the disease site is driven only by the particles’ nano-dimensions and PEGylated surface through the enhanced permeability and retention (EPR) effect [30], which results from enhanced vascular permeability and the absence of a functioning lymphatic system, and is not related to any specific recognition of the target.

In addition to causing quick clearance, nonspecific interactions of nanomaterials with proteins from complex biological samples (e.g., human blood serum, plasma and tissue extracts) hamper the full exploitation of ex vivo nano-based diagnostics and arrays [31]. Novel diagnostic nanomaterials are emerging for the detection and quantification of less abundant biomarkers in biological samples and are envisioned to provide ground-breaking tools for personalized nanomedicine [32]. These nanoparticles and nanostructures possess many unique and advantageous physical properties when applied as ultra-sensitive signal transducers and protein biosensors in the fields of molecular diagnostics and proteomics. Their nanoscale dimensions also result in increases in information quality, quantity and density. Major examples include nanocantilevers, nanowires, nanotube arrays and oligonucleotide-modified gold nanoparticle-based bio-barcode assays that enable multi-biomarker detection [1]. However, the development of these approaches with high sensitivity and selectivity faces several bottlenecks including deconvolution of noise from the signal, especially in regard to biofouling. For the analysis of proteomic signatures, a major challenge will be the identification of signatures from low-concentration molecular species, in the presence of extremely high concentrations of non-specific serum proteins. Nonspecific binding remains a major concern which may lead to false positive signals and low signal-to-noise ratios for a given assay. For various applications such as affinity biosensors or nanoarrays, it is critical to block possible sites for nonspecific binding and/or treat nanomaterials with surface coatings that combine an ultralow fouling background with abundant biorecognition elements. To solve this problem, nonfouling coating materials such as zwitterionic polymers, PEG and its derivates have been developed to prevent nonspecific protein adsorption when exposed to complex media [33, 34]. For example, combined with a surface plasma resonance (SPR) sensor, the protein arrays created using zwitterionic poly(carboxybetaine acrylamide) are able to detect specific cancer biomarkers and monitor the kinetics of antigen-antibody interactions from 100% human blood plasma with high specificity and sensitivity [33]. The background noise was very low due to significantly minimized total nonspecific protein adsorption on the functionalized zwitterionic surface.

Limiting the immunogenicity

Decreasing the immunogenicity of a nanomaterial is also of critical importance since therapeutic nanoconstructs have dimensions very similar to those of pathogens for which recognition signals were positively selected for evolution [35]. The understanding of the immune reactions to therapeutic and diagnostic nanomaterials is still poorly characterized and additional knowledge is required to ensure which characteristics warrant repeated systemic administration without adverse reactions.

For example, in preclinical studies, the phenomenon aptly named accelerated blood clearance (ABC) has been observed in animal models for various types of nanoconstructs [3638]. In this effect, an initial sensitization of the animals to the nanomaterial triggers a transient immune response and induction of Immunoglobulin M (IgM) antibody which prompts rapid clearance of the subsequently administered doses by increased capture in the liver and the spleen [1214]. The factors that impact the appearance of this phenomenon are multifaceted and include the nature of the payload of the nanomaterial [39, 40], the dose administered [3941], and other physicochemical characteristics of each nanoconstruct [41, 42]. The encapsulation of cytotoxic compounds seems to highly diminish the ABC effect, possibly through a deleterious effect on the B cells responsible for the secretion of IgM [39, 40]. In the current context where all nanomedicines on the market contain anticancer drugs, the manifestations of ABC have had limited significance. However, the future development of nanomedicines for all types of diseases and encapsulating a variety of drugs will certainly have to address that problem before nanomaterials can be repeatedly and consistently administered.

Understanding nanomaterial-protein interactions is also important for the development of safer and better tolerated nanomedicine. PEGylated liposomes are known to exhibit prolonged circulation time in blood and have had success in translation to the clinic. However, infusion of therapeutic liposomal drugs such as Doxil® as well as other amphiphilic lipids which have reached the bedside (e.g., Cremophor EL®) could lead to a hypersensitivity syndrome called complement activation-related pseudoallergy (CARPA). The CARPA syndrome differs from anaphylaxis since it does not involve IgE but arises as a consequence of activation of the complement (C) system. Also, CARPA improves upon subsequent exposure and can be mitigated in patients by reducing the infusion rate as opposed to anaphylaxis where re-exposition usually triggers a more serious reaction [43].

Moghimi et al. have demonstrated that liposomes prepared using anionic phospholipid-PEG conjugates caused CARPA, partly because the highly cationic region of the globular C1q protein binds with the anionic charge localized on the phosphate oxygen of the lipid-PEG conjugate through electrostatic interaction. This induces activation of the complement cascade, opsonization of the nanoparticle surface and anaphylatoxin production (reflected in significant rises in SC5b-9, C4d, C3a and C5a levels in human sera) [44]. CARPA is mostly mild and transient, but in some patients, it can be severe or even lethal. In addition, a main manifestation of complement activation is cardiopulmonary distress; therefore, CARPA may be a safety issue primarily in cardiac patients.

Several methods have been explored to circumvent the problem. A previous study revealed that removal of the negative charge by methylation of the phosphate oxygen of lipid-PEG conjugates totally prevented complement activation. Others have recently synthesized a range of neutral lipopolymers and variations thereof for liposome engineering [45]. Remarkably, preliminary investigations have demonstrated that such lipopolymer-incorporated liposomes are poor activators of the human and porcine complement system when compared to vehicles bearing anionic lipid-PEG conjugates [46]. The nanoformulations prepared with neutral lipopolymers may hold great potential to treat patients with severe CARPA response or cardiac disease. More studies have been conducted to test the CARPA concept and the immunological interactions of liposomal and amphiphilic polymeric nanoparticles [47, 48]. In addition to the CARPA reactions observed in the clinics, complement activation also leads to opsonisation of the nanomaterials and enhances their clearance by the MPS. Therefore, any measure to prevent its activation could translate into increased circulation times and efficiency. Figure 1 demonstrates the different pathways that trigger the complement system and how physicochemical properties of nanomaterials can switch the activation process from one pathway to another [4955].

pathways of complement cascade activation nihms-401532-f0001

pathways of complement cascade activation nihms-401532-f0001

The physicochemical properties of the nanomaterial surface can trigger the different pathways of complement cascade activation [4955]. The classical pathway is activated through deposition of specific proteins like antibodies and others. The lectin pathway is triggered by the recognition of the surface by a Mannose-binding Lectin (MBL) through pathogen-associated motifs. The lectin subsequently interacts with a serine protease (MASP) to elicit the formation of a C3-convertase (C4b2a) analogously to the classical pathway. The spontaneous tickover responsible for the alternative pathway activation is constantly present in plasma. When not properly regulated, the preferred deposition of the C3b products on the surface of the nanomaterial amplifies the cascade activation. All 3 pathways lead to C5-convertases that cleave C5 and lead to the deposition of the terminal membrane attack complex which can lyse pathogens and senescent cells, further releasing proinflammatory mediators. The release of proinflammatory chemoattractants is symbolized by the yellow outburst.

Exploiting the beneficial aspects of protein-binding

The nanomaterial-protein interactions should not only be viewed as being disadvantageous, as some preferential interactions can be used to guide the distribution of nanoparticles to specific tissues. For example, decoration of nanomaterial with specific proteins prior to injection has been exploited for particular targeting purposes [5658].

More recently, a possibly higher response rate in a subset of patients observed during the first clinical studies on albumin-coated paclitaxel (nab-PTX, Abraxane®) sparked a flash of enthusiasm in the drug delivery community. In this study, it was found that different response rates between individual patients receivingnab-PTX could be explained by degrees of expression in the extratumoral protein SPARC (secreted protein acidic and rich in cysteine) [59]. SPARC is a secreted matricellular glycoprotein with high binding affinity to albumin which functions to regulate cell-matrix interactions [60]. Its overexpression is associated with increased tumor invasion and metastasis, leading to poor prognosis in multiple tumor types including breast, prostate, and head and neck cancers [61]. In this context, the prospect that SPARC-positive patients would respond better to nab-PTX was particularly appealing.

Desai et al. tested this hypothesis by correlating the clinical response and SPARC tumor expression in a retrospective analysis of 60 patients receiving nab-PTX as monotherapy against head and neck cancer [59]. It was found that response to nab-PTX was higher for SPARC-positive patients (83%) than SPARC-negative patients (25%). As shown in Figure 2, a possible explanation for the positive correlations between SPARC expression and the drug is that the interactions of albumin and SPARC in the tumor interstitium could facilitate the accumulation of nab-PTX in the tumor. Furthermore, the albumin-drug interactions were thought to facilitate the transport of paclitaxel molecules across endothelial barriers via gp60 receptor and caveolin-1 mediated transcytosis [59].

Mechanisms for the transport and accumulation of albumin-bound paclitaxel in tumor nihms-401532-f0002

Mechanisms for the transport and accumulation of albumin-bound paclitaxel in tumor nihms-401532-f0002

Mechanisms for the transport and accumulation of albumin-bound paclitaxel in tumors. Binding of albumin-bound paclitaxel complexes to the gp60 receptor and subsequent caveolin-1 mediated transcytosis results in transport across the endothelial barrier of the tumor vasculature. SPARC, an albumin-binding protein present in the tumor interstitium, enhances accumulation of the complexes in tumor tissue. Figure taken from reference [59].

As further supporting evidence, a study in animals with multiple tumor xenografts also showed correlations between the relative efficacy of nab-PTX and SPARC expression. In this study, the albumin-containing formulation was compared to polysorbate-based docetaxel. In comparison with control groups, the effect ofnab-PTX in HER2-positive breast tumors with increasing SPARC expression seemed superior to that witnessed in MDA-MB-231/HER2-positive tumors with low SPARC expression [62]. It should be noted, however, that differences between the pharmacological agents used (paclitaxel vs. docetaxel) and the large discrepancies between the doses of drug administered in the different groups strongly limit the conclusions that can be drawn from this study.

To complicate matters, a recent study yielded confounding evidence about the implication of SPARC on the efficacy of nab-PTX. In animals bearing patient-derived non-small cell lung cancer (NSCLC) tumor xenografts, the response to nab-PTX could not be correlated to SPARC expression. In this study, the improved antitumor effect of the albumin-based formulation over solvent-solubilized PTX could also be observed in some SPARC-negative tumors and the induction of SPARC expression in low-responsive tumors could not enhance activity [63]. This implies the possibility of other mechanisms being implicated to explain the response to nab-PTX. In this study, the compared doses of drugs (30 mg/kg/day of nab-PTX vs. 13.4 mg/kg/day of solvent-formulated PTX) were reputedly equitoxic. However, these doses were ascertained based on the tolerability of the compound in mice [64]. Hence, it still remains difficult to address if the benefits of nab-PTX over solvent-formulated PTX are uniquely owed to improved tolerability or to real targeting manifestations.

In conclusion, more efforts are needed before we can ascertain the role of SPARC expression as a biomarker for personalized anticancer therapies using albumin-based formulations. For one, there is a current lack of understanding of the stability of the 130-nm albumin-encapsulated PTX nanoparticles once it is introduced in the blood. Some reports mention that, upon dilution, the nanoparticles dissolve into individual albumin-PTX complexes [65], but the nature of these interactions between the drug and proteins remain unclear. Finally, larger prospective clinical validations in multiple tumor types are required to investigate the correlations between SPARC expression and response to treatment. As of now, the only published clinical justification that establishes association between nab-PTX and SPARC expression is a retrospective analysis of a 60-patient clinical phase II study [59].

The impact of nanomaterial-protein interactions on personalized nanomedicine

From the preceding examples, it is clear that further understanding of the interactions between proteins and nanomaterials are required to further establish their potential for personalized medicine. The role of blood proteins on the clearance and immunological mechanisms must be better defined in order to more effectively implement nanoconstructs for therapeutic purposes. Patients display inter-individual variability in the circulating levels of various proteins (e.g., lipoproteins, immunoglobulins, cytokines). These differences can explain the variations in each patient’s response to therapeutics or their higher susceptibility to side effects (i.e., CARPA is observed only in a “reacting” subset of patient population) [43]. Similarly, the homeostasis of blood component can also be intensely affected by health conditions or diseases [66]. For example, physiological stress can trigger overexpression of acute-phase proteins and some of these proteins (e.g., C-reactive protein) can enhance complement activation and macrophage uptake when fixed on the surface of pathogens and senescent cells [67, 68]. The impact of such conditions on the fate of therapeutic nanomaterial must be ascertained before nanomedicine can be used efficiently in a variety of diseases.

In addition, nanomaterial-protein interactions must also be further understood to optimally exploit their beneficial effects on the activity or distribution of nanoconstructs. The example of SPARC is particularly relevant because if the protein is confirmed as a predictive biomarker of response to treatment, the albumin-based formulation would become the first nanomedicine approved for individualized therapy. However, extensive additional preclinical and clinical evidence is required before patients screened based on SPARC expression can receive personalized treatments.

2.2 Ligand-mediated interactions

Nanomaterials can be designed to specifically recognize a target with a surface ligand. These interactions can be utilized to preferentially concentrate a therapeutic nanoconstruct at a diseased tissue in vivo [69] or to bind and detect a biomarker for ex vivo diagnostic purposes [1]. The dimensions of the nanomaterials and the opportunity for polyvalent decoration of their surface with ligands contribute to their potential as effective homing and recognition devices. Throughout evolution, pathogens have exploited the multivalent patterning of a ligand on their surface to considerably enhance their affinity and tropism for their target [35, 70]. Likewise, on artificial constructs, a simple increase in the stoichiometry of a ligand can sometimes drastically enhance the ability to bind a substrate [71].

The decoration of a nanoparticle’s surface with a ligand can also trigger receptor-mediated endocytosis by cells expressing the right target on their membrane, a process that has considerable implications for targeted delivery [72]. Ligand-mediated interactions provide many opportunities for personalized medicine including differential spatial localization, intentional homing of nanoparticles to active diseased sites, and elimination of off-target adverse effects. Figure 3A and B illustrate the active binding of nanoparticles to cell surfaces for vascular targeting and tumor cell targeting. Ligand-functionalized nano-based therapeutic systems or imaging contrast agents therefore represent unrivaled platforms to improve the specificity and sensitivity of treatment and diagnostic tools.

Nanoparticles with ligands specific for endothelial cell surface markers nihms-401532-f0003

(A) Nanoparticles with ligands specific for endothelial cell surface markers allow for binding and accumulation to tumor vasculature. (B) Once in the tumor tissue, nanoparticles with ligands specific for tumor cell markers can actively bind to tumor cells,

The ligands used to decorate nanoparticles can include antibodies, engineered antibody fragments, proteins, peptides, small molecules, and aptamers [73]. For both applications, two types of targets exist: targets that are ubiquitously-expressed in all tissues and targets that are specific to diseased cells. Herein several examples of ligand-receptor interactions exploiting both categories will be presented, and special attention will be given to a few nanoplatforms that are targeted through ligand-receptor interactions and have made their way successfully to clinical trials [74].

2.2.1 Ubiquitous targets

The active targeting of drug delivery systems with transferrin (Tf), a 80-kDa blood-circulating glycoprotein, is a concept which dates back to the late-1980s [75]. Several characteristics make the targeting of transferrin receptors (TfR) attractive and an abundance of systems exploiting this internalization pathway have been designed. First, although the TfR is expressed in all types of tissue to satisfy the ferric (II) iron requirements of dividing cells, the hyper-proliferation of cancer cells makes it an attractive overexpressed target in tumors [76]. Secondly, the endocytosed TfR is very rapidly recycled to the cell surface after internalization [77, 78] which makes it an appealing, almost non-saturable, entryway into the cells. Thirdly, the TfR is believed to facilitate the transport of macromolecules and nanoconstructs across the blood-brain barrier [77], representing a rare opportunity to enable penetration to the central nervous system. For all these reasons, the targeting of therapeutic nanomaterials through Tf has been widely studied.

Recently, Davis et al. reported the first human trial of targeted siRNA delivery using polymeric nanoparticles containing Tf-modified cyclodextrin (CALAA-01) [79, 80]. In this study, human Tf was used as a targeting ligand for binding to TfR, which is typically upregulated on cancer cells and trigger cellular uptake via clathrin-coated pits. These targeted nanoparticles were administered intravenously to patients with melanoma where they circulated and localized in tumors (Figure 4). The Tf on the nanoparticle surface was able to bind to overexpressed TfR on cancer cells, and the nanoparticles were internalized via receptor-mediated endocytosis (Figure 4d). Tumor biopsies from melanoma patients obtained after treatment showed the presence of intracellularly localized nanoparticles in amounts that correlated with dose levels of the nanoparticles administered. Furthermore, a reduction was found in both the specific messenger RNA and the protein levels when compared to tissue obtained before dosing of the targeted nanoconstructs.

Figure 4

Assembly and function of targeted cyclodextrin nanoparticles containing siRNA. (a) Nanoparticles consist of four components: (i) a water-soluble, linear cyclodextrin-containing polymer (CDP), (ii) an adamantane (AD)-PEG conjugate (AD-PEG), (iii) the targeting

The receptor tyrosine kinase EGFR is another potent and well-studied target for anticancer drug delivery systems which is constitutively expressed on the surface of cells throughout the body. In response to the binding of its ligands (i.e., various growth factors), EGFR is significantly involved in cell signaling pathways associated with growth, differentiation and proliferation. EGFR exists on the cell surface and is overexpressed in multi-drug resistant (MDR) cancer cells [81, 82]. Milane et al. utilized this overexpression through the development of EGFR-targeted polymeric nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor) [82]. The safety and efficacy of nanoparticle treatment were tested in a mouse orthotopic model of MDR human breast cancer. It was observed that this nanocarrier system demonstrated superior efficacy and safety relative to free drug combinations (paclitaxel/lonidamine solution) and single agent treatments in nanoparticle and solution forms. The targeted nanoparticles loaded with a combination of paclitaxel and lonidamine were the only treatment group that achieved sustained decrease in tumor volume. In addition, treatment with the EGFR-targeted lonidamine/paclitaxel nanoparticles decreased tumor density and altered the MDR phenotype of the tumor xenografts, decreasing the MDR character of the xenografts as evidenced by a drop in the expression of P-glycoprotein (Pgp) and EGFR. In another study, a versatile nanodiamond (ND) construct that incorporates anti-EGFR monoclonal antibodies (mAb), a fluorescent imaging agent and paclitaxel has been developed for multimodal imaging and the treatment of triple-negative subtype of breast cancer (TNBC) [83]. EGFR is expressed at high levels in at least 20% of breast cancers overall, but in 60-70% of patients with TNBC [84], which makes EGFR a potential treatment target. The enhanced cellular internalization of anti-EGFR mAb conjugated ND was only observed in the EGFR-overexpressing MDA-MB-231 cells but not in the basal EGFR expressing MCF7 cells. The data suggested that targeting through the mAb moiety increased specificity and internalization within EGFR-overexpressing breast cancer cells, which subsequently enhanced therapeutic activity of targeted conjugates. To monitor receptor-mediated endocytosis, Lidke et al. used quantum dots (QDs) conjugated to epidermal growth factor (EGF) to study erbB/HER receptor-mediated cellular response to EGF in living human epidermoid carcinoma A431 cells, assigning the mechanism of EGF-induced signaling to heterodimerization of erbB1 and erbB2 monomers and uncovering retrograde transport of endocytosed QD probes [85].

Finally, other examples of ubiquitously-occurring receptors being exploited for active targeting of ligand-functionalized therapeutics exist. For instance, various macromolecular drug conjugates and nanoparticulate systems were studied to take advantage of the overexpression of the folate receptor in tumor cells for the purpose of enhanced delivery as well as diagnosing and imaging malignant masses with improved specificity and sensitivity [86, 87]. Similarly, the retinol-binding protein, which is constitutively expressed in the brain, the spleen, the eyes, the genital organs and in lower quantities in the heart and lungs, was recently exploited to target stellate cells in the liver to alleviate cirrhotic fibrosis [88, 89]. In this approach, the favored non-specific distribution of the liposomes in the liver might contribute to enhancing the interactions between the nanomaterials and their target on the surface of the cells.

Cell-specific targets

Targeting to molecules that are differentially expressed at high levels by certain tissues offers a way to enhance accumulation at specific sites in the body. The exploitation of targets which are distinctively expressed in certain organs offers the possibility to further enhance the specificity of a treatment. The use of prostate-specific membrane antigen (PSMA) is a good example of a tissue-specific receptor that has been efficiently used to target anticancer drug-loaded nanoparticles. The first generation of prostate-specific nanoparticles incorporated PSMA-binding aptamers on their surface to promote internalization by cancer cells. In a mouse xenograft model, one single intratumoral injection of aptamer-functionalized nanoparticles loaded with docetaxel was able to show a considerably higher proportion of complete tumor regression and significantly prolonged survival rates [90]. Similar aptamer-decorated particles were also shown to be able to incorporate prodrugs of a hydrophilic platinum compound [91]. In order to translate these findings to the clinic, a formulation using a low molecular weight ligand with high affinity for PSMA was developed. These formulations using urea-based ligands provided the advantages of being easier to scale-up, while simultaneously not presenting the potential immunological problems associated with the presence of nucleic acids on the surface of the nanomaterial. A docetaxel-containing formulation functionalized with the PSMA-specific ligand, BIND-014, is currently in phase I clinical trials. Preliminary data showed stable disease in patients at doses below the commonly used regimen for the commercially-available, solvent-based docetaxel formulation [6].

Other specific targets have been investigated to optimize the interactions of therapeutic and diagnostic nanomaterials with diseased cells. For example, anti-CD33 monoclonal antibody has been successfully exploited to target leukemic cells since CD33 is a surface antigen expressed on over 80% of leukemia blast cells from acute myeloid leukemia (AML)-suffering patients but not on healthy cells [92]. Gemtuzumab, a monoclonal antibody to CD33 linked to a cytotoxic drug, was approved by the FDA in 2000 for use in patients over the age of 60 with relapsed AML. Upon the conjugation of anti-CD33 monoclonal antibody, the modified polymer/liposome hybrid nanovectors demonstrated enhanced internalization by CD33+ leukemic cell lines while limited interaction was found for nanovectors decorated with an isotype-matched control antibody [93]. In addition, the drug-loaded anti-CD33 nanoformulation exhibited the highest cytotoxicity against CD33+ leukemic cells, suggesting a promising targeted nanotherapeutics for the treatment of AML. The cancer cell-specific anti-nucleosome monoclonal antibody 2C5 (mAb 2C5), which recognizes the surface of various tumor cells (but not normal cells) via tumor cell surface-bound nucleosomes, was also attached to polymeric micelles, making the resulting micelles capable of specifically targeting a broad range of tumors [94]. Intravenous administration of tumor-specific 2C5 micelles loaded with paclitaxel into experimental mice bearing Lewis lung carcinoma resulted in an increased accumulation of paclitaxel in the tumor compared with free drug or paclitaxel in nontargeted micelles and in enhanced tumor growth inhibition.

The increasing availability of monoclonal antibodies for targeted therapy at large has fostered the interest of antibody-functionalized targeted nanomaterial for many years [9598]. However, the presence of these large biological macromolecules (Ab or Ab fragments) can seriously compromise their circulation times in the bloodstream, and their ability to traffic to their intended destination in vivo [99]. Therefore, large efforts have been put in the development of less immunogenic targeting moieties (e.g., peptides, small molecules) [100,101] which might possibly have brighter futures for in vivo applications.

2.2.3 Ligand-mediated in vitro diagnosis

In comparison, the immunologic properties of antibodies are much less of a hindrance for ex vivo diagnostic applications, and the field has benefited greatly from the specific-binding properties of these molecules to recognize and detect biomarkers of interest [1]. Several nanomaterials can be modified with different combinations of specific markers to rapidly screen molecular profiling of small populations of cancer cells at good signal-to-noise levels [102], which is of clinical importance for early cancer detection. An example of such technique named “bioorthogonal nanoparticle detection” (BOND) was developed by Weissleder and colleagues [102]. In this work, live cells were labeled with trans-cyclooctene-modified antibodies (anti-HER-2, EpCAM and EGFR, respectively) followed by coupling with tetrazine-modified fluorescent-labeled iron oxide nanoparticles (Figure 5A and B). The transverse relaxation rate (R2) was measured for ~ 1000 cells, a sample size in line with clinical specimens, using a miniaturized diagnostic magnetic resonance detector. As shown in Figure 5C, markers signals were nearly at normal levels for benign fibroblasts and leukocytes (except for CD45, naturally expressed in the latter) while tumor cells showed considerable heterogeneity in the expression of the different markers. The nuclear magnetic resonance (NMR) signals correlated well with the actual expression levels that were independently determined by flow cytometry using a larger sample size (Figure 5C). This BOND platform demonstrated its application in clinically-oriented molecular profiling by utilizing the polyvalent interactions between engineered nanomaterials and their targets of interest on cell surfaces.

Figure 5

(A and B) Two-step process for targeting biomarkers on cancer cells. Live cells are labeled with TCO-modified antibodies followed by covalent reaction with Tz-modified fluorescent0labeled iron oxide nanoparticles. (C) Cell profiling using a miniaturized

Similarly, small molecules can also be utilized for specific recognition. For example, the self-assembly properties of mannose-functionalized nanoobjects upon interactions with the lectin-coated E. Coli bacterial wall was utilized to detect the presence of the pathogen at different concentrations [103]. In this work, the material becomes highly fluorescent by spatially-rearranging itself in a polymeric fiber structure upon interaction with bacteria. Similarly, in a two-step approach, Weissleder et al. decorated the surface of gram-positive bacteria by targeting the surface D-Ala-D-Ala functional groups on the pathogen with vancomycin-trans-cyclooctene conjugates [104]. The presence of these conjugates is subsequently detected using tetrazine-functionalized magnetofluorescent nanoparticles which can attach covalently in situ with the cyclooctene moieties [102, 104].

Selection of ligands

Depending on the intended application, the ligands chosen in the nanomaterial design will highly influence the efficacy of the system. For ex vivo diagnosis, the nanoparticles are expected to immobilize on the cell surface via ligand-receptor interactions as a diagnostic tag. The high affinity and specificity of the ligands are of paramount importance for the reduction of false negatives and positives, respectively. In contrast, nanoparticles that serve as delivery vehicles for drugs will have other considerations. For example, considering that intracellular delivery of drug-loaded nanoparticles could provide enhanced therapeutic effects, selection techniques have been developed to distinguish internalizing ligands from non-internalizing ligands [105, 106]. Hild et al. elegantly showed that QDs modified with agonists binding to G protein-coupled receptors could be internalized whereas the same nanoparticles modified with antagonists could not [107]. The functionalization of the nanomaterial with the appropriate ligand dictates the fate of the nanoparticle, allowing for either simple flagging of the cell surface or further uptake to deliver a payload using the same target. Recently, Xiao et al. designed a cell-uptake selection strategy to isolate a group of cancer-cell specific internalizing RNA aptamers (Figure 6A) [108]. In this strategy, selection was carried out against prostate cancer cells using counter selection with non-prostate and normal prostate cells to remove non-specific strands. The internalizing ligands were preferentially collected by deleting non-internalizing, membrane-bound aptamers. The cell uptake properties of nanoparticles functionalized with the identified aptamers were confirmed to be highly specific and efficient (Figure 6B).

selection process for isolating RNA aptamers capable of cell-specific internalization in prostate cancer cells nihms-401532-f0006

selection process for isolating RNA aptamers capable of cell-specific internalization in prostate cancer cells nihms-401532-f0006

(A) Cell-uptake selection process for isolating RNA aptamers capable of cell-specific internalization in prostate cancer cells. (B) Visualization of aptamer-functionalized nanoparticle internalization by PC3 cells using confocal fluorescence microscopy.

Further efforts are now underway to identify ligands with the appropriate affinity and to apply these binding ligands to specifically engineer nanomaterials for diagnosis and targeted therapy [109]. One might note, however, that for a specific ligand, the internalizing properties of the nanomaterial can also depend on multiple physicochemical properties, like size [110] and surface density [111]. The biological processes emerging from successful internalization of the nanomaterials by the cells will be discussed in Section 2.3.

Considerations for personalized medicine

In the near future, the availability of ligand-functionalized therapeutic nanomaterial will have a clear impact on the individualized treatment of diseases. In this context, the detection and monitoring of the target expression before initiating therapy and during the whole treatment will clearly be of utmost importance. Similarly, multivalent nanoparticles are complex objects in which behavior depends on a variety of physicochemical properties [6, 112]. Presently, efforts should be made to better understand how ligand-functionalized nanomaterials interact with their targets. In parallel, a better comprehension of the correlations between target expression patterns and cancer prognosis is also required. When both of these aspects are addressed, the therapeutic targets to select for the rational design of nanomedicine will become clearer.

Interactions during intracellular processing

Once endocytosed, nanomaterials are internalized and remain entrapped in transport vesicles which traffic along the endolysosomal scaffold, thereby exerting key effects on subcellular organelles. Intracellular trafficking and the fate of nanomaterials are linked to their physicochemical properties and endocytic pathways [113116]. For example, nanoparticles taken up by clathrin-dependent receptor-mediated endocytosis (RME) are typically destined for lysosomal degradation; whereas, clathrin-independent RME internalization leads to endosomal accumulation and sorting to a nondegradative path [116]. While some drug delivery systems aim to avoid lysosomal degradation [117], recent studies have utilized directed delivery to this environment for the enzymatic release of therapeutics [116, 118]. Understanding the key intracellular interactions of nanoparticles has allowed researchers to engineer nanoparticles for highly specialized delivery. Appropriate design and engineering of nanocarriers could therefore allow for controlled intracellular delivery of therapeutics to individual intracellular compartments, which provides benefits to therapies associated with these unique organelles, including cancer therapy, gene therapy, and lysosomal storage disease (LSD) treatments. Furthermore, by offering an alternative to passive diffusion as an entryway into the cells, the design of nanomaterials that can be internalized by receptor-mediated endocytosis and thus release their active drugs inside subcellular organelles might provide a useful means to circumvent efflux pump-mediated drug resistance [119]. Here we briefly discuss several examples where the physiological endosomal and lysosomal environment can be exploited to develop responsive drug delivery systems.

Intracellular drug release

Polymer-drug conjugates were among the earliest formulations designed to preferentially release their payload inside the cell. Poly[N-(2-hydroxypropyl)methacrylamide] (HPMA) was the first synthetic polymer-drug conjugate to enter clinical trials in 1994. Others, like degradable polyglutamate (PGA), have also been widely clinically investigated as anticancer nanomedicines [118]. These nanosized drug delivery systems are based on the covalent conjugation of chemotherapeutics to hydrophilic polymers, which markedly improves solubility as well as alters drug biodistribution and pharmacokinetics. Conjugates have longer half-life (typically > 1 h) than free drug (< 5 min) when circulating in the blood, leading to significantly increased drug concentrations in tumors [120122]. Since most drugs need to be released from the macromolecule to exert their pharmacological effect, the nature of the linker between the drug and the polymer is therefore of crucial importance (Figure 7). Although the chemical reacting groups on both the macromolecule and the drug dictate the character of the linker available, various classes of bonds with passive or physiologically-triggered cleavage have been studied [123]. Clinical experience has shown that rapid degradation of ester bonds in the bloodstream could lead to suboptimal distribution of the drug in the tumor [124127]. Therefore, if the drug exerts its effects through an intracellular pharmacological receptor, it can be beneficial to design the conjugate with a lysosomally-degradable peptidyl linker (e.g., Gly-Phe-Leu-Gly). This type of linker is stable in the bloodstream but can be cleaved by the lysosomal protease cathepsin B once internalized over 24-48 h [114, 118, 128]. Lysosomes and lysosomal hydrolase malfunctions have been associated with several aspects of malignant transformation, including the loss of cell growth control, altered regulation of cell death, and acquisition of chemo-resistance and of metastatic potential [129]. Lysosomal protease-mediated drug release is thus a key conceptual design principle for the chemotherapy of cancer with nanomedicine [118]. An exciting clinical program is assessing a PGA-paclitaxel conjugate (CT-2103; Opaxio) using the Gly-Phe-Leu-Gly linker [120, 130]. In this system, paclitaxel is released to a small extent by slow hydrolytic release, but is released mainly through lysosomal cathepsin B degradation of the polymer backbone [131]. Experiments in cathepsin-B-homozygous knockout mice confirmed the importance of enzyme degradation and intracellular delivery. Clinical studies showed that a significant number of patients responded to stable disease profiles, particularly in patients with mesothelioma, renal cell carcinoma, NSCLC and in paclitaxel-resistant ovarian cancer [120]. In a recent randomized phase III clinical trial, PGA-paclitaxel demonstrated reduced severe side effects and superior therapeutic profiles compared with gemcitabine or vinorelbine as a first-line treatment for poor performance status NSCLC patients [132, 133]. Additionally, in comparison with men this trial showed increased survival in women treated with PGA-paclitaxel, specially marked in pre-menopausal women [134]. It should also be noted that activity might correlate with estrogen levels which increase expression of cathepsin B [135]. If these findings are confirmed in larger studies, PGA-paclitaxel could be used as a potential gender-specific first-line therapy to treat women with NSCLC.

Tumor cell internalization of polymer-drug conjugates nihms-401532-f0007

Tumor cell internalization of polymer-drug conjugates nihms-401532-f0007

Tumor cell internalization of polymer-drug conjugates occurs through several possible mechanisms, including fluid-phase pinocytosis (in solution), non-specific membrane binding (due to hydrophobic or charge interactions) resulting in receptor-mediated

In addition to lysosomally-cleavable peptide linkers, pH-sensitive cis-aconityl, hydrazone and acetal linkages that respond to changes in intracellular pH have also been used [115]. They can be hydrolyzed under the local acidic pH (6.5-4) within endosomal and lysosomal vesicles [136]. As such, pH-sensitive [137140] or reduction-specific [141, 142] nanoparticle formulations have been designed to facilitate the intracellular delivery of active components. Once low molecular weight drugs are released in the endosome, they are free to escape the intracellular vesicles by diffusion. However, for high molecular weight or charged compounds (e.g., proteins or nucleic acids), passive diffusion through the membrane is difficult and the formulation needs to further provide endosome-disruptive properties to allow for intracytosolic delivery.

Considerable effort has been made to design various types of endosomolytic formulations, especially for the delivery of siRNA and other therapeutic nucleic acids. siRNA must escape from endosome compartments before endosomal/lysosomal degradation occurs in order to exert their gene silencing activity. A wide range of delivery systems have been developed, including dendrimers, liposomes, cationic lipid-like compounds (lipidoids), cyclodextrin, polyethyleneimine (PEI) and others, to facilitate endosomal escape and ensure cytosolic delivery of the therapeutics. In these systems, membrane-disruptive properties can be obtained by using proteins and peptides [143, 144], polymers [145, 146] or simply by incorporating a high number of ionisable amine groups to exploit the proton sponge effect [117]. Figure 8 illustrates the mechanisms of the proton sponge effect, in which nucleic acids are released from polyamine-containing nanoparticles in acidic endosomes. The key to understanding the proton pump hypothesis is the lysosomal proton pump (v-ATPase), which is responsible for acidification of the lysosomal compartment. Within acidifying lysosomal compartments, unsaturated amines on the nanoparticle surface are capable of sequestering protons that are supplied by the proton pump, continuing pump activity and leading to the retention of one Cl- anion and one water molecule for each proton that enters the lysosome. Ultimately, this process causes lysosomal swelling and rupture, leading to siRNA-loaded particle deposition in the cytoplasm [20].

The proton sponge effect nihms-401532-f0008

The proton sponge effect nihms-401532-f0008

The proton sponge effect allows for cationic nanoparticles to escape endosomal and lysosomal vesicles and enter the cytoplasm. When cationic nanoparticles enter acidic vesicles, unsaturated amino groups sequester protons supplied by v-ATPase (proton pump).

Finally, increasing attention has been focused on the targeting of therapeutic agents to specific organelles. This can be achieved by attaching subcellular targeting ligands on the surface of nanomaterials to redirect their accumulation to desired compartments. For instance, Niemann-Pick type A and B are rare genetic LSDs associated with a deficiency of acid sphingomyelinase (ASM), a single enzyme required for the metabolism of lipids, glycoproteins or mucopolysaccharides [147]. A recent study demonstrated that the specific delivery of recombinant ASM to lysosomes by nanocarriers coated with antibody against intercellular adhesion molecule-1 (ICAM-1) could alleviate lysosomal lipid accumulation and improve the efficacy of enzyme replacement therapy [147].

Considerations for personalized medicine

The utilization of intracellular enzymes to trigger the therapeutic activity of nanoconstructs has considerable implications for personalized medicine. As differences in enzyme expression between individuals and pathologies are expected, the sophisticated systems described above might prove more beneficial in a certain subset of patient populations. For example, if the effect of gender-specific cathepsin B expression on the efficacy of PGA-paclitaxel is further confirmed in clinical trials, the appeal of the drug conjugate to treat women-specific cancer types (e.g., ovarian, breast) will certainly be strengthened. More generally, the linkers that can be cleaved by an intracellular protease of interest (e.g., Gly-Phe-Leu-Gly linker) might turn out to be very useful for the design of future drug delivery systems to treat patients overexpressing the target proteases.

The development of drug delivery systems which can effectively deliver their payload inside the cells is also crucial for the future of nucleic acid-based therapies. These therapies hold great promises as treatment and prevention methods for various diseases. For example, successful delivery of siRNA could inhibit the expression of MDR transporters and may restore tumors’ chemosensitivity to treatment [148, 149]. In this context, the combination of conventional chemotherapeutics with siRNA-based therapeutics represents a promising therapy for patients with chemoresistance malignancies.

Engineered nanomaterials for personalized medicine applications

Nanomaterials have evolved significantly over the last few years and nanomedicine has brought unprecedented advances in the diagnosis, imaging and treatment of a variety of diseases. Presently, nearly 250 nano-sized products exist in various stages of development, including nanomaterials with different compositions, physicochemical characteristics, surface functionality and geometry [150]. The following section will explore some examples of the applications of nanomaterials relevant to personalized medicine and the associated design features based on an understanding of nano-bio interactions.

Ex vivo diagnostics

The identification of biomarkers represents the first step in attaining an individually tailored medicine. Biomarkers could be mutant genes, RNAs, proteins, lipids or metabolites that are associated with a specific pathological stage or clinical outcome. Molecular profiling studies on biomarker discoveries have shown that gene expression patterns can be used to identify cancer classification, yielding new insights into tumor pathology such as stage, grade, clinical course and response to treatment [151]. Alizadeh et al. were the first to report the correlation between gene expression patterns and clinically distinct subtypes of cancer based on their study of diffuse large B-cell lymphoma [152]. The concept of a specific molecular profile for each patient’s tumor was later validated [153, 154]. By linking biomarkers with cancer behavior, it is possible to improve diagnosis, assess response to treatment and evaluate progression of cancer based on each patient’s molecular profile [155].

The enhanced interactions that occur between nanomaterials and biomacromolecules (e.g., proteins and nucleic acids) markedly improve the sensitivities of current detection methods. Nanomaterial surfaces can be tailored to selectively bind biomarkers and sequester them for subsequent high-sensitivity proteomic tests [156]. For example, nanoparticles containing DNA sequences complementary to messenger RNAs of biomarker genes can be used as simple and semi-quantitative beacons for the detection of the expression patterns of biomarkers in a single cell [157]. A bio-barcode assay has been recently developed based on oligonucleotide modified gold nanoparticles for high-throughput detection of nucleic acid and protein targets [15]. This approach utilizes gold nanoparticles functionalized with oligonucleotides and antibodies to target either a patient’s DNA or a protein sample and can detect multiple markers with high accuracy (95%). This nanoparticle-based bio-barcode assay has extraordinarily high sensitivity (10−18 M) similar to that of PCR-based assays but without the need for lengthy amplification procedures [14, 15]. Furthermore, this approach does not suffer from the problems often associated with conventional fluorescent probes for microarray labeling, such as photobleaching (loss of signal after exposure to light), which opens a new avenue for developing highly selective panel assays for early detection of a wide range of diseases. This technology has been approved by the FDA for genetic screening to determine drug sensitivity and to detect genetic mutations. It is currently being validated for the detection of proteins found in prostate cancer, ovarian cancer, and Alzheimer’s disease [16].

Likewise, the simultaneous use of nanomaterials with different ligands can allow concurrent detection and precise profiling of the epitopes present in cell specimens. Yezhelyev et al. demonstrated the detection and quantification of multiple biomarkers in human breast cancer cells and biopsies using QDs conjugated with primary antibodies against HER2, ER, PR, EGFR and mTOR [158]. The parallel evaluations of three specimens revealed distinct molecular profiles: one tumor biopsy over-expressed EGFR, another ER and PR, and the third one ER and HER2. This high throughput ex vivo screening analysis could be used to identify the molecular signatures of an individual patient’s tumor, and to correlate a panel of cancer biomarkers with the clinically distinct subset of biomarkers present in the patient’s tumor.

Nanomaterials can also be used to harvest disease-relevant biomarkers in the sample for early detection. Luchini et al. used Poly(N-isopropylacrylamide) hydrogel nanoparticles to harvest and concentrate low molecular weight (LMW) biomarkers (e.g., proteins and metabolites) from biological fluids via electrostatic interactions [159]. The hydrogel nanoparticles possessed defined porosity and negatively- and positively-charged groups for a rapid one-step sequestration and concentration of the ionized LMW fractions from complex serum molecules. The captured peptides or proteins were protected from further enzymatic degradation and were readily extracted from the particles by electrophoresis. When using the nanoporous sieves presented in this study, the proteins are denatured when eluted out of particles and then analyzed by MS for biomarker discovery. The denaturation step may hinder subsequent applications that require the analytes to be in their native state (e.g., immunoassays, enzymatic assays). Therefore, it is necessary to develop novel nanoparticles which preserve the conformational integrity of the isolated proteins. Combined with current proteomic technologies, these nanoparticles provide enormous enhancement of rare biomarkers associated with disease.

In vivo imaging

In recent years, several medical diagnostic technologies have been developed for clinical imaging and detection, including fluorescence imaging, positron emission tomography (PET), single-photon-emission computer tomography (SPET), and magnetic resonance imaging (MRI). These methods require injection of fluorescent trackers, radionuclides or contrast agents. The development of contrast agents able to target specific molecules could advance the molecular characterization of disease, from the identification of disease-associated molecular pathways to the clinical monitoring of relevant biomarkers before and after treatment [5]. Nanomaterials have been explored as platforms for the development of novel contrast agents because they are easily functionalized, possess high contrast, and have tunable physicochemical properties [5].

Various formulations of superparamagnetic iron oxide nanoparticles (SPIONs) are approved or are under clinical investigation for imaging. A key advantage of SPIONs in comparison to other inorganic or heavy metal-based MRI contrast agents is their innocuity. Particles can be degraded to iron and iron oxides molecules that are metabolized, stored in intracellular pools as ferritin, and incorporated into hemoglobin [160]. Administration of 100-200 mg iron/kg in rodent models elicited no detectable side effects [160, 161], a dose well above that used for MRI procedures (< 5 mg/kg). Ferumoxides (Feridex I.V.®) and ferucarbotan (Resovist®) are clinically approved as the first generation SPIONs and are suitable for T2- and T2*-weighted imaging. These contrast agents rely on passive targeting strategies to detect and evaluate lesions of the liver associated with an alteration in the MPS [162]. Their distinctive in vivo behavior dictates their utility in the clinic: ferumoxides, administered via slow infusion, for the detection of small focal lesions with high accuracy during delayed phase imaging [163] and ferocarbotan, which can be administered as a rapid bolus, to produce higher liver-to-tumor contrast during dynamic imaging [164]. Two other SPIONs formulations are currently in clinical trials as contrast agents for MR angiography (MRA). Supravist (Ferucarbotran, a T1-weighted reformulation of Resovist) and VSOP-C184 (7-nm, citrate-coated SPION formulation) have generated first-class images comparable to those using gadolinium (Gd) based agents but with favorable safety, tolerability, and efficacy data [165167]. These nanoparticle-based MRA agents will likely play an important role in advancing angiography as imaging modality for personalized medicine due to their advantages of long plasma half-life and ultra-small sizes that facilitate the detection of small vessels with slow and/or complex flow [165, 168]. SPIONs are now being developed to track cell movement in vivo following transplantation with the long-term goal of developing and monitoring personalized cell-based therapies [169].

For similar applications and as an alternative approach to the use of MRI, others have utilized QDs as probes for high resolution molecular imaging of cellular components and for tracking a cell’s activities and movements inside the body [170, 171]. With the capability of single-cell detection, these nanomaterials enable the real-time characterization of properties of certain cancer cells that distinguish them from closely related non-pathogenic cells.

Since targeted cancer treatments are selected on the basis of the expression patterns of specific biomarkers, there is an urgent need for detecting and monitoring the changes in biomarker expression in situ in a non-invasive manner. Nanoparticles are in development to maximize the specificity of contrast agents by exploiting receptor-ligand interactions. Targeted nanoparticles are able to accumulate at sites where the molecular target is expressed, increasing the local concentration of contrast agents.

One example is the 18F-labeled ABY-025 affibody, a compact three-helix bundle that binds HER-2 [5, 172]. When tested in animals, the 18F-labeled ABY-025 was able to directly assess HER-2 expression in vivousing PET and monitor changes in receptor expression in response to therapeutic interventions [172]. Lee and colleagues also reported that herceptin-conjugated magnetic nanoparticles that target HER-2 could significantly enhance MR sensitivity compared with currently available probes, enabling the detection of a tumor mass as small as 50 mg [173]. The correlation of the signal observed by non-invasive imaging modalities with receptor expression could be utilized to perform follow-up studies without the need for biopsies to evaluate treatment efficacy and direct therapy tailoring.

In the near future, in vivo imaging techniques using nanomaterials will go beyond the field of oncology. Monocrystalline iron oxide particles functionalized with anti-myosin Fab fragments are in preclinical development to detect myocardial infarcts [174]. Similarly, combination approaches using two or more imaging modalities are particularly appealing. Cross-linked iron oxide nanoparticles (CLION) activated by proteases were prepared by encapsulating iron oxide nanoparticles within polymer-Cy5.5 conjugates, combining fluorescence and MRI imaging to assess the enzymatic activity in plaques [175178]. In this system, the fluorescence of the multiple Cy5.5 molecules was quenched until the lysine-lysine bonds were cleaved by cathepsin B, which is upregulated in atherosclerotic lesions. The CLION developed initially for tomography was also able to image vulnerable plaques and infarcted lesions. Other multi-modal nanoparticle-based contrast agents include fluorescently labeled gadolinium-conjugated gold nanoparticles [179] and paramagnetic lipid-coated QDs [180].

Theranostic nanoparticles

Theranostic nanoparticles integrate molecular imaging and drug delivery, allowing the imaging of therapeutic delivery as well as follow-up studies to assess treatment efficacy [181183]. Theranostic nanoparticles can serve as useful tools to explore the fundamental process of drug release after cellular internalization of nanoparticles, which could provide key insights into the rational design of targeted nanocarriers for personalized treatment.

For example, a smart core-shell QD platform, namely QD-aptamer (doxorubicin), was engineered to sense drug release (Figure 9) [183]. A10 RNA aptamer was used to recognize the extracellular domain of PSMA. The intercalation of doxorubicin within the double-stranded “GC” dinucleotide segment of the A10 aptamer on the surface of QDs resulted in quenching of both QD and doxorubicin fluorescence (“OFF” state). Upon receptor-mediated endocytosis of targeted QD conjugates into PSMA-expressing prostate cancer cells, the released doxorubicin induced the recovery of fluorescence from both the QDs and doxorubicin (“ON” state). This system allowed sensing of the intracellular release of doxorubicin and enabled the synchronous fluorescent localization and killing of cancer cells.

QD-aptamer (doxorubicin) system

QD-aptamer (doxorubicin) system

(a) Schematic of a QD-aptamer (doxorubicin) system capable of fluorescence resonance energy transfer (FRET). Doxorubicin is able to intercalate with the A10 PSMA aptamer bound to the QD surface, quenching both QD and doxorubicin fluorescence through a

Another elegant design is the drug-containing paramagnetic nanoparticles targeted to various atherosclerotic plaque lesions components including the αvβ3 integrin [184], fibrin [185], and collagen type III [186], allowing both targeted MR imaging and drug delivery. Animal studies were performed using αvβ3-targeted nanoparticles containing the anti-angiogenesis drug fumagillin repeatedly administered to atherosclerotic rabbits [184]. The results demonstrated that nanoparticle accumulation enabled imaging of the atherosclerotic lesion and generated an anti-angiogenic effect. Advances in this field will pave the way for detecting disease, targeting therapies, and assessing response with one single nanoparticle agent.

Targeted therapies

One of the major avenues of personalized nanomedicine is the development of delivery platforms that can specifically target diseased tissues (i.e., tumor) [187]. In theory, drug targeting would not only ensure a more effective treatment of the target tissue, but also permit a much lower overall dose to be administered than conventional drug delivery, reducing adverse side effects and increasing patient compliance. Two approaches, both passive and active targeting, have been utilized to home nanoparticles to active sites in disease conditions.

Passive targeting takes advantage of the inherent biophysicochemical properties of the nanoparticles (size, shape, charge and flexibility etc.). This phenomenon is most often associated with EPR effects in tumors. A recent in vivo breast cancer study in rodents showed that the passive targeting approach can be used to personalize treatment [188]. Individualized therapy in its simplest form could be achieved by studying the intratumoral accumulation of iodine-containing liposomes by X-ray tomography to predict the deposition of therapeutic doxorubicin-loaded liposomes in the diseased tissue [188]. If tumor accumulation is found to correlate with the patient’s susceptibility to treatment, this approach could be used to identify individuals with lesions possessing leaky vasculature and who would benefit the most from nanosized formulation.

Actively targeted personalized therapies involve surface modification of drug carriers with ligands such as antibodies, peptides, aptamers, and small molecules that specifically bind to tissues of interest. The drug can then be delivered to the target cells through receptor-mediated internalizing interactions as presented in section 2.2 and 2.3. The binding targets of the modified nanocarriers include differentially overexpressed receptors/antigens on the plasma membrane of disease cells and the differentially overexpressed extra-cellular matrix proteins in diseased tissues. For instance, a peptide-conjugated nanoparticle was shown to target the vascular basement membrane exposed on injured vasculature [189]. The C-11 peptide decorating the nanoparticles showed high affinity for collagen IV, which represents 50% of the vascular basement membrane. This targeted nanoparticle platform holds particular promise for treatments of targeted blood vessel walls such as catheter or stent-induced cardiovascular injuries.

Intracellular organelles can also be targeted. Direct DNA delivery to the mitochondrial matrix has been suggested for the treatment of genetic diseases associated with mitochondrial genome defects [190]. Lee et al. conjugated the mitochondrial leader peptide, a peptide derived from the nucleocytosol-expressed but mitochondria-localized ornithine transcarbamylase, to polyethylenimine using a disulfide bond to render the resultant PEI-MLP conjugates mitochondriotropic [190]. In vitro delivery tests of rhodamine-labeled DNA into living cells demonstrated that PEI-MLP/DNA complexes were localized at mitochondrial sites. The data suggested that PEI-MLP can deliver DNA to the mitochondrial sites and may be useful for the development of direct mitochondrial gene therapy.

Combination therapies

The combination of multiple therapeutic agents in a single nanocarrier has been proposed as an alternative approach to increase the efficacy of anticancer treatments through synergistic interactions while mitigating drug resistance [191]. As a proof of concept, Kolishetti et al. developed a targeted therapeutic nanoparticle system for co-delivery of cisplatin and docetaxel, two drugs with different metabolic targets, to prostate cancer cells [192]. In this approach, a Pt(IV) cisplatin prodrug-polymer conjugate was blended with PLGA-PEG and docetaxel to form nanoparticles (Figure 10) [192]. The dual-drug encapsulated nanoparticles were then conjugated with the A10 aptamer to target PSMA overexpressing cancer cells. In vitro studies demonstrated that the aptamer targeted, dual-drug loaded nanoparticles were 5 to 10 times more cytotoxic than respective single drug encapsulating nanoparticles.

Pt(IV)-PLA drug conjugates were blended with PLGA-PEG and docetaxel to form nanoparticles  nihms-401532-f0010

Pt(IV)-PLA drug conjugates were blended with PLGA-PEG and docetaxel to form nanoparticles nihms-401532-f0010

Pt(IV)-PLA drug conjugates were blended with PLGA-PEG and docetaxel to form nanoparticles capable of delivering chemotherapy drug combinations. The nanoparticle surface was then functionalized with the A10 aptamer to target the nanoparticles to PSMA receptors.

The release of multiple payloads can also be tailored to enhance efficacy. Sengupta et al. synthesized a biphasic “nanocell” with a lipid layer containing combretastatin and a hydrophobic core containing PLGA-doxorubicin conjugates [193]. This construct enabled temporal release of the two drugs: combrestatin was released first to collapse the blood vessels and trap the particles inside the tumor, followed by the release of doxorubicin to kill the tumor cells focally without being diluted by the blood circulation. The polymeric nanocell was compared with liposomes co-encapsulating combretastatin and doxorubicin, which lack the differential drug release kinetics. In murine models bearing Lewis lung carcinoma and B16/F10 melanoma, the nanocell platform resulted in better tumor reduction, longer median survival time, and lower systemic toxicity. This study demonstrated that sequential delivery and scheduling of combinatorial drugs are important parameters that influence drug synergism and side effects.

Finally, combination strategies are particularly appealing in the case of siRNA delivery where the knockdown of specific genes can lead to tremendous improvement in the efficiency of drugs. For instance, MDR-1 gene silencing and paclitaxel co-therapy in PLGA nanoparticles was shown to significantly contribute in overcoming tumor multidrug resistance in vivo [194]. Taken together, the development of combination nanotherapeutic strategies that combine gene silencing and drug delivery could provide a more potent therapeutic effect, especially in refractory tumors.

Research on the development of combinational therapies is on the rise. However, this area will benefit from further investigations involving: (1) the discovery of efficacious molecular targets in cancer cells and better understanding of drug activity in these cells; (2) understanding the pharmacokinetics of different drugs by simultaneously delivering multiple therapeutic agents to the target site; (3) the demonstration of the contribution of each component of the combination to the treatment effect; (4) the development of nanocarriers that allow for precisely-controlled loading and release of two or more drugs with variable properties; and (5) the evaluation of responses to treatment among patients following the use of combination therapies.

Challenges with nanomaterials for personalized nanomedicine
Toxicity of nanomaterials

The uncertain health hazard potential of nanomaterials is probably the most significant hurdle for regulatory approval and commercialization of nanomedical products [195]. The unique physical and chemical properties of nanomaterials (i.e. small size, increased reactivity, high surface-to-volume ratio, etc.) while are likely to provide health benefits, may also be associated with deleterious effects on cells and tissues [187, 196]. Nanomaterials have dimensions similar to organelles found in the cell and have the potential to interfere with vital cellular functions, resulting in potential toxicity [197]. While engineered nanomaterials offer improved half-life circulation, this implies that the time required for clearance of loaded drug will also be prolonged. Accordingly, some nanoparticles may be retained in the body not only for days, but potentially for years. Some nanomaterials such as metal nanoparticles, metal oxide nanoparticles, QDs, fullerenes and fibrous nanomaterials were found to induce chromosomal fragmentation, DNA strand breakages, point mutations, oxidative DNA adducts and alterations in gene expression [198], sometimes even through cellular barriers [199]. In these cases, the safety profile becomes a major concern. Although there have been no reported examples of clinical toxicity due to nanomaterials thus far, early studies indicate that nanomaterials could initiate adverse biological interactions that can lead to toxicological outcomes [200]. Since the mechanisms and severity of nanotoxicity are not fully predictable or testable with current toxicological methods, the toxicity of nanomaterials is rapidly emerging as an important area of tangential study in the nanomedicine research field.

There are many different factors to consider when designing nanomaterials and an understanding of how different parameters affect toxicity can aid in designing safer nanomaterials for medical applications. Some important parameters to consider include size, shape, surface area, charge, state of aggregation, crystallinity, and the potential to generate reactive oxygen species (ROS) [200]. Size is a significant factor and can influence the distribution and toxicity of a material. Studies with gold nanoparticles (AuNPs) in four different cell lines demonstrated that both toxicity and the mechanism of cell death were size-dependent [201]. 1.4 nm AuNPs were 60-fold more toxic than 15 nm AuNPs and cell death from 1.4 nm AuNPs was due to necrosis while 1.2 nm AuNPs caused apoptosis of the cells [201]. The toxicity of the 1.4 nm AuNPs was due to the ability to intercalate with DNA while AuNPs of larger sizes were unable to intercalate with the DNA [202]. Size can affect both the distribution within the body as well as the distribution within a cell [203, 204]. Studies of QDs in macrophages have shown that QD size influences subcellular trafficking, with the smallest QDs able to target histones in the cell nucleus [204]. Composition is another factor that influences the toxicity of nanomaterials. QDs may create a health hazard due to toxic heavy metal elements such as cadmium that are incorporated into the QDs [205]. It may, however, be possible to reduce the potential toxicity of nanomaterials such as QDs by adding a coating or nanoshell [206].

Carbon nanotubes (CNTs) are a nanomaterial that has great potential in various medical applications. However, concerns have emerged over its toxicity due to its shape, which resembles asbestos fibers [207]. Longer CNTs have been shown to act like indigestible fibers that lead to frustrated phagocytosis and granuloma formation [208]. Studies in mice have shown that frustrated phagocytosis can lead to massive release of oxygen radicals by immune cells, which can result in chronic granulomatous inflammation and potentially mesothelioma if the CNTs are in the pleural cavity or peritoneum [209]. CNTs can cause mutagenic effects through the generation of inflammation and direct interaction with components of the cell. Exposure of mice to CNTs by inhalation increased the rate of mutation of the K-ras gene locus in the lung, with the mutations occurring during times of maximum inflammation in the tissue [210]. CNTs can also interact directly with the cellular cytoskeleton, including the microtubule system during the formation of the mitotic spindle apparatus, leading to aberrant cell division [211].

Nanomaterials such as titanium dioxide can cause toxicity based on crystalline structure. Cytotoxic studies showed that the anatase form of titanium dioxide was 100 times more toxic than the rutile form, and that the toxicity correlated with the generation of ROS under UV light [212]. Oxidative stress and the generation of ROS is a key injury mechanism that promotes inflammation and atherogenesis, resulting in adverse health events [213, 214]. The surface composition also plays a role in nanomaterial toxicity. Discontinuous crystal planes and material defects can act as sites for ROS generation [200]. The presence of transition metals or organic chemicals on the surface of nanomaterials can also result in oxygen radical formation and oxidative stress [215].

The degradability of a nanomaterial is another important parameter to consider for toxicity. If nondegradable nanomaterials have no mechanism of clearance from the body, they can accumulate in organs and cells and exert toxic effects. Injectable gold compounds have been used for the treatment of rheumatoid arthritis and the accumulation of gold compounds in the body over time may cause toxic effects in patients [216]. However, biodegradable materials may also cause toxic effects if the degraded components of the material are toxic [217].

In addition, the nanomaterial charge is a significant contributor to the toxicity of the material. Increased in vitro cytotoxicity and in vivo pulmonary toxicity has been observed for cationic polystyrene nanospheres when compared with anionic or neutral polystyrene [218, 219]. Interestingly, the mechanism of toxicity for cationic nanospheres was dependent on the cell type and uptake mechanism [219]. In macrophages, particles entered the cell through phagosomes and caused lysosomal rupture due to the proton sponge effect. Upon entry into the cytosol, the particles caused an increase in Ca2+ uptake by mitochondria and oxidative stress, leading to apoptosis. In epithelial cells, cationic particles entered through caveolae. The particles also induced an increase in mitochondrial Ca2+ uptake and oxidative stress, but cell death was by necrosis.

As new nanomaterials are developed, it is important to consider potential mechanisms of toxicity. Nanomaterials have the increased potential to cross biological barriers and obtain access to tissues and cells as a result of their physicochemical properties. As novel properties are introduced into nanomaterials resulting in new interactions with biological systems, it is possible that new mechanisms of injury and toxicological paradigms might emerge [200]. A further understanding of how nanomaterials interact with biological systems may provide better methods to engineer nanomaterials to minimize toxicity [20].

Mass transport

Efficient delivery of nanotherapeutics is another challenge encountered in regards to nanomaterials. The small size of nanoparticles may result in acceleration or delay in their intended action. They may also accumulate non-specifically in certain tissues after administration. Enormous efforts have been expended towards achieving targeted delivery through modification of nanoparticles with antibodies, small molecules, aptamers and/or peptides. However, the biodistribution of nanotherapeutical agents is primarily governed by their ability to negotiate through biological barriers including the mononuclear phagocyte system (MPS), endothelial/epithelial membranes, complex networks of blood vessels, and abnormal blood flow. In addition, drug delivery is further inhibited by barriers such as enzymatic degradation and molecular/ionic efflux pumps that expel drugs from target cells. A full understanding of the interactions between nanomaterials and biological systems will open the door to rational design of nanomedicines and hence improve their biodistribution.

Complexity of nanopharmaceuticals, characterization, stability and storage

To design therapeutics and diagnostics that are functional for personalized use, multiple components will be integrated into a single nanomaterial, requiring multiple steps such as chemical synthesis, formulation and purification. Those procedures will inevitably lower the yield and increase the production cost. In addition, scale-up and manufacturing under current good manufacturing practice (cGMP) will be challenging. In general, multifunctional nanotherapeutics have more variables within their physicochemical properties, which make it more difficult to predict the fate and action after administration. The characterization of nanotherapeutic agents also poses a challenge to manufacturers as well as regulators in terms of chemical, physical, magnetic, optical and biological properties. It would be difficult to monitor a wide range of physicochemical parameters including composition, structure, shape, size, size distribution, concentration, agglomeration, surface functionality, porosity, surface area, surface charge, and surface specification after nanotherapeutic agents are administered.

Stability and storage are also hurdles that must be addressed for clinical practice. For example, biodegradable polymers have been widely used as nanotherapeutic carriers. Depending on their chemical and morphological properties, a polymer will start degrading after nanoparticle formulation in aqueous/organic solvents, which usually results in a change in physicochemical properties (such as agglomeration, particle size, surface charge, drug loading, drug release profile), and can in turn affect the performance in vivo. As such, storage conditions may be critical to the shelf life of nanotherapeutics. For example, the measurement result of nanoparticle size, surface charge, polymer degradation rate and drug release profile may be quite different when nanotherapeutics are stored in deionized water, as opposed to phosphate buffered saline (PBS) or human blood serum.

Limitations and obstacles of personalized nanomedicine

While personalized nanomedicine holds much promise, there are also many challenges associated with it that need to be overcome in order for it to reach its full potential. Manipulating materials at the nanoscale level is difficult and complex due to novel nanoscale interactions, forces and effects that can complicate the reliability, predictability and utility of nanomedical products. Moreover, the potential risks of nanomedicine products and the uncertainties associated with those risks make it difficult to design and obtain consent in clinical trials to assess the clinical utility of such products.

Regulatory approval of nanomedicine products may present another major obstacle. Personalized treatment strategies are inherently not designed to be safe and efficacious for a population, but rather for an individual. Due to the complexity and differences among individual patients in terms of therapeutic response, clinical outcome, genetic profile and many other factors, it is inconceivable to evaluate and approve an exponentially large combinatorial library of possible nanoparticle configurations with various sizes, shapes, surface modifications and therapeutic payloads, especially when considering the long time and high cost associated with the development of an average therapeutic. On the other hand, as the nanomaterials involved in personalized medical applications become more advanced and multifunctional, they may increasingly challenge and eventually invalidate traditional regulatory categories and criteria. Thus, regulatory reform is necessary to facilitate the translation of nano-based medical products into clinical use. It will be critical for the Food and Drug Administration (FDA) to make adjustments and additional requirements to provide predictable and well-defined evaluation pathways for nanomedicine products, and to adapt regulatory requirements when appropriate to keep pace with rapidly emerging nanomaterials and nanotechnologies.

The incorporation of nanomaterials and nanotechnology into personalized medicine also brings up ethical issues. Nanodiagnostics and genetic testing offer the opportunity to collect more personal data on patients than ever before [220]. In particular, the use of point-of-care nanodevices that may bypass a health care professional will have a large impact on mass collection of personal data. This large volume of molecular-level data collected by such nanodevices will challenge the health care system in terms of storage and handling as well as privacy issues, and may raise questions for patients who will receive a torrent of medical information that will inevitably contain false positive and other misleading data [187].

The advances in nanomaterials and nanobiotechnology will play an important role in the development of cutting-edge diagnostic and therapeutic tools, which are an essential component of personalized medicine. While nanomedicine products face safety, scientific, regulatory and ethical issues, personalized medicine also encounters challenges and obstacles. A major obstacle with personalized approaches such as genetic testing is heterogeneity. A recent study demonstrated that a tumor’s genetic makeup can vary significantly within a single tumor [221]. The study showed that, within a single tumor, about 2/3 of the mutations found in a single biopsy was not uniformly detected throughout all the sampled regions of the same patient’s tumors. These results elucidated that a single biopsy cannot be considered representative of the landscape of genetic abnormalities in a tumor and that current practices may miss important genetic mutations that could affect the treatment of the disease [222]. Moreover, there were significant differences between mutations in the original tumor and the site of metastasis. The tumor discovered at diagnosis may be very different from the tumor that is growing or exposed to different treatments. However, getting additional biopsies from patients at different stages could be costly and inconvenient for patients. These findings represent a significant challenge for personalized medicine, as the use of genetic testing to direct therapy may be more complex than currently thought.

Economic considerations

The economical conundrums behind the advance of personalized nanomedicine are intricate. On the one hand, given the important resources devoted to the development of complex nanomaterial systems, the choice to focus only on the treatment of a subset of the population (i.e., HER-2 positive breast cancer patients) might be a difficult one to make. The aforementioned risks and challenges associated with the design of nanomaterial remain similar whether it is to treat all patients suffering from cancer or just a cohort showing a specific mutation. Therefore, the financial gain-to-risk ratio strongly leans towards applications which benefit larger populations. On the other hand, the proof of efficacy needed to obtain regulatory approval might be easier to obtain with a system rationally designed for a specific subpopulation where the prognosis with standard treatment is particularly grim. The evaluation of therapeutic candidates in patients that are more likely to benefit from it might speed up clinical trials and facilitate regulatory approval of the nanomaterial.

In this context, what makes nanomaterials remarkably appealing are their versatility and the ability to transfer the efforts dedicated to the development of one platform to other applications. The example of the CLION system, where the imaging platform was translated from oncology to cardiovascular applications was mentioned in section 3.2 [175178], but others also exist. For example, liposomes similar to the commercially-available doxorubicin liposomal formulations were recently proposed to act as scavenging nanomaterials for drug detoxification [223, 224]. Similarly, 2-hydroxypropyl-β-cyclodextrin, an excipient which forms nanosized complexes with multiple drugs, was shown to overcome cholesterol metabolism dysfunction in Niemann-Pick Type C [225, 226]. It was approved in 2011 for the intravenous and intrathecal treatment of this very rare LSD.

Finally, the development of treatments for orphan or “niche” diseases might provide attractive entryways to the clinic for nanomaterials. The favorable benefit-to-risk ratio expressly encountered in disorders for which no current treatment exist can prove an efficient way of showing the feasibility of an approach as well as the tolerability and safety of a novel material. In this perspective, scientists at the Children’s Hospital of Philadelphia have invested tremendous efforts in developing an adenovirus-based treatment for Leber Congenital Amaurosis (LCA), a very rare degenerative disease which irremediably leads to blindness [227229]. This gene delivery vector, which is now in phase II/III for LCA, was developed in parallel with an analogous formulation containing encoding DNA for the human coagulation factor IX, for the treatment of hemophilia B [230]. These examples, showcasing the versatility of drug delivery systems, offer strong support to the future contribution of nanomedicine to personalized medicine.

Conclusions

In summary, the application of nanomaterials in the realm of medicine has demonstrated tremendous potential from early diagnosis of disease to the development of highly effective targeted therapeutics. As our understanding of health and disease become more refined at the molecular level, the potential of nanomaterials to address the biological complexities of diseases will increase. Likewise, opportunities to develop patient- and disease-specific therapeutics or diagnostic modalities will emerge.

Contemporary chemistry and material science enable the fabrication of a virtually infinite library of nanomaterials. In the near future, these materials will be engineered to efficiently optimize interactions with biological systems for a range of medical applications. For the purpose of targeted therapy and diagnostic imaging, nanocarriers should possess improved stability, extended circulation half-life, favorable biodistribution profiles, lower immunotoxicity as well as targeting to specific tissues, cells and subcellular organelles. Proper ligands will also be chosen based on differential expression of molecular markers on diseased cells to produce patient-specific nanomedicines. When used for detection and diagnosis, nanomaterials should be engineered to avoid non-specific protein absorption and specifically recognize the targets of interest with high affinity. In this context, an in-depth understanding and thorough investigation of how nanomaterials interact with biological structures is required. In order to promote the development of nanomedicines into clinically feasible therapies, there is an urgent need for complete characterization of nanomaterial interactions with biological milieus that drive possible toxicological responses. Medical products must be demonstrated to not only be effective but also safe before they are approved for patient use. Some experimental studies have indicated that engineered nanomaterials could exhibit unique toxicological properties in cell culture and in animal models that may not be predicted from the toxicological assessment of the bulk version of the same materials. To establish a database and appropriated standardized protocols for toxicity assessment, the mechanism of nanomaterial-induced toxicity must be fully explored and nanomaterials must be investigated in vitro and in vivo (e.g., absorption, distribution, metabolism, excretion and toxicological studies) on a particle-by-particle basis.

In parallel, the concept of personalized medicine is also particularly appealing from the perspective of optimizing treatments for an individual patient. Nevertheless, this is a nascent field that has yet to reach its full potential. A potential error may be to succumb to over-enthusiasm and adopt personalized therapeutic practices without strong evidence that personalized treatment is superior to conventional approaches. Even in the field of antibody-based targeted anticancer treatments, which benefited from a head-start in individualized therapies, each clinical or genomic study brings new understanding of the intricate phenomena involved in treating the disease [231]. The understanding of all genomic components of complex diseases like cancer is still unraveling. One should therefore be careful before jumping to conclusions in identifying a particular biomarker as the new ubiquitous target that will eradicate the disease once and for all.

Although significant challenges exist, including regulatory issues and scientific challenges associated with manufacturing nanomedical products, the development and deployment of personalized nanomedicines holds enormous promise for the future treatment of complex diseases. Some nanomedicine products are already in clinical trials, and many others are in various phases of preclinical development. Critical and rational assessment of clinical needs coupled with an improved understanding of physicochemical parameters of nanomaterials that define their effects on the biological system will foster the development of efficient and safe nanomedicine. It is therefore practical to envision a future translation of personalized nanomedicine to the bedside.

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Pancreatic Cancer and Crossing Roads of Metabolism

Curator: Demet Sag, PhD

 

PART I: Pancreatic Cancer

  • Intro
  • What is Pancreas cancer
  • What are the current and possible applications for treatment and early diagnosis
  • How pancreatic cancer is related to obesity, overweight, BMI, diabetes
  • Genetics of Pancreatic Cancer

PART II : Translational Research on Molecular Genetics Studies at Immune Response Mechanism 

  • Natural Killer Cells
  • IL-17
  • Chemokines

search_result- pancreatic cancer clinical trial studies

https://clinicaltrials.gov/ct2/results?term=Pancreatic+Cancer&Search=Searchpc 1

PART I: Pancreatic Cancer

Introduction:

Our body works a s a system even during complex diseases that is sometimes forgotten.  From nutrition to basic immune responses since we are born we start to change how we respond and push the envelope to keep hemostasis in our body.

During this time additional factors also increase or decrease the rate of changes such as life style, environment, inherited as well acquired genetic make-up, types of infections, weight and stress only some of them. As a result we customized our body so deserve a personalized medicine for a treatment. Customized approach is its hype with developing technology to analyze data and compare functional genomics of individuals.

However, still we need the basic cell differentiation to solve the puzzle to respond well and connect the dots for physiological problems.  At the stem of the changes there is a cell that respond and amplify its reaction to gain a support to defend at its best . Thus, in this review I like to make a possible connection for pancreatic cancer, obesity-diabetes and innate immune response through natural killer cells.

Pancreatic cancer is one of the most lethal malignancies. Pancreatic cancer is one of the most difficult cancers to treat. Fewer than 5% of patients survive more than 5 years after diagnosis. The 5-year survival rate is despite therapeutic improvements still only 6%. More than 80% of the pancreatic tumors are classified as pancreatic ductal adenocarcinoma (PDA).

When cells in the pancreas that secrete digestive enzymes (acinar cells) turn into duct-like structures, pancreatic cancer can develop. Oncogenic signaling – that which causes the development of tumors – can influence these duct-like cells to form lesions that are a cancer risk.

 

Crossing roads

The recent publication brought up the necessity to understand how pancreatic cancer and IL17 are connected.

Schematic diagram showing the central role of IL-17B–IL-17RB signaling in pancreatic cancer metastasis.

Adapted from an illustration by Heng-Hsiung Wu and colleagues

http://jem.rupress.org/content/212/3/284/F2.large.jpg

 

Simply, obesity and diabetes increases the risks of cancers, cardiovascular disease, hypertension, and type-2 DM.  There is a very big public health concern as obesity epidemic, the incidence of diabetes is increasing globally, with an estimated 285 million people, or 6.6% of the population from 20 to 79 years of age, affected this is especially more alarming as child obesity is on the rise.

According to a World Health Organization (WHO) report showing that 400 million people are obese in the world, with a predicted increase to 700 million by 2015  and in the US, 30–35 percent of adults are obese.  In addition, high BMI and increased risk of many common cancers, such as liver, endometrium, breast, pancreas, and colorectal cancers have a linear increasing relationship.

The BMI is calculated by dividing body weight in kilograms by height squared in meters kg/m2). The current standard categories of BMI are as follows: underweight, <18.5; normal weight, 18.5–24.9; overweight, 25.0–29.9; obese, 30.0–34.9; and severely obese, > or = 35.0).

Furthermore, natural killer cells not only control innate immune responses but have function in other immune responses that was not recognized well before.

Recently, there have been reports regarding Natural Killer cells on was about the function of IL17 that is produced by iNKT, a subtype of NK, for a possible drug target.  In addition, regulation of receptors that are up or downregulated by NK cells for a precise determination between compromised cells and healthy cells.

Therefore, instead of sole reliance on SNPs, or GWAS for early diagnostics or only organ system base pathology, compiling the overall health of the system is necessary for a proper molecular diagnostics and targeted therapies.

  • What is Pancreas cancer

SNAP SHOT:

Incidence

  • It is a rare type of cancer.
  • 20K to 200K US cases per year

 Medically manageable

Treatment can help

 Requires a medical diagnosis

  1. lab tests or imaging
  2. spreads rapidly and has a poor prognosis.
  3. treatments may include: removing the pancreas, radiation, and chemotherapy.

 Ages affected; even though person may develop this cancer from age 0 to 60+ there is a high rate of incidence after age 40.

 

People may experience:

  • Pain: in the abdomen or middle back
  • Whole body: nausea, fatigue, or loss of appetite
  • Also common: yellow skin and eyes, fluid in the abdomen, weight loss, or dark urine
  • The pancreas secretes enzymes that aid digestion and hormones that help regulate the metabolism of sugars.

Prescription

  • Chemotherapy regimen by injection: Irinotecan, Gemcitabine (Gemzar), Oxaliplatin (Eloxatin)
  • Other treatments: Leucovorin by injection, Fluorouracil by injection (Adrucil)

 

Also common

  • Chemotherapy regimen: Gemcitabine-Oxaliplatin regimen, Docetaxel-Gemcitabine regimen
  • Procedures: Radiation therapy, Pancreatectomy, surgery to remove pancreatic tumors

 

Specialists

  • Radiologist: Uses images to diagnose and treat disease within the body.
  • Oncologist: Specializes in cancer.
  • Palliative medicine: Focuses on improving quality of life for terminally ill patients.
  • General surgeon: Performs a range of surgeries on the abdomen, skin, breast, and soft tissue.
  • Gastroenterologist: Focuses on the digestive system and its disorders.

What are the current and possible applications for treatment and early diagnosis

Diagnostics

Several imaging techniques are employed in order to see if cancer exists and to find out how far it has spread. Common imaging tests include:

  • Ultrasound – to visualize tumor
  • Endoscopic ultrasound (EUS) – thin tube with a camera and light on one end
  • Abdominal computerized tomography (CT) scans – to visualize tumor
  • Endoscopic retrograde cholangiopancreatography (ERCP) – to x-ray the common bile duct
  • Angiogram – to x-ray blood vessels
  • Barium swallows to x-ray the upper gastrointestinal tract
  • Magnetic resonance imaging (MRI) – to visualize tumor
  • Positron emission tomography (PET) scans – useful to detect if disease has spread

 

New solutions in Diagnostics;

The study, published in Nature Communications, suggests that targeting the gene in question – protein kinase D1 (PKD1) – could lead to new ways of halting the development of one of the most difficult tumors to treat.

“As soon as pancreatic cancer develops, it begins to spread, and PKD1 is key to both processes. Given this finding, we are busy developing a PKD1 inhibitor that we can test further,” says the study’s co-lead investigator, Dr. Peter Storz.

Do we have new markers?

Is it possible check the cancer along with glucose levels or insulin at the point of care or companion diagnostics?

Therapy

New Solutions in Therapies

ABRAXANE (paclitaxel formulated as albumin bound nanoparticles; nab-paclitaxel), in combination with gemcitabine, has been recommended for use within NHS Scotland by the Scottish Medicines Consortium (SMC) for the treatment of metastatic adenocarcinoma of the pancreas.

The SMC decision is based on results from the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, published in the October 2013 edition of the New England Journal of Medicine, which demonstrated an increase in median overall survival of 1.8 months when compared to gemcitabine alone [(8.5 months vs. 6.7 months respectively) (HR 0.72; 95% CI 0.62 to 0.83 P<0.001)]. 

Updated results from post-hoc analysis of the MPACT trial based on an extended data cut-off (8 months) at the time the trial was closed demonstrated an increase in the median overall survival benefit of 2.1 months when compared to gemcitabine alone [(8.7 months vs. 6.6 months respectively) (HR 0.72,95% CI = 0.62 to 0.83, P<.001)].

Using radioactive bacteria to stop the spread of pancreatic cancer – scientists from Albert Einstein College of Medicine of Yeshiva University used bacteria to carry radioisotopes commonly used in cancer treatment directly into pancreatic cancer cells. They found in animal experiments that the incidence of secondary tumors went down dramatically – i.e. the cancer was much less likely to spread (metastasize).

Targeting stroma is another approached that is followed by TGen to potentially extend patient survival in all cases including advanced cases based on a report at Clinical Cancer Research, published online by the American Association for Cancer Research. Thus this eliminates one of the limiting factor to reach tumor cells and destroying the accumulation of stroma — the supporting connective tissue that includes hyaluronan and few other collagen types.

One of the study leaders, Andrew Biankin, a Cancer Research UK scientist at the University of Glasgow in the UK said that “Being able to identify which patients would benefit from platinum-based treatments would be a game-changing moment for treating pancreatic cancer, potentially improving survival for a group of patients.” 

 In the journal Nature, the international team- including scientists from Cancer Research UK showed the evidence of large chunks of DNA being shuffled around, which they were able to classify according to the type of disruption they created in chromosomes.

The study concludes there are four subtypes of pancreatic cancer, depending on the frequency, location and types of DNA rearrangement. It terms the subtypes: stable, locally rearranged, scattered and unstable.

Can we develop an immunotherapy?

 Genetics of Pancreatic Cancer 

There are many ongoing studies to develop diagnostics technologies and treatments. However, the etiology of PC is not well understood. Pancreas has dual functions that include 2% of endocrine hormone secretion and 98% exocrine secretion, enzymes, to help digestion. As a result, pancreatic cancer is related to obesity, overweight, diabetes.

First, eliminating the risk factors can be the simplest path. Next approach is dropping the obesity and diabetes to prevent the occurrence of cancers since in the U.S. population, 50 percent are overweight, 30 percent are medically obese and 10 percent have diabetes mellitus (DM). Tobacco smoking, alcohol consumptions, chronic pancreatitis, and genetic risk factors, have been recognized as potential risk factors for the development and progression of PC.

Many studies showed that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers.  Thus, these agents are thought to be the target to diagnose or cure PC.

Type 2 diabetes mellitus has been associated with an increased risk of several human cancers, such as liver, pancreatic, endometrial, colorectal, breast, and bladder cancer. The majority of the data show that metformin therapy decreases, while insulin secretagog drugs slightly increase the risk of certain types of cancers in type 2 diabetes.

Metformin can decrease cell proliferation and induce apoptosis in certain cancer cell lines. Endogenous and exogenous (therapy induced) hyperinsulinemia may be mitogenic and may increase the risk of cancer in type 2 diabetes. Type 2 diabetes mellitus accounts for more than 95% of the cases.

In PDA these cells have been reported to express specific genes such as Aldh1 or CD133. To date, more than 20 case-control studies and cohort and nested case-control studies with information on the association between diabetes and pancreatic cancer, BMI and cancer, and obesity and cancer have been reported.

Meta analysis and cohort studies:

 

  1. Meta studies for Diabetes and PC

Most of the diabetes and PC studies were included in two meta-analyses, in 1995 and in 2005, investigating the risk of pancreatic cancer in relation to diabetes.

The first meta-analysis, conducted in 1995, included 20 of these 40 published case-control and cohort studies and reported an overall estimated relative risk (RR) of pancreatic cancer of 2.1 with a 95% confidence interval (CI) of 1.6-2.8. These values were relatively unchanged when the analyses were restricted to patients who had diabetes for at least 5 years (RR, 2.0 [95% CI, 1.2-3.2]).

The second meta-analysis, which was conducted in 2005, included 17 case-control and 19 cohort and nested case-control studies published from 1996 to 2005 and demonstrated an overall odds ratio (OR) for pancreatic cancer of 1.8 and 95% CI of 1.7-1.9 .   Individuals diagnosed with diabetes within 4 years before their pancreatic cancer diagnosis had a 50% greater risk of pancreatic cancer than did those diagnosed with diabetes more than 5 years before their cancer diagnosis (OR, 2.1 [95% CI, 1.9-2.3] versus OR, 1.5 [95% CI, 1.3-1.8]; P = 0.005).

  1. In a recent pooled analysis of 2192 patients with pancreatic cancer and 5113 cancer-free controls in three large case-control studies conducted in the United States (results of two of the three studies were published after 2005),
  2. Risk estimates decreased as the number of years with diabetes increased.
  3. Individuals with diabetes for 2 or fewer, 3-5, 6-10, 11-15, or more than 15 years had ORs (95% CIs) of 2.9 (2.1-3.9), 1.9 (1.3-2.6), 1.6 (1.2-2.3), 1.3 (0.9-2.0), and 1.4 (1.0-2.0), respectively (P < 0.0001 for trend).

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  1. Meta Studies between BMI and PC

Meta studies in 2003 and 2008 showed a week positive association between BMI and PC.  In 2003, a meta-analysis of six case-control and eight prospective studies including 6,391 PC cases 2% increase in risk per 1 kg/m2 increase in BMI. In 2008, 221 datasets, including 282,137 incidence of cancer cases with 3,338,001 subjects the results were similar  RR, 1.12; CI, 1.02–1.22.

In 2007, 21 prospective studies handled , 10 were from the United States, 9 were from Europe, and 2 were from Asia and studies was conducted including 3,495,981 individuals and 8,062 PC cases. There was no significant difference between men and women and the estimated summary risk ratio (RR) per 5 kg/m2 increase in BMI was 1.12 (95% CI, 1.06–1.17) in men and women combined.

This study concluded that concluded that there was a positive association between BMI and risk of PC, per  a 5 kg/m2 increase in BMI may be equal to  a 12% increased risk of PC.

  • The location and type of the obesity may also signal for a higher risk. The recent Women’s Health Initiative study in the United States among 138,503 postmenopausal showed that  women central obesity  in relation to PC (n=251) after average of 7.7 years of follow-up duration demonstrated that central adiposity is related to developing PC at a higher risk. Based on their result “women in the highest quintile of waist-to-hip ratio have a 70 percent (95% CI, 10–160%) greater risk of PC compared with women in the lowest quintile”
  • Age of obesity or being overweight versus risk of developing PC was also examined.
  • Regardless of their DM status they were at risk and decreased their survival even more so among men than women between age of 14-59.

overweight   14 to 39 years   (highest odds ratio [OR], 1.67; 95% CI, 1.20–2.34) or

obese            20 to 49 years     (highest OR, 2.58; 95% CI, 1.70–3.90)   , independent of DM status.

  • This association was different between men and women from the ages of 14 to 59:

stronger in men               (adjusted OR, 1.80; 95% CI, 1.45–2.23)

weaker in women            (adjusted OR, 1.32; 95% CI, 1.02–1.70).

  • The effect of BMI , obesity and overweight had reduced overall survival of PC regardless of disease stage and tumor resection status

high BMI (= or > 25)                          20 to 49 years , an earlier onset of PC by 2 to 6 years.

obese patients: hazard ratio,               1.86, 95% CI, 1.35–2.56).

overweight or obese                             30 to 79 years,  in the year prior to recruitment

overweight patients: hazard ratio,       1.26, 95% CI, 0.94–1.69;

Similarly, the authors concluded that:

  • Being overweight or obese during early adulthood was associated with a greater risk of PC and a younger age of disease onset, whereas obesity at an older age was associated with a lower overall survival in patients diagnosed with PC.
  • More recently, several large prospective cohort studies with a long duration of follow-up has been conducted in the U.S. showing a positive association between high BMI and the risk of PC (adjusted RR 1.13–1.54), suggesting the role of obesity and overweight with higher risk in the development and eventual death due to PC.
  • Although the role of smoking and gender in the association of obesity and PC is not clear, the new evidence strongly supports a positive association of high BMI with increased risk of PC, consistent with the majority of early findings; however, all recent studies strongly suggest that obesity and overweight are independent risk factor of PC.
  • Diabetes was associated with a 1.8-fold increase in risk of pancreatic cancer (95% CI, 1.5-2.1).

How pancreatic cancer is related to obesity, overweight, BMI, diabetes

 pc3

Connections in Physiology and Pathology:

Altogether cumulative data suggest that DM has a three-fold increased risk for the development of PC and a two-fold risk for biliary cancer insulin resistance and abnormal glucose metabolism, even in the absence of diabetes, is associated with increased risk for the development of PC.  Obesity alters the metabolism towards insulin resistance through affecting gene expression of inflammatory cytokines, adipose hormones such as adipokines, and PPAR-γ.

Furthermore, adiponectin also pointed out to be a negative link factor for cancers such as colon, breast, and PC.  Therefore, insulin resistance is one of the earliest negative effects of obesity, early altered glucose metabolism, chronic inflammation, oxidative stress and decreased levels of adipose hormone adiponectin and PPAR-γ, key regulators for adipogenesis.

Potential pathways directly linking obesity and diabetes to pancreatic cancer. Obesity and diabetes cause mutiple alterations in glucose and lipid hemastasis, microenvironments, and immune responses, which result in the activation of several oncogenic signaling pathways.

These deregulations increase cell survival and proliferation, eventually leading to the development and progression of pancreatic cancer. ROS, reactive oxygen species; IGF-1, insulin-like growth factor-1; IR, insulin receptors; IGF-1R, insulin-like growth factor-1 receptors; TNFR, tumor necrosis factor receptors; TLR, Toll-like receptors; HIF-1α, hypoxia-inducible factor-α1; AMPK, AMP kinase; IKK, IκB kinase; PPAR-γ, peroxisome proliferator-activated receptor-γ; VEGF, vascular endothelial growth factor; MAPK, MAP kinase; mTOR, mammalian target of rapamycin; TSC, tuberous sclerosis complex; Akt, protein kinase B. PI3K, phosphoinositide-3-kinase; STAT3, activator of transcription-3; JNK, c-Jun NH2-terminal kinase.

Top six pathways interacting with obesity or diabetes in modifying the risk of pancreatic cancer are Chemokine Signaling, Pathways in cancer, Cytokine-cytokine receptor interaction, Calcium signaling pathway. MAPK signaling pathway.

This analysis showed

  • GNGT2,
  • RELA,
  • TIAM1,
  • CBLC,
  • IFNA13, 
  • IL22RA1, 
  • IL2RA
  • GNAS,
  • MAP2K7,
  • DAPK3, 
  • EPAS1 and 
  • FOS as contributor genes.

  Furthermore, top overrepresented canonical pathways, including

  1. Role of RIG1-like Receptors in Antiviral Innate Immunity,
  2. Role of PI3K/AKT Signaling in the Pathogenesis of Influenza, and
  3. Molecular Mechanisms of Cancer

in genes interacting with risk factors (P < 10−8) are

  • TRAF6, 
  • RELA,
  • IFNA7,
  • IFNA4,
  • NFKB2,
  • IFNA10,
  • IFNA16,
  • NFKB1,
  • IFNA1/IFNA13,
  • IFNA5,
  • IFNA14,
  • IFNA,
  • GSK3B,
  • IFNA16,
  • IFNA14,
  • TP53,
  • FYN,
  • ARHGEF4,
  • GNAS,
  • CYCS ,
  • AXIN1,
  • ADCY4,
  • PRKAR2A,
  • ARHGEF1 ,
  • CDC42,
  • RAC,3
  • SIN3A,
  • RB1,
  • FOS ,
  • CDH1,
  • NFKBIA,
  • GNAT1,
  • PAK3,
  • RHOA,
  • RASGRP1,
  • PIK3CD,
  • BMP6,
  • CHEK2, and
KEGG code Pathway description Risk factor No. of genes/genes with marginal effecta No. of SNPs/eigenSNPs in the interaction analysisb PG x Ec Major contributing genesd
hsa04062e Chemokine Signalinge Obesity 175/27 695/181 3.29 × 10−6 GNGT2 RELA TIAM1
hsa05200 Pathways in cancer Obesity 315/37 806/212 5.35 × 10−4 CBLC RELA
hsa04060 Cytokine-cytokine receptor interaction Obesity 247/36 422/149 6.97 × 10−4 IFNA13 IL22RA1 IL2RA
hsa04020 Calcium signaling pathway Diabetes 171/24 759/190 1.57 × 10−4 GNAS
hsa04010 MAPK signaling pathway Diabetes 260/32 523/154 3.56 × 10−4 FOS MAP2K7
hsa05200 Pathways in cancer Diabetes 315/37 806/212 4.46 × 10−4 DAPK3 EPAS1 FOS

aNumber of genes making up the pathway/ number of genes survived the PCA-LRT (P ≤ 0.10).

bNumber of SNPs in the “reconstructed” pathways/number of principal components for LRT.

cP value was estimated by LRT in logistic regression model with adjustment of age, sex, study site, pack years(continuous), obesity or diabetes as appropriate, and five principal components for population structure.

dGenes with PG x E ≤ 0.05 in logistic regression and P ≤ 0.10 in PCA-LRT.

ePathways remained significant after Bonferroni correction (P < 1.45 × 10−4)

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Top overrepresented canonical pathways in genes interacting with risk factors (P < 10−8)

Biological process Risk factor P Valuea Ratiob Contributing genes
Role of RIG1-like Receptors in Antiviral Innate Immunity Obesity 6.71 × 10−11 12/49 (0.25) TRAF6 RELA IFNA7 IFNA4 NFKB2 IFNA10 IFNA16 NFKB1
IFNA1/IFNA13 IFNA5 IFNA14 IFNA6
Role of PI3K/AKT Signaling in the Pathogenesis of Influenza Obesity 8.64 × 10−9 12/74 (0.12) RELA IFNA7 IFNA4 NFKB2 GSK3B IFNA10 IFNA16 NFKB1
IFNA1/IFNA13 IFNA5 IFNA14 IFNA6
Molecular Mechanisms of Cancer Diabetes 1.03 × 10−9 24/378 (0.063) TP53 FYN ARHGEF4 GNAS CYCS AXIN1 ADCY4 PRKAR2A
ARHGEF1 CDC42 RAC3 SIN3A RB1 FOS CDH1 NFKBIA GNAT1
PAK3 RHOA RASGRP1 PIK3CD BMP6 CHEK2 E2F2

aCalculated using Fisher’s exact test (right-tailed).

bNumber of genes interacting with a risk factor of interest (P ≤ 0.05) in a given pathway divided by total number of genes making up that pathway.

Pancreatic Cancer and Diabetes:

We conclude that diabetes type II has a fundamental influence on pancreatic ductal adenocarcinoma by stimulating cancer cell proliferation, while metformin inhibits cancer cell proliferation. Chronic inflammation had only a minor effect on the pathophysiology of an established adenocarcinoma.

  • Diabetes increases tumor size and proliferation of carcinoma cells
  • Diabetes does not decrease cell death in carcinomas
  • Diabetes II like syndrome reduces the number of Aldh1+cells within the tumor
  • Metformin decreases tumor size and proliferation of carcinoma cells

 

Much is known about factors increasing the likelihood to develop PDA. Identified risk factors include among others chronic pancreatitis, long lasting diabetes, and obesity. Patients with chronic and especially hereditary pancreatitis have a very high relative risk of developing pancreatic cancer of 13.3 and 69.0, respectively. Patients with diabetes and obesity have a moderately increased relative risk of 1.8 and 1.3. These studies indicate that a substantial number of patients with PDA also suffer from local inflammation or diabetes.

http://www.biomedcentral.com/1471-2407/15/51/figure/F3?highres=y

http://www.biomedcentral.com/content/figures/s12885-015-1047-x-4.jpg

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Potential mechanisms underlying the associations of diabetes and cancer.

  • AdipoR1/R2, adiponectin receptor 1/2;
  • AMPK, 5′-AMPactivated protein kinase;
  • IGF-1, insulin-like growth factor-1;
  • IGF-1R, insulin-like growth factor-1 receptor;
  • IKK, IκA;B kinase; IR, insulin receptor;
  • IRS-1, insulin receptor substrate-1;
  • MAPK, mitogen-activated-protein-kinase;
  • mTOR, mammalian target of rapamycin;
  • NF-κA;B, nuclear factor-κA;B;
  • ObR, leptin receptor;
  • PAI-1, plasminogen activator inhibitor-1;
  • PI3-K, phosphatidylinositol 3-kinase;
  • ROS, Reactive oxygen species;
  • TNF-α, tumor necrosis factor- α;
  • TNF-R1, tumor necrosis factor-receptor 1;
  • uPA, urokinase-type plasminogen activator;
  • uPAR, urokinase-type plasminogen activator receptor;
  • VEGF, vascular endothelial growth factor;
  • VEGFR, vascular endothelial growth factor receptor.

http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=3238796_nihms-277874-f0001.jpg

Type 2 diabetes mellitus is likely the third modifiable risk factor for pancreatic cancer after cigarette smoking and obesity. The relationship between diabetes and pancreatic cancer is complex. Diabetes or impaired glucose tolerance is present in more than 2/3rd of pancreatic cancer patients.

Epidemiological investigations have found that long-term type 2 diabetes mellitus is associated with a 1.5-fold to 2.0-fold increase in the risk of pancreatic cancer. A causal relationship between diabetes and pancreatic cancer is also supported by findings from prediagnostic evaluations of glucose and insulin levels in prospective studies.

Insulin resistance and associated hyperglycemia, hyperinsulinemia, and inflammation have been suggested to be the underlying mechanisms contributing to development of diabetes-associated pancreatic cancer.

Stem Cells

http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=3410675_nihms295920f1.jpg

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932318/

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“A study by Permert et al.using glucose tolerance tests in patients with newly diagnosed pancreatic cancer showed that 75% of patients met criteria for diabetes. Pannala et al. used fasting blood glucose values or previous use of antidiabetic medications to define diabetes in patients with pancreatic cancer (N.=512) and age-matched control non-cancer subjects attending primary care clinics (N.=933) “

Distribution of fasting blood glucose among pancreatic cancer cases and controls. From Pannala et al.

“ They reported a nearly seven-fold higher prevalence of diabetes in pancreatic cancer patients compared to controls (47% vs. 7%). In a retrospective study using similar criteria, Chari et al. found the prevalence of diabetes in pancreatic cancer patients to be 40%.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932318/

 

Relationship between type 2 diabetes and risk of pancreatic cancer in case-control and nested case control studies. “Diamond: point estimate representing study-specific relative risks or summary relative risks with 95% CIs. Horizontal lines: represent 95% confidence intervals (CIs). Test for heterogeneity among studies: P<0.001, I2=93.6%. 1, cohort studies (N.=27) use incidence or mortality rate as the measurements of relative risk; 2, cohort studies (N.=8) use standardized incidence/mortality rate as the measurement of relative risk. From Benet al.”

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932318/

Table II

Sensitivity and specificity for biomarkers for pancreatic cancer.

Biomarker Study Sensitivity Specificity N.
CA19-9 Goonetilleke 68 79 82 Meta-analysis
Steinberg 69 81 90 Meta-analysis
CA125 Duraker 85 57 78 123
Haguland 86 45 76 95
CEA Ni 87 45 75 68
Haglund 86 54 76 95
Zhao 88 25 86 143
Duraker 85 39 91 123
SPan-1 Kiriyama 74 81 76 64
Chung 89 92 83 67
Kobayashi 90 82 85 200
Du-PAN 2 Satake 83 48 85 239
Sawabu 91 72 94 32
Kawa 92 64 200

NIHMS552557.html

PART II:  Targets for Immunomodulation to develop a therapy


Natural Killer Cells:

Natural Killer cells usually placed under non-specific immune response as a first defend mechanism during innate immunity.  NKs responses to innate immune reactions but not only viruses but also bacteria and parasitic infections develop a new line of defense.  These reactions involve amplification of many cytokines based on the specific infection or condition.  Thus, these activities help NKs to evolve.

However, their functions proven to be more than innate immune response since from keeping the pregnancy term to prevent recurrent abortions to complex diseases such as cancer, diabetes and cardiovascular conditions they have roles thorough awakening chemokines and engaging them specifically with their receptors to activate other immune cells.  For example, there is a signaling mechanism connection between NKs and DCs to respond attacks.  Furthermore, there are interactions between various types of immune cells and they are specific for example between NK and Tregs.

During pregnancy there is a special kind of interaction between NK cells and Tregs.

  • There can be several reasons such as to protect pregnancy from the immunosuppressive environment so then the successful implantation of the embryo and tolerance of the mother to the embryo can be established. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation.
  • During cancer development tumors want to build a microenvironment through an array of highly orchestrated immune elements to generate a new environment against the host. In normal pregnancy, decidua, the uterine endometrium,  is critical for the development of placental vasculature.
  • This is the region gets thicks and thin during female cycles to prevent or accept pregnancies. As a result, mother nature created that 70% of all human decidual lymphocytes are NK cells, defined as uterine or decidual NK (dNK) cells.
  • The NK cell of decidua (dNK) and  peripheral blood NK cells are different since  dNK cells are characterized as CD56brightCD16CD3, express killer cell immunoglobulin-like receptors and exhibit low killing capacity despite the presence of cytolytic granules, and a higher frequency of CD4+CD25bright   

The lesson learn here is that pregnancy and mammary tissue are great examples of controlling cellular differentiation and growth since after pregnancy all these cells go back to normal state.

Understanding these minute differences and relations to manipulate gene expression may help to:

  1. Develop better biomaterials to design long lasting medical devices and to deliver vaccines without side effects.
  2. Generate safer vaccines as NKcells are the secret weapons in DC vaccination and studying their behavior together with T-cell activation in vaccinated individuals might predict clinical outcome.
  3. Establish immunotherapies based on interactions between NK cells and Tregs for complex diseases not only cancer, but also many more such as autoimmune disorder, transplants, cardiovascular, diabetes.

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Trascription factors are the silence players of the gene expression that matches input to output as a cellular response either good or bad but this can be monitored and corrected with a proper meical device or diagnostics tool to provide successful treatment regimen.

  • Therefore, the effects of Tregs on NK during gene regulation analyzed and compared among other living organisms for concerved as well as signature sequence targets even though the study is on human.
  • Unfortunatelly we can’t mutate the human for experimental purposes so comparative developmental studies now its widely called stem cell biology with a system biology approach may help to establish the pathway.

NK and T reg regulation share a common interest called T box proteins. These proteins are conserved and also play role in development of heart at very early development, embryology.  What is shared among all T-box is simply lie behind the capacity for DNA binding through the T-box domain and transcriptional regulatory activity, which plays a role in controlling the expression of developmental gene in all animal species.

 The Special T box protein: T-bet

The first identified T-box protein was Brachyury (T). in a nut shell

  • The T-box domain is made up of about 180 amino-acid residues that includes a specific sequence of DNA
  • called T-box  domain,  TCACACCT between residues 135 and 326 in mouse.
  • However, T-bet which is the T-box protein expressed in T cells and also called as TBX21 is quite conserved in 18 members of the T-box protein (TBX) family
  • since it has a crucial dual role during development and for coordination of both innate and adaptive immune responses.

T-Bet was originally cloned for its role in Th1 lineage, it has a role in Th2 development, too. 

The whole mechanism based on direct activation and modulation mechanisms in that  T-Bet directly activates IFN-γ gene transcription and enhances development of Th1 cells at the same time modulates IL-2 and Th2 cytokines in an IFN-γ-independent manner that creates an attenuation of Th2 cell development.

Thus, certain lipids ligands or markers can be utilized during vaccine design to steer the responses for immune therapies against autoimmune diseases.   As a result, tumors can be removed and defeated by manipulating NKs action.

 

INKT:

NKT has functions in diabetes, asthma. One cell type that has been proposed to contribute immensely to the development of asthma is NKT cells, which constitute a small population of lymphocytes that express markers of both T cells (T-cell receptor, TCR) and NK cells (e.g., NK1.1, NKG2D). NKT cells can be subdivided into at least three subtypes, based on their TCR. Type I NKT cells or invariant NKT (iNKT) cells express invariant TCR chains (V14–J18 in mice and V24–J18 in humans) coupled with a limited repertoire of V chains (V8, V7 and V2 in mice and V11 in humans).

The studies in the past decade showed the protective mechanism of NKT cells during the development of Type 1 diabetes can be complex.

  1. First, NKT cells can impair the differentiation of anti-islet reactive T cells into Th1 effector cells in a cell–cell contact dependent manner, which did not require Th2 cytokine production or CD1d recognition.
  2. Second, NKT cells accumulating in the pancreas can indirectly suppress diabetogenic CD4+T cells via IFN-γ production.
  3. Last, anergic iNKT cells induced by protracted αGalCer stimulation can induce the production of noninflammatory DCs, which inhibit diabetes development in an Ag-specific fashion.

These findings point to an important protective role for NKT cells during autoimmune pathogenesis in the pancreas.

A crucial role has been suggested for invariant natural killer T cells (iNKT) in regulating the development of asthma, a complex and heterogeneous disease characterized by airway inflammation and airway hyperreactivity (AHR).

iNKT cells constitute a unique subset of T cells responding to endogenous and exogenous lipid antigens, rapidly secreting a large amount of cytokines, which amplify both innate and adaptive immunity.

IL17:

Terashima A et al (2008) identified a novel subset of natural killer T (NKT) cells that expresses the interleukin 17 receptor B (IL-17RB) for IL-25 (also known as IL-17E) and is essential for the induction of Airway hypersensitive reaction (AHR). IL-17RB is preferentially expressed on a fraction of CD4(+) NKT cells but not on other splenic leukocyte populations tested.

They strongly suggested that IL-17RB(+) CD4(+) NKT cells play a crucial role in the pathogenesis of asthma.

NKT connection can be established between through targeting IL17 and IL17RB. There is a functional specialization of interleukin-17 family members. Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F).

Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses.

 There is no one easy answer for the role of IL-17 in pancreatic cancer as there are a number of unresolved issues and but it can be only suggested that  pro-tumorigenic IL-17 activity is confined to specific subsets of patients with pancreatic cancer since there is a increased expression of IL-17RB in these patients about ∼40% of pancreatic cancers presented on their histochemical staining (IHC-  immunohistochemistry.

IL17 and breast cancer:

In addition, during breast cancer there is an increased signaling of interleukin-17 receptor B (IL-17RB) and IL-17B.  They promoted tumor formation in breast cancer cells in vivo and even created acinus formation in immortalized normal mammary epithelial cells in vitro cell culture assays.

  • Furthermore, the elevated expression of IL-17RB not only present itself  stronger than HER2 for a better prognosis but also brings the shortest survival rate if patients have increased  IL-17RB and HER2 levels.
  • However, decreased level of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumor growth.  This may prompt a different independent  role for  IL-17RB and HER2  in breast cancer development.
  • In addition, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells.

These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.

IL 17 and Asthma:

A requirement for iNKT cells has also been shown in a model of asthma induced with air pollution, ozone and induced with respiratory viruses chronic asthma studied in detail. In these studies specific types of NKT cells found to that specific types of NK and receptors trigger of asthma symptoms. Taken together, these studies indicate that both Th2 cells (necessary for allergen-specific responses) and iNKT cells producing IL-4 and IL-13 are required for the development of allergen-induced AHR.

Although CD4+ IL-4/IL-13-producing iNKT cells (in concert with antigen-specific Th2 cells) are crucial in allergen-induced AHR, NK1.1IL-17-producing iNKT cells have a major role in ozone-induced AHR.

A main question in iNKT cell biology involves the identification of lipid antigens that can activate iNKT cells since this allow to identify which microorganisms to attack as  a result, the list of microorganisms that produce lipids that activate iNKT cells is rapidly growing.

Invariant natural killer T cells (iNKT) cell function in airway hyperreactivity (AHR). iNKT cells secrete various cytokines, including Th2 cytokines, which have direct effects on hematopoietic cells, airway smooth muscle cells, and goblet cells. Alternatively, iNKT cells could regulate other cell types that are known to be involved in asthma pathogenesis, e.g., neutrophils and alveolar macrophages.

http://www.nature.com/mi/journal/v2/n5/images/mi200996f1.jpg

Chemokines:

Chemokines  have a crucial role in organogenesis of various organs including lymph nodes, arising from their key roles in stem cell migration. Moreover, most homeostatic chemokines can control the movement of lymphocytes and dendritic cells and eventually adaptive immunity. Chemokines are heparin-binding proteins with 4 cysteine residues in the conserved positions.

The human chemokine system has about 48 chemokines. They are subgrouped based on:

  • Number of cysteines
  • Number of amino acid separating cysteines
  • Presence or absence of ELR motif includes, 3-amino acid sequence, glutamic acid-leucine-arginine
  • functionally classified as inflammatory, homeostatic, or both, based on their expression patterns

Chemokines are structurally divided into 4 subgroups :CXC, CC, CX3C, and C. X represent an aminoacid so the first 2 cysteines are separated by 1 is grouped as CXC and 3 amino acids is called CX3C chemokines but in CC  the first 2 cysteines are adjacent. In the C chemokines there is no second and fourth cysteines.

Various types of inflammatory stimuli induce abundantly the expression of inflammatory chemokines to induce the infiltration of inflammatory cells such as granulocytes and monocytes/macrophages.

  • inflammatory chemokines are CXC chemokines with ELR motif and CCL2.
  • homeostatic chemokines are expressed constitutively in specific tissues or cells.

cmi20132f2

Chemokines exert their biological activities by binding their corresponding receptors, which belong to G-protein coupled receptor (GPCR) with 7-span transmembrane portions. Thus, the target cell specificity of each chemokine is determined by the expression pattern of its cognate receptor .

Moreover, chemokines can bind to proteoglycans and glycosaminoglycans with a high avidity, because the carboxyl-terminal region is capable of binding heparin.

Consequently, most chemokines are produced as secretory proteins, but upon their secretion, they are immobilized on endothelium cells and/or in extracellular matrix by interacting with proteoglycans and glycosaminoglycans. The immobilization facilitates the generation of a concentration gradient, which is important for inducing the target cells to migrate in a directed way.

The human chemokine system.

Chemokine receptor Chemokines Receptor expression in
Leukocytes Epithelium Endothelium
CXCR1 CXCL6, 8 PMN +
CXCR2 CXCL1, 2, 3, 5, 6, 7, 8 PMN + +
CXCR3 CXCL4, 9, 10, 11 Th1, NK +
CXCR4 CXCL12 Widespread + +
CXCR5 CXCL13 B
CXCR6 CXCL16 Activated T +
CXCR7 (ACKR3) CXCL12, CXCL11 Widespread + +
Unknown CXCL14 (acts on monocytes)
CCR1 CCL3, 4, 5, 7, 14, 15, 16, 23 Mo, Mϕ, iDC, NK + +
CCR2 CCL2, 7, 8, 12, 13 Mo, Mϕ, iDC, NK
activated T, B
+ +
CCR3 CCL5, 7, 11, 13, 15, 24, 26, 28 Eo, Ba, Th2 +
CCR4 CCL2, 3, 5, 17, 22 iDC, Th2, NK, T, Mϕ
CCR5 CCL3, 4, 5, 8 Mo, Mϕ, NK, Th1
activated T
+
CCR6 CCL20 iDC, activated T, B +
CCR7 CCL19, 21 mDC, Mϕ, naïve T
activated T
+
CCR8 CCL1, 4, 17 Mo, iDC, Th2, Treg
CCR9 CCL25 T +
CCR10 CCL27, 28 Activated T, Treg +
Unknown CCL18 (acts on mDC and naïve T)
CX3CR1 CX3CL1 Mo, iDC, NK, Th1 +
XCR1 XCL1, 2 T, NK
Miscellaneous Scavenger receptors for chemokines
Duffy antigen (ACKR1) CCL2, 5, 11, 13, 14
CXCL1, 2, 3, 7, 8
D6 (ACKR2) CCL2, 3, 4, 5, 7, 8, 12
CCL13, 14, 17, 22
CCRRL1 (ACKR4) CCL19, CCL21, CCL25

Leukocyte anonyms are as follows. Ba: basophil, Eo: eosinophil, iDC: immature dendritic cell, mDC: mature dendritic cell, Mo: monocyte, Mϕ: macrophage, NK: natural killer cell, Th1: type I helper T cell, Th2: type II helper T cell, and Treg: regulatory T cell.

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There are differences between  human liver and peripheral NK cells. Regulation of NK cell functions by CD226, CD96 and TIGIT.close. CD226 binding to CD155 or CD112 at the cell surface of transformed or infected cells triggers cytotoxic granule exocytosis and target cell lysis by natural killer (NK) cells. TIGIT, CD226, CD96 and CRTAM ligand specificity and signalling.close.

Regulation of NK cell-mediated cancer immunosurveillance through CD155 expression.close.   CD155 is frequently overexpressed by cancer cells.

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Liver NK cells Circulating NK cells References
CD3-CD56+ 30.6% (11.6–51.3%) 12.8% (1–22%) 17
CD56bright/total NK cell ~50% ~10% 18,19
CD56dim/total NK cell ~50% ~90% 18,19
CD27 high low 20,21
CD16 + 18,22
CD69 +/−, higher +/− 16
Chemokine receptor CCR7 and CXCR3
(CD56bright)
CXCR1, CX3CR1
(CD56dim)
13,23
Inhibitory receptor (NKG2A) high low 24
Natural cytotoxicity higher high 18,19
TRAIL high low 1
Perforin, Granzyme B high low 2
Cytokine production high
(MIP-1α/β, IL-10,
TNF-α, TNF-β, IFN-γ,
GM-CSF)
low
(TNF-α, TNF-β, IFN-γ,
GM-CSF, IL-10)
18
ADCC high 25
  • In conclusion, having to develop precise early diagnostics is about determining the overlapping genes as key among diabetes, obesity, overweight and pancreas functions even pregnancy can be suggested.

 

  • It seems feasible to develop an immunotherapy for pancreatic cancer with the focus on chemokines and primary  signaling between iNKT and Tregs such as one of the recent plausable target IL-17 and IL17 RB.

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Berger NA1Obesity and cancer pathogenesis. Ann N Y Acad Sci. 2014 Apr;1311:57-76. doi: 10.1111/nyas.12416.

De Souza AL1, Saif MW. Diabetes and pancreatic cancer. JOP. 2014 Mar 10;15(2):118-20. doi: 10.6092/1590-8577/2286.

Timofte D et al Metabolic disorders in patients operated for pancreatic cancer.  Rev Med Chir Soc Med Nat Iasi. 2014 Apr-Jun;118(2):392-8.

Lowenfels AB, Maisonneuve P. Epidemiologic and etiologic factors of pancreatic cancer. Hematol Oncol Clin North Am. 2002;16:1–16.

Lowenfels AB, Sullivan T, Fiorianti J, Maisonneuve P. The epidemiology and impact of pancreatic diseases in the United States. Curr Gastroenterol Rep.2005;7:90–95.

Michaud DS. Epidemiology of pancreatic cancer. Minerva Chir. 2004;59:99–111.

Schuster DP. Obesity and the Development of Type 2 Diabetes: the Effects of Fatty Tissue Inflamation. Dovepress; 2010. pp. 253–262.

WHO. World Health Organization Fact Sheet for World Wide Prevalence of Obesity. 2006. http://www.who.int/mediacentre/factsheets/fs311/en/index.html.

Chang S et al, State ranks of incident cancer burden due to overweight and obesity in the United States, 2003. Obesity (Silver Spring) 2008;16:1636–1650.

Lewis L. Lanie  Evolutionary struggles between NK cells and viruses Nature Reviews Immunology 8, 259-268 (April 2008) | doi:10.1038/nri2276

Seth, S. et alThe murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1. Biochem. Biophys. Res. Commun. 364, 959–965 (2007).

de Andrade et al DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins. Immunol. Cell Biol. 92, 237–244 (2014).

Orange, J. S. Formation and function of the lytic NK-cell immunological synapse. Nature Rev. Immunol. 8, 713–725 (2008).

Lagrue, K. et alThe central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapseImmunol. Rev. 256, 203–221 (2013).

Vyas, Y. M. et alSpatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactionsJ. Immunol. 167, 4358–4367 (2001).

Shibuya, K. et alCD226 (DNAM-1) is involved in lymphocyte function-associated antigen 1 costimulatory signal for naive T cell differentiation and proliferationJ. Exp. Med. 198,1829–1839 (2003).

Lozano, E. et al  The CD226/CD155 interaction regulates the proinflammatory (TH1/TH17)/anti-inflammatory (TH2) balance in humans. J. Immunol. 191, 3673–3680 (2013).

Maier, M. K. et alThe adhesion receptor CD155 determines the magnitude of humoral immune responses against orally ingested antigensEur. J. Immunol. 37, 2214–2225(2007).

Pende, D. et alExpression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction.Blood 107, 2030–2036 (2006).

O’Leary et al  T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nature Immunol. 7, 507–516(2006).

Sanchez-Correa, B. et alDecreased expression of DNAM-1 on NK cells from acute myeloid leukemia patientsImmunol. Cell Biol. 90, 109–115 (2012).

Mamessier, E. et alHuman breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J. Clin. Invest. 121, 3609–3622 (2011).

Nakai, R. et alOverexpression of Necl-5 correlates with unfavorable prognosis in patients with lung adenocarcinoma. Cancer Sci. 101, 1326–1330 (2010).

Tane, S. et alThe role of Necl-5 in the invasive activity of lung adenocarcinomaExp. Mol. Pathol. 94, 330–335 (2013).

Sloan, K. E. et alCD155/PVR plays a key role in cell motility during tumor cell invasion and migrationBMC Cancer 4, 73 (2004)

Chan, C. J., Smyth, M. J. & Martinet, L. Molecular mechanisms of natural killer cell activation in response to cellular stress. Cell Death Differ. 21, 5–14 (2014).

Li, M. et al. T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-γ production of natural killer cells via β-arrestin 2-mediated negative signaling. J. Biol. Chem. 289, 17647–17657 (2014).

Guma, M. et al. Imprint of human cytomegalovirus infection on the NK cell receptor repertoireBlood 104, 3664–3671 (2004).

Sharma S. Natural killer cells and regulatory T cells in early pregnancy loss.

Int J Dev Biol. 2014;58(2-4):219-29. doi: 10.1387/ijdb.140109ss. Review.

Mukaida N, Sasaki S, Baba T. Chemokines in cancer development and progression and their potential as targeting molecules for cancer treatment.  Mediators Inflamm. 2014;2014:170381. doi: 10.1155/2014/170381. Epub 2014 May 22. Review.

Van Elssen CH, Oth T, Germeraad WT, Bos GM, Vanderlocht J.  Natural killer cells: the secret weapon in dendritic cell vaccination strategies.Clin Cancer Res. 2014 Mar 1;20(5):1095-103. doi: 10.1158/1078-0432.CCR-13-2302. Review.

Gardner AB, Lee SK, Woods EC, Acharya AP. Biomaterials-based modulation of the immune system. Biomed Res Int. 2013;2013:732182. doi: 10.1155/2013/732182. Epub 2013 Sep 22. Review.

Pedroza-Pacheco I, Madrigal A, Saudemont A. Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy. Cell Mol Immunol. 2013 May;10(3):222-9. doi: 10.1038/cmi.2013.2. Epub 2013 Mar 25. Review.

Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ.  The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013 Feb;138(2):105-15. doi: 10.1111/imm.12036. Review.

Tian Z, Chen Y, Gao B.Natural killer cells in liver disease.  Hepatology. 2013 Apr;57(4):1654-62. doi: 10.1002/hep.26115. Review.

Joyce S, Girardi E, Zajonc DM. J NKT cell ligand recognition logic: molecular basis for a synaptic duet and transmission of inflammatory effectors. Immunol. 2011 Aug 1;187(3):1081-9. doi: 0.4049/jimmunol.1001910. Review.

Diana J, Gahzarian L, Simoni Y, Lehuen A. Innate immunity in type 1 diabetes.  Discov Med. 2011 Jun;11(61):513-20. Review.

Wu L, Van Kaer L.Natural killer T cells in health and disease. Front Biosci (Schol Ed). 2011 Jan 1;3:236-51. Review.

Cantorna MT.  Why do T cells express the vitamin D receptor? Ann N Y Acad Sci. 2011 Jan;1217:77-82. doi: 10.1111/j.1749-6632.2010.05823.x. Epub 2010 Nov 29. Review.

Key Papers:

These papers, Gilfian et all and Iguchi-Manaka et al,  were the first to show the role of CD226 in NK cell- and CD8+ T cell-mediated tumour immunosurveillance using Cd226−/− mice.

  • Gilfillan, S.et alDNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. J. Exp. Med. 205, 2965–2973 (2008).
  • Iguchi-Manaka, A.et alAccelerated tumor growth in mice deficient in DNAM-1 receptor.  Exp. Med. 205, 2959–2964 (2008).

Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector functionCancer Cell 26, 923–937 (2014).
This study shows that TIGIT is expressed by PD1+ exhausted tumour-infiltrating T cells and that targeting these receptors with monoclonal antibodies represents a promising strategy to restore CD8+ T cell functions in cancer or in chronic infectious disease.

Khakoo, S. I. et alHLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infectionScience 305, 872–874 (2004).

Fang, M. et alCD94 is essential for NK cell-mediated resistance to a lethal viral disease.Immunity 34, 579–589 (2011).
This study using CD94-deficient mice shows that the activating receptor formed by CD94 and NKG2E is essential for the resistance of C57BL/6 mice to mousepox.

Pradeu, T., Jaeger, S. & Vivier, E. The speed of change: towards a discontinuity theory of immunity? Nature Rev. Immunol. 13, 764–769 (2013).
This is an outstanding review on the formulation of a new immune paradigm ‘the discontinuity theory’

Further Reading:

Vol 13, No 4 (2012): July – p. 330-469 Molecular Biology of Pancreatic Cancer: How Useful Is It in Clinical Practice? ABSTRACT  HTML  PDF
George H Sakorafas, Vasileios Smyrniotis
Vol 13, No 4 (2012): July – p. 330-469 Endoscopic Findings of Upper Gastrointestinal Lesions in Patients with Pancreatic Cancer ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Hiroyuki Watanabe, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Seiji Yano
Vol 13, No 5 (2012): September – p. 470-547 Two Avirulent, Lentogenic Strains of Newcastle Disease Virus Are Cytotoxic for Some Human Pancreatic Tumor Lines In Vitro ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Megan Delimata, Sooraj Tejaswi
Vol 14, No 3 (2013): May – p. 221-303 Duration of Diabetes and Pancreatic Cancer in a Case-Control Study in the Midwest and the Iowa Women’s Health Study (IWHS) Cohort ABSTRACT  HTML  PDF
Sarah A Henry, Anna E Prizment, Kristin E Anderson
Vol 16, No 1 (2015): January – p. 1-99 Endoscopic Management of Pain in Pancreatic Cancer ABSTRACT  HTML  PDF
Parit Mekaroonkamol, Field F Willingham, Saurabh Chawla
Vol 14, No 2 (2013): March – p. 109-220 Advancements in the Management of Pancreatic Cancer: 2013 ABSTRACT  HTML  PDF
Muhammad Wasif Saif
Vol 15, No 5 (2014): September – p. 413-540 New-onset Diabetes: A Clue to the Early Diagnosis of Pancreatic Cancer ABSTRACT  HTML  PDF
Suresh T Chari
Vol 13, No 5 (2012): September – p. 470-547 Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies ABSTRACT  HTML  PDF
Fumiaki Nozawa, Mehmet Yalniz, Murat Saruc, Jens Standop, Hiroshi Egami, Parviz M Pour
Vol 14, No 5 (2013): September – p. 475-527 Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Daisuke Ishikawa, Shigeki Nanjo, Shinji Takeuchi, Tadaaki Yamada, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Toshifumi Gabata, Osamu Matsui, Hiroko Ikeda, Yasushi Takamatsu, Sakae Iwakami, Seiji Yano
Vol 13, No 1 (2012): January – p. 1-123 Newcastle Disease Virus LaSota Strain Kills Human Pancreatic Cancer Cells in Vitro with High Selectivity ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Sooraj Tejaswi, Megan Delimata
Vol 13, No 3 (2012): May – p. 252-329 Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma ABSTRACT  HTML  PDF
Sabine Kersting, Monika S Janot, Johanna Munding, Dominique Suelberg, Andrea Tannapfel, Ansgar M Chromik, Waldemar Uhl, Uwe Bergmann
Vol 14, No 4 (2013): July – p. 304-474 A Proteomic Comparison of Formalin-Fixed Paraffin-Embedded Pancreatic Tissue from Autoimmune Pancreatitis, Chronic Pancreatitis, and Pancreatic Cancer ABSTRACT  HTML  PDF  SUPPL. TABLES 1-4 (PDF)
Joao A Paulo, Vivek Kadiyala, Scott Brizard, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 13, No 4 (2012): July – p. 330-469 Highlights on the First Line Treatment of Metastatic Pancreatic Cancer ABSTRACT  HTML  PDF
Krishna S Gunturu, Jamie Jarboe, Muhammad Wasif Saif
Vol 14, No 2 (2013): March – p. 109-220 Pancreatic Cancer: Updates on Translational Research and Future Applications ABSTRACT  HTML  PDF
Evangelos G Sarris, Konstantinos N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474 Pancreatic Cancer: What About Screening and Detection? ABSTRACT  HTML  PDF
Froso Konstantinou, Kostas N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474 Diabetes and Pancreatic Cancer ABSTRACT  HTML  PDF
Najla Hatem El-Jurdi, Muhammad Wasif Saif
Vol 13, No 5 (2012): September – p. 470-547 Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 1: Basic Studies ABSTRACT  HTML  PDF
Murat Saruc, Fumiaki Nozawa, Mehmet Yalniz, Atsushi Itami, Parviz M Pour
Vol 14, No 2 (2013): March – p. 109-220 Analysis of Endoscopic Pancreatic Function Test (ePFT)-Collected Pancreatic Fluid Proteins Precipitated Via Ultracentrifugation ABSTRACT  HTML  PDF  SUPPL.(XLS)  SUPPL.(PDF)
Joao A Paulo, Vivek Kadiyala, Aleksandr Gaun, John F K Sauld, Ali Ghoulidi, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 16, No 1 (2015): January – p. 1-99 Regulation Mechanisms of the Hedgehog Pathway in Pancreatic Cancer: A Review ABSTRACT  HTML  PDF
Kim Christin Honselmann, Moritz Pross, Carlo Maria Felix Jung, Ulrich Friedrich Wellner, Steffen Deichmann, Tobias Keck, Dirk Bausch
Vol 14, No 5S (2013): September (Suppl.) – p. 528-602 History of Previous Cancer in Patients Undergoing Resection for Pancreatic Adenocarcinoma ABSTRACT  PDF
Francesca Gavazzi, Maria Rachele Angiolini, Cristina Ridolfi, Maria Carla Tinti, Marco Madonini, Marco Montorsi, Alessandro Zerbi
Vol 13, No 4 (2012): July – p. 330-469 Molecular Biology of Pancreatic Cancer: How Useful Is It in Clinical Practice? ABSTRACT  HTML  PDF
George H Sakorafas, Vasileios Smyrniotis
Vol 13, No 4 (2012): July – p. 330-469 Endoscopic Findings of Upper Gastrointestinal Lesions in Patients with Pancreatic Cancer ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Hiroyuki Watanabe, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Seiji Yano
Vol 13, No 5 (2012): September – p. 470-547 Two Avirulent, Lentogenic Strains of Newcastle Disease Virus Are Cytotoxic for Some Human Pancreatic Tumor Lines In Vitro ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Megan Delimata, Sooraj Tejaswi
Vol 14, No 3 (2013): May – p. 221-303 Duration of Diabetes and Pancreatic Cancer in a Case-Control Study in the Midwest and the Iowa Women’s Health Study (IWHS) Cohort ABSTRACT  HTML  PDF
Sarah A Henry, Anna E Prizment, Kristin E Anderson
Vol 16, No 1 (2015): January – p. 1-99 Endoscopic Management of Pain in Pancreatic Cancer ABSTRACT  HTML  PDF
Parit Mekaroonkamol, Field F Willingham, Saurabh Chawla
Vol 14, No 2 (2013): March – p. 109-220 Advancements in the Management of Pancreatic Cancer: 2013 ABSTRACT  HTML  PDF
Muhammad Wasif Saif
Vol 15, No 5 (2014): September – p. 413-540 New-onset Diabetes: A Clue to the Early Diagnosis of Pancreatic Cancer ABSTRACT  HTML  PDF
Suresh T Chari
Vol 13, No 5 (2012): September – p. 470-547 Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies ABSTRACT  HTML  PDF
Fumiaki Nozawa, Mehmet Yalniz, Murat Saruc, Jens Standop, Hiroshi Egami, Parviz M Pour
Vol 14, No 5 (2013): September – p. 475-527 Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Daisuke Ishikawa, Shigeki Nanjo, Shinji Takeuchi, Tadaaki Yamada, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Toshifumi Gabata, Osamu Matsui, Hiroko Ikeda, Yasushi Takamatsu, Sakae Iwakami, Seiji Yano
Vol 13, No 1 (2012): January – p. 1-123 Newcastle Disease Virus LaSota Strain Kills Human Pancreatic Cancer Cells in Vitro with High Selectivity ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Sooraj Tejaswi, Megan Delimata
Vol 13, No 3 (2012): May – p. 252-329 Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma ABSTRACT  HTML  PDF
Sabine Kersting, Monika S Janot, Johanna Munding, Dominique Suelberg, Andrea Tannapfel, Ansgar M Chromik, Waldemar Uhl, Uwe Bergmann
Vol 14, No 4 (2013): July – p. 304-474 A Proteomic Comparison of Formalin-Fixed Paraffin-Embedded Pancreatic Tissue from Autoimmune Pancreatitis, Chronic Pancreatitis, and Pancreatic Cancer ABSTRACT  HTML  PDF  SUPPL. TABLES 1-4 (PDF)
Joao A Paulo, Vivek Kadiyala, Scott Brizard, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 13, No 4 (2012): July – p. 330-469 Highlights on the First Line Treatment of Metastatic Pancreatic Cancer ABSTRACT  HTML  PDF
Krishna S Gunturu, Jamie Jarboe, Muhammad Wasif Saif
Vol 14, No 2 (2013): March – p. 109-220 Pancreatic Cancer: Updates on Translational Research and Future Applications ABSTRACT  HTML  PDF
Evangelos G Sarris, Konstantinos N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474 Pancreatic Cancer: What About Screening and Detection? ABSTRACT  HTML  PDF
Froso Konstantinou, Kostas N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474 Diabetes and Pancreatic Cancer ABSTRACT  HTML  PDF
Najla Hatem El-Jurdi, Muhammad Wasif Saif
Vol 13, No 5 (2012): September – p. 470-547 Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 1: Basic Studies ABSTRACT  HTML  PDF
Murat Saruc, Fumiaki Nozawa, Mehmet Yalniz, Atsushi Itami, Parviz M Pour
Vol 14, No 2 (2013): March – p. 109-220 Analysis of Endoscopic Pancreatic Function Test (ePFT)-Collected Pancreatic Fluid Proteins Precipitated Via Ultracentrifugation ABSTRACT  HTML  PDF  SUPPL.(XLS)  SUPPL.(PDF)
Joao A Paulo, Vivek Kadiyala, Aleksandr Gaun, John F K Sauld, Ali Ghoulidi, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 16, No 1 (2015): January – p. 1-99 Regulation Mechanisms of the Hedgehog Pathway in Pancreatic Cancer: A Review ABSTRACT  HTML  PDF
Kim Christin Honselmann, Moritz Pross, Carlo Maria Felix Jung, Ulrich Friedrich Wellner, Steffen Deichmann, Tobias Keck, Dirk Bausch
Vol 14, No 5S (2013): September (Suppl.) – p. 528-602 History of Previous Cancer in Patients Undergoing Resection for Pancreatic Adenocarcinoma ABSTRACT  PDF
Francesca Gavazzi, Maria Rachele Angiolini, Cristina Ridolfi, Maria Carla Tinti, Marco Madonini, Marco Montorsi, Alessandro Zerbi

Patents

1.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week10/OG/html/1412-2/US08974784-20150310.html

Anti-pancreatic cancer antibodies: David M. Goldenberg, Mendham, NJ (US); Hans J. Hansen, Picayune, MS (US); Chien-Hsing Chang, Downingtown, PA (US); …

2.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week42/OG/html/1407-3/US08865413-20141021.html

A method of diagnosing pancreatic cancer in a human, the method comprising detecting the level of golgi apparatus protein 1 in a sample from the …

3.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week10/OG/html/1412-2/US08974802-20150310.html

A method for the treatment of pancreatic cancer, which comprises the administration to a human patient with pancreatic cancer of an effective …

4.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week50/OG/html/1409-3/US08912191-20141216.html

A method of treatment of melanoma, colorectal cancer, or pancreatic cancerwherein the treatment inhibits the progress of, reduces the rate of …

5.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week10/OG/html/1412-2/US08975401-20150310.html

A method of treating a cancer selected from breast cancer, hepatocellular carcinoma … gastric carcinoma, leukemia and pancreatic cancer in a subject …

6.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week42/OG/html/1407-3/US08865173-20141021.html

Treatments for pancreatic cancer metastases: Suzanne M. Spong, San Francisco, CA (US); Thomas B. Neff, Atherton, CA (US); and Stephen J. Klaus, San …

7.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week48/OG/html/1409-1/US08901093-20141202.html

Custom vectors for treating and preventing pancreatic cancer: Dennis L. Panicali, Acton, MA (US); Gail P. Mazzara, Winchester, MA (US); Linda R. …

8.       www.uspto.gov

http://www.uspto.gov/web/patents/patog/week09/OG/html/1412-1/US08969366-20150303.html

A method for treating a disease selected from the group consisting of melanoma, stomach cancer, liver cancer, colorectal cancerpancreatic …

9.       Drug composition cytotoxic for pancreatic cancer cells

http://www.uspto.gov/web/patents/patog/week13/OG/html/1401-1/US08685941-20140401.html

Drug composition cytotoxic for pancreatic cancer cells: James Turkson, Orlando, Fla. (US) Assigned to University of Central Florida Research …

10.    [PDF] J. John Shimazaki, Esq. 1539 Lincoln Way, Suite 204

http://www.uspto.gov/web/offices/com/sol/foia/tac/2.66/74713131.pdf

  1. John Shimazaki, Esq. 1539 Lincoln Way, Suite 204 … containing the Of fice Action because Applicant™s president™s father was ill withpancreatic

11.    [PDF] Written Comments on Genetic Diagnostic Testing Study

http://www.uspto.gov/aia_implementation/gen_e_lsi_20130207.pdf

Page 5 of 23 extracolonic cancers of LS include liver cancerpancreatic cancer, gall bladder duct cancer, prostate cancer, sarcomas, thyroid cancer …

12.    Detection of digestive organ cancer, gastric cancer …

http://www.uspto.gov/web/patents/patog/week02/OG/html/1410-2/US08932990-20150113.html

Detection of digestive organ cancer, gastric cancer, colorectal cancerpancreatic cancer, and biliary tract cancer by gene expression profiling

13.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week06/OG/html/1399-2/US08648112-20140211.html

wherein said cancer is selected from the group consisting of a sarcoma, … a nervous system cancer, prostate cancerpancreatic cancer, and colon can …

14.    Treatment of hyperproliferative diseases with vinca …

http://www.uspto.gov/web/patents/patog/week45/OG/html/1408-2/US08883775-20141111.html

A method of treating or ameliorating a hyperproliferative disorder selected from the group consisting of glioblastoma, lung cancer, breast cancer . …

15.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week30/OG/html/1404-5/US08791125-20140729.html

A method for treating a Weel kinase mediated cancer selected from the group consisting of breast cancer, lung cancerpancreatic cancer, colon …

16.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week08/OG/html/1411-4/US08962891-20150224.html

wherein said proliferative disorder is breast cancer or pancreatic cancer. …

17.    Immunoconjugates, compositions for making them, and …

http://www.uspto.gov/web/patents/patog/week40/OG/html/1407-1/US08852599-20141007.html

A method for treating a cancer in a subject suffering from such cancer, … pancreatic cancer, ovarian cancer, lymphoma, colon cancer, mesothelioma, …

18.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week11/OG/html/1400-3/US08673898-20140318.html

A method of treating cancer, … lung cancer, melanoma, neuroblastomas, oral cancer, ovarian cancerpancreatic cancer, prostate cancer , rectal cance …

19.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week43/OG/html/1407-4/US08871744-20141028.html

A method for treating a subject having breast cancer, ovarian cancer, or pancreatic cancer in need of therapy thereof comprising administering to …

20.    [PDF] Pamela Scudder <pscudder@windstream.net> Sent: Saturday …

http://www.uspto.gov/sites/default/files/aia_implementation/gene-comment-scudder.pdf

My daughter died of ovarian cancer. My other daughter and many … (mutation) is known to cause a higher incidence of pancreatic (for instance) cancer …

21.    Methods of treating cancer using pyridopyrimidinone …

http://www.uspto.gov/web/patents/patog/week48/OG/html/1409-1/US08901137-20141202.html

A method of treating pancreatic cancer which method comprises administering to a patient a therapeutically effective amount of a compound that is:

22.    Heteroaryl substituted pyrrolo[2,3-B]pyridines and pyrrolo …

http://www.uspto.gov/web/patents/patog/week02/OG/html/1410-2/US08933086-20150113.html

A method of treating pancreatic cancer in a patient, comprising administering to said patient a therapeutically effective amount of a compound …

23.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week49/OG/html/1409-2/US08906934-20141209.html

… wherein the cell proliferative disorder is selected from the group consisting of cervical cancer, colon cancer, ovarian cancerpancreatic cancer, …

24.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week32/OG/html/1405-2/US08802703-20140812.html

A method of inhibiting MEK in a cancer cell selected from the group consisting of human melanoma cells and human pancreatic cancer cells …

25.    Antibody-based arrays for detecting multiple signal …

http://www.uspto.gov/web/patents/patog/week08/OG/html/1399-4/US08658388-20140225.html

A method for performing a multiplex, high-throughput immunoassay for facilitating a cancer diagnosis, the method comprising:

26.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week48/OG/html/1409-1/US08901147-20141202.html

A method for the treatment of colorectal cancer, lung cancer, breast cancer, prostatecancer, urinary cancer, kidney cancer, and pancreatic …

27.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week16/OG/patentee/alphaY.htm

Yamaue, Hiroki; to Onco Therapy Science, Inc. Combination therapy for pancreatic cancer using an antigenic peptide and chemotherapeutic agent 08703713 …

28.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week48/OG/patentee/alphaP_Utility.htm

… The Custom vectors for treating and preventing pancreatic cancer … system and apparatus for control of pancreatic beta cell function to improve …

29.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week16/OG/patentee/alphaW.htm

Whatcott, Cliff; and Han, Haiyong, to Translational Genomics Research Institute, The Therapeutic target for pancreatic cancer cells 08703736 Cl. …

30.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week10/OG/patentee/alphaG.htm

Goldenberg, David M.; Hansen, Hans J.; Chang, Chien-Hsing; and Gold, David V., to Immunomedics, Inc. Anti-pancreatic cancer antibodies 08974784 Cl. …

31.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week42/OG/patentee/alphaD.htm

… Narayan, Vaibhav; and Patterson, Scott, to Celera Corporation Pancreatic cancertargets and uses thereof 08865413 Cl. 435-7.1. Domsch, Matthew L.; …

32.    [PDF] 15 March 2005 – United States Patent and Trademark Office

http://www.uspto.gov/web/trademarks/tmog/20050315_OG.pdf

15 March 2005 – United States Patent and Trademark Office

33.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week10/OG/html/1412-2/US08975248-20150310.html

Combinations of therapeutic agents for treating cancer: … myeloma, colorectal adenocarcinoma, cervical carcinoma and pancreatic carcinoma, …

34.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week05/OG/patentee/alphaG_Utility.htm

… Inc. Medium-chain length fatty acids, salts and triglycerides in combination with gemcitabine for treatment of pancreatic cancer 08946190 Cl. …

35.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week13/OG/patentee/alphaT_Utility.htm

Turkson, James; to University of Central Florida Research Foundation, Inc. Drug composition cytotoxic for pancreatic cancer cells 08685941 Cl. 514-49.

36.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week31/OG/patentee/alphaG_Utility.htm

… David M., to Immunomedics, Inc. Anti-mucin antibodies for early detection and treatment of pancreatic cancer 08795662 Cl. 424-130.1. Gold, …

37.    [PDF] www.uspto.gov

http://www.uspto.gov/web/trademarks/tmog/20110816_OG.pdf

http://www.uspto.gov

38.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week29/OG/patentee/alphaG.htm

Goggins, Michael G.; and Sato, Norihiro, to Johns Hopkins University, The Aberrantly methylated genes in pancreatic cancer 08785614 Cl. 536-24.3. …

39.    www.uspto.gov

http://www.uspto.gov/web/patents/patog/week46/OG/html/1408-3/US08889697-20141118.html

wherein said cancer is pancreatic cnacer, chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL …

40.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week39/OG/patentee/alphaM_Utility.htm

Malafa, Mokenge P.; and Sebti, Said M., to University of South Florida Delta-tocotrienol treatment and prevention of pancreatic cancer 08846653 Cl. …

41.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week02/OG/patentee/alphaK_Utility.htm

… Taro, to National University Corporation Kanazawa University Detection of digestive organ cancer, gastric cancer, colorectal cancerpancreatic …

42.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week11/OG/patentee/alphaK_Utility.htm

Kirn, David; to Sillajen Biotherapeutics, Inc. Oncolytic vaccinia virus cancer therapy 08980246 Cl. 424-93.2. Kirn, Larry J.; …

43.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week39/OG/patentee/alphaM_Utility.htm

Malafa, Mokenge P.; and Sebti, Said M., to University of South Florida Delta-tocotrienol treatment and prevention of pancreatic cancer 08846653 Cl. …

44.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week35/OG/patentee/alphaS_Utility.htm

list of patentees to whom patents were issued on the 2nd day of september, 2014 and to whom reexamination certificates were issued during the week …

45.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week42/OG/patentee/alphaS.htm

… Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer 08865748 Cl. …

46.    [PDF] Paper No. 12 UNITED STATES PATENT AND TRADEMARK OFFICE …

http://www.uspto.gov/sites/default/files/ip/boards/bpai/decisions/prec/bhide.pdf

high incidence of ras involvement, such as colon and pancreatic tumors. By … withcancer or pre-cancerous states will serve to treat or palliate the …

47.    CPC Scheme – C07K PEPTIDES – United States Patent and …

http://www.uspto.gov/web/patents/classification/cpc/html/cpc-C07K.html

PEPTIDES (peptides in … Cancer-associated SCM-recognition factor, CRISPP} [2013‑01] … Kazal type inhibitors, e.g. pancreatic secretory inhibitor, …

48.    Class Definition for Class 514 – DRUG, BIO-AFFECTING AND …

http://www.uspto.gov/web/patents/classification/uspc514/defs514.htm

… compound X useful as an anti-cancer … certain rules as to patent … Cystic fibrosis is manifested by faulty digestion due to a deficiency of pa …

49.    United States Patent and Trademark Office

http://www.uspto.gov/web/patents/classification/cpc/html/cpc-G01N_3.html

Cancer-associated SCM-recognition factor, CRISPP . G01N 2333/4748. . . . . … Bovine/basic pancreatic trypsin inhibitor (BPTI, aprotinin) G01N …

50.    Class Definition for Class 530 – CHEMISTRY: NATURAL RESINS …

http://www.uspto.gov/web/patents/classification/uspc530/defs530.htm

CLASS 530 , CHEMISTRY: NATURAL … Typically the processes of this subclass include solvent extraction of pancreatic … as well as with some forms of …

51.    CPC Definition – A61K PREPARATIONS FOR MEDICAL, DENTAL, OR …

http://www.uspto.gov/web/patents/classification/cpc/html/defA61K.html

PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES … i.e. Pancreatic stem cells are classified in A61K 35/39, … preparations containing cancer a …

52.    Class 530: CHEMISTRY: NATURAL RESINS OR DERIVATIVES …

http://www.uspto.gov/web/offices/ac/ido/oeip/taf/def/530.htm

Typically the processes of this subclass include solvent extraction of pancreatic … 828 for cancer -associated proteins … provided for in Class …

53.    United States Patent and Trademark Office

http://www.uspto.gov/web/patents/classification/cpc/html/cpc-G01N_1.html

Home page of the United States Patent and … Pancreatic cells} G01N 33/5073 … – relevant features relating to a specifically defined cancer are …

54.    *****TBD***** – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/classification/shadowFiles/defs514sf.htm?514_971&S&10E&10F

class 514, drug, bio-affecting and body treating compositions …

55.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week47/OG/patentee/alphaN_Utility.htm

… Dale E., to Buck Institute for Age Research, The Reagents and methods for cancertreatment and … useful for diagnosis and treatment of pancreati …

56.    United States Patent and Trademark Office

http://www.uspto.gov/web/patents/classification/cpc/html/cpc-C12Y_2.html

Pancreatic ribonuclease (3.1.27.5) C12Y 301/27006. . Enterobacter ribonuclease (3.1.27.6) C12Y 301/27007. . Ribonuclease F (3.1.27.7) C12Y 301/27008. …

57.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week01/OG/patentee/alphaI_Utility.htm

Institute for Cancer Research: See … and Segev, Hanna, to Technion Research & Development Foundation Limited Populations of pancreatic …

58.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week53/OG/patentee/alphaC.htm

Cancer Research Technology Limited: See–Collins, Ian; Reader, John Charles; Klair, Suki; Scanlon, Jane; Addison, Glynn; and Cherry, Michael 08618121 …

59.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week12/OG/patentee/alphaP_Utility.htm

… to University Health Network Cyclic inhibitors of carnitine palmitoyltransferase and treating cancer … progenitor cells and pancreatic endocrine …

60.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week47/OG/patentee/alphaI.htm

… to King Fahd University of Petroleum and Minerals Cytotoxic compounds for treatingcancer … or preventing a pancreatic dysfunction 08894972 Cl …

61.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week50/OG/patentee/alphaC.htm

… and Taylor-Papadimitriou, Joyce, to Københavns Universitet Generation of a cancer-specific … to CuRNA, Inc. Treatment of pancreatic …

62.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week29/OG/patentee/alphaP_Utility.htm

… to Cedars-Sinai Medical Center Drug delivery of temozolomide for systemic based treatment of cancer … Pancreatic enzyme compositions and …

63.    Class 424: DRUG, BIO-AFFECTING AND BODY TREATING …

http://www.uspto.gov/web/offices/ac/ido/oeip/taf/def/424.htm

… a disclosed or even specifically claimed utility (i.e., compound X having an attached radionuclide useful as an anti-cancer diagnostic or …

64.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week25/OG/patentee/alphaT_Utility.htm

… Chang-Jer, to Gold Nanotech Inc. Physical nano-complexes for preventing and treating cancer and … and protective solution for protecting pancrea …

65.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week27/OG/patentee/alphaA_Utility.htm

… Thomas T., to Penn State Research Foundation, The In vivo photodynamic therapy ofcancer via a near infrared … of pancreatic beta-cells by …

66.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week32/OG/patentee/alphaB_Utility.htm

Birnie, Richard; to University of York, The Cancer vaccine 08802619 Cl. 514-1. Birtwhistle, Daniel P.; Long, James R.; and Reinke, Robert E., …

67.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week20/OG/patentee/alphaC_Utility.htm

… to Cornell University Method for treating cancer 08729133 Cl. 514-673 … methods for promoting the generation of PDX1+ pancreatic cells …

68.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week49/OG/patentee/alphaL_Utility.htm

… Kurt, to Abbvie Biotherapeutics Inc. Compositions against cancer antigen LIV-1 and uses … H., to Amylin Pharmaceuticals, LLC Pancreatic …

69.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week11/OG/patentee/alphaS_Utility.htm

… Kenji; and Matsuda, Hirokazu, to Kyoto University Molecular probe for imaging ofpancreatic islets and use … use in the treatment of cancer …

70.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week36/OG/patentee/alphaK.htm

… Emi; Matsumi, Chiemi; and Saitoh, Yukie, to Actgen Inc Antibody having anti-cancer … The Plectin-1 targeted agents for detection and treatment …

71.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week53/OG/patentee/alphaK.htm

list of patentees to whom patents were issued on the 31th day of december, 2013 and to whom reexamination certificates were issued during the week …

72.    Patentee Index – United States Patent and Trademark Office

http://www.uspto.gov/web/patents/patog/week40/OG/patentee/alphaK_Utility.htm

… Uemoto, Shinji; and Kawaguchi, Yoshiya, to Kyoto University Method of culturingpancreatic islet-like tissues by a … of breast cancer 08853183 …

Clinical Trials:

Region Name   Number of Studies
World 1824  
Africa   [map]   10  
Central America   [map]   4  
East Asia   [map]   179  
Japan 40   [studies]
Europe   [map]   444  
Middle East   [map]   46  
North America 1189  
Canada   [map]   102   [studies]
Mexico 11   [studies]
United States   [map]   1144   [studies]
Alabama 60   [studies]
Alaska 4   [studies]
Arizona 107   [studies]
Arkansas 23   [studies]
California 235   [studies]
Colorado 79   [studies]
Connecticut 51   [studies]
Delaware 15   [studies]
District of Columbia 36   [studies]
Florida 187   [studies]
Georgia 77   [studies]
Hawaii 15   [studies]
Idaho 11   [studies]
Illinois 139   [studies]
Indiana 94   [studies]
Iowa 51   [studies]
Kansas 39   [studies]
Kentucky 48   [studies]
Louisiana 46   [studies]
Maine 11   [studies]
Maryland 189   [studies]
Massachusetts 142   [studies]
Michigan 116   [studies]
Minnesota 114   [studies]
Mississippi 14   [studies]
Missouri 91   [studies]
Montana 27   [studies]
Nebraska 42   [studies]
Nevada 32   [studies]
New Hampshire 25   [studies]
New Jersey 64   [studies]
New Mexico 27   [studies]
New York 230   [studies]
North Carolina 111   [studies]
North Dakota 22   [studies]
Ohio 136   [studies]
Oklahoma 41   [studies]
Oregon 54   [studies]
Pennsylvania 180   [studies]
Rhode Island 23   [studies]
South Carolina 72   [studies]
South Dakota 23   [studies]
Tennessee 115   [studies]
Texas 212   [studies]
Utah 36   [studies]
Vermont 11   [studies]
Virginia 69   [studies]
Washington 83   [studies]
West Virginia 12   [studies]
Wisconsin 74   [studies]
Wyoming 9   [studies]
North Asia   [map]   24  
Pacifica   [map]   39  
South America   [map]   30  
South Asia   [map]   23  
Southeast Asia   [map]   25  

Search Results for ‘pancreas cancer’

Genomics and Epigenetics: Genetic Errors and Methodologies – Cancer and Other Diseases on March 25, 2015 |  Read Full Post »

@Mayo Clinic: Inhibiting the gene, protein kinase D1 (PKD1), and its protein could stop spread of this form of Pancreatic Cancer on February 24, 2015  Read Full Post »

The Changing Economics of Cancer Medicine: Causes for the Vanishing of Independent Oncology Groups in the US on November 26, 2014 | Read Full Post »

Autophagy-Modulating Proteins and Small Molecules Candidate Targets for Cancer Therapy: Commentary of Bioinformatics Approaches on September 18, 2014 |  Read Full Post »

New Immunotherapy Could Fight a Range of Cancers on June 4, 2014  Read Full Post »

Locally Advanced Pancreatic Cancer: Efficacy of FOLFIRINOX  on June 1, 2014  Read Full Post »

 

ipilimumab, a Drug that blocks CTLA-4 Freeing T cells to Attack Tumors @DM Anderson Cancer Center on May 28, 2014 | Read Full Post »

NIH Study Demonstrates that a New Cancer Immunotherapy Method could be Effective against a wide range of Cancers  on May 12, 2014 |

Cancer Research: Curations and Reporting Posted in on May 6, 2014 | Read Full Post »

Cancer Research: Curations and Reporting: Aviva Lev-Ari, PhD, RN  on April 20, 2014 | Read Full Post »

Prologue to Cancer – e-book Volume One – Where are we in this journey? on April 13, 2014 | Read Full Post »

 

Epilogue: Envisioning New Insights in Cancer Translational Biology on April 4, 2014 | Read Full Post »

 

A Synthesis of the Beauty and Complexity of How We View Cancer

on March 26, 2014 Read Full Post »

 

Pancreatic Cancer Diagnosis: Four Novel Histo-pathologies Screening Characteristics offers more Reliable Identification of Cellular Features associated with Cancer

on November 13, 2013 | Read Full Post »

 

What`s new in pancreatic cancer research and treatment?

on October 21, 2013 | Read Full Post »

 

Family History of Cancer may increase the Risk of Close Relatives developing the Same Type of Cancer as well as Different Types

on July 25, 2013 Read Full Post »

 

2013 Perspective on “War on Cancer” on December 23, 1971

on July 5, 2013 Read Full Post »

 

Mesothelin: An early detection biomarker for cancer (By Jack Andraka) on April 21, 2013 |  Read Full Post »

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

on April 11, 2013 |  Read Full Post »

New methods for Study of Cellular Replication, Growth, and Regulation on March 25, 2015 Read Full Post »

Diet and Diabetes on March 2, 2015 |  Read Full Post »

Neonatal Pathophysiology on February 22, 2015 |  Read Full Post »

Endocrine Action on Midbrain on February 12, 2015 | Read Full Post »

Gastrointestinal Endocrinology on February 10, 2015 | Read Full Post »

Parathyroids and Bone Metabolism on February 10, 2015 | Read Full Post »

Pancreatic Islets on February 8, 2015 | Read Full Post »

Pituitary Neuroendocrine Axis on February 4, 2015 |Read Full Post »

Highlights in the History of Physiology on December 28, 2014 | Read Full Post »

Outline of Medical Discoveries between 1880 and 1980 on December 3, 2014 | Read Full Post »

Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present on November 21, 2014  Read Full Post »

Implantable Medical Devices to 2015 – Industry Market Research, Market Share, Market Size, Sales, Demand Forecast, Market Leaders, Company Profiles, Industry Trends on November 17, 2014 | Read Full Post »

Pharmacological Action of Steroid Hormones on October 27, 2014 | Read Full Post »

Metabolomics Summary and Perspective on October 16, 2014 | Read Full Post »

Pancreatic Tumors take nearly 20 years to become Lethal after the first Genetic Perturbations – Discovery @ The Johns Hopkins University  on October 15, 2014 |Read Full Post »

Isoenzymes in cell metabolic pathways on October 6, 2014 | Read Full Post »

Metformin, thyroid-pituitary axis, diabetes mellitus, and metabolism on September 28, 2014 | Read Full Post »

Carbohydrate Metabolism on August 13, 2014 | Read Full Post »

A Primer on DNA and DNA Replication on July 29, 2014 | Read Full Post »

The Discovery and Properties of Avemar – Fermented Wheat Germ Extract: Carcinogenesis Suppressor on June 7, 2014 | Read Full Post »

Previous Articles posted on Prostate Cancer

@Mayo Clinic: Inhibiting the gene, protein kinase D1 (PKD1), and its protein could stop spread of this form of Pancreatic Cancer 2012pharmaceutical 2015/02/24
Published
Thymoquinone, an extract of nigella sativa seed oil, blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death. larryhbern 2014/07/15
Published
Moringa Oleifera Kills 97% of Pancreatic Cancer Cells in Vitro larryhbern 2014/06/21
Published
The Gonzalez protocol: Worse than useless for pancreatic cancer sjwilliamspa 2014/06/17
Published
An alternative approach to overcoming the apoptotic resistance of pancreatic cancer 2012pharmaceutical 2014/06/03
Published
Locally Advanced Pancreatic Cancer: Efficacy of FOLFIRINOX 2012pharmaceutical 2014/06/01
Published
Consortium of European Research Institutions and Private Partners will develop a microfluidics-based lab-on-a-chip device to identify Pancreatic Cancer Circulating Tumor Cells (CTC) in blood 2012pharmaceutical 2014/04/10
Published
Pancreatic Cancer Diagnosis: Four Novel Histo-pathologies Screening Characteristics offers more Reliable Identification of Cellular Features associated with Cancer 2012pharmaceutical 2013/11/13
Published
What`s new in pancreatic cancer research and treatment? 2012pharmaceutical 2013/10/21
Published
Pancreatic Cancer: Genetics, Genomics and Immunotherapy tildabarliya 2013/04/11
Published
Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed 2012pharmaceutical 2012/10/24
Published
Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University 2012pharmaceutical 2012/10/24
Published
Personalized Pancreatic Cancer Treatment Option 2012pharmaceutical 2012/10/16
Published
Battle of Steve Jobs and Ralph Steinman with Pancreatic cancer: How we lost ritusaxena 2012/05/21
Published
Early Biomarker for Pancreatic Cancer Identified pkandala 2012/05/17
Published
Usp9x: Promising therapeutic target for pancreatic cancer ritusaxena 2012/05/14
Published
War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert sjwilliamspa 2015/03/27
Published
Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease 2012pharmaceutical 2015/02/15
Published
Pancreatic Islets larryhbern 2015/02/08
Publ
Vol 13, No 4 (2012): July – p. 330-469 Molecular Biology of Pancreatic Cancer: How Useful Is It in Clinical Practice? ABSTRACT  HTML  PDF
George H Sakorafas, Vasileios Smyrniotis
Vol 13, No 4 (2012): July – p. 330-469 Endoscopic Findings of Upper Gastrointestinal Lesions in Patients with Pancreatic Cancer ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Hiroyuki Watanabe, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Seiji Yano
Vol 13, No 5 (2012): September – p. 470-547 Two Avirulent, Lentogenic Strains of Newcastle Disease Virus Are Cytotoxic for Some Human Pancreatic Tumor Lines In Vitro ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Megan Delimata, Sooraj Tejaswi
Vol 14, No 3 (2013): May – p. 221-303 Duration of Diabetes and Pancreatic Cancer in a Case-Control Study in the Midwest and the Iowa Women’s Health Study (IWHS) Cohort ABSTRACT  HTML  PDF
Sarah A Henry, Anna E Prizment, Kristin E Anderson
Vol 16, No 1 (2015): January – p. 1-99 Endoscopic Management of Pain in Pancreatic Cancer ABSTRACT  HTML  PDF
Parit Mekaroonkamol, Field F Willingham, Saurabh Chawla
Vol 14, No 2 (2013): March – p. 109-220 Advancements in the Management of Pancreatic Cancer: 2013 ABSTRACT  HTML  PDF
Muhammad Wasif Saif
Vol 15, No 5 (2014): September – p. 413-540 New-onset Diabetes: A Clue to the Early Diagnosis of Pancreatic Cancer ABSTRACT  HTML  PDF
Suresh T Chari
Vol 13, No 5 (2012): September – p. 470-547 Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies ABSTRACT  HTML  PDF
Fumiaki Nozawa, Mehmet Yalniz, Murat Saruc, Jens Standop, Hiroshi Egami, Parviz M Pour
Vol 14, No 5 (2013): September – p. 475-527 Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Daisuke Ishikawa, Shigeki Nanjo, Shinji Takeuchi, Tadaaki Yamada, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Toshifumi Gabata, Osamu Matsui, Hiroko Ikeda, Yasushi Takamatsu, Sakae Iwakami, Seiji Yano
Vol 13, No 1 (2012): January – p. 1-123 Newcastle Disease Virus LaSota Strain Kills Human Pancreatic Cancer Cells in Vitro with High Selectivity ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Sooraj Tejaswi, Megan Delimata
Vol 13, No 3 (2012): May – p. 252-329 Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma ABSTRACT  HTML  PDF
Sabine Kersting, Monika S Janot, Johanna Munding, Dominique Suelberg, Andrea Tannapfel, Ansgar M Chromik, Waldemar Uhl, Uwe Bergmann
Vol 14, No 4 (2013): July – p. 304-474 A Proteomic Comparison of Formalin-Fixed Paraffin-Embedded Pancreatic Tissue from Autoimmune Pancreatitis, Chronic Pancreatitis, and Pancreatic Cancer ABSTRACT  HTML  PDF  SUPPL. TABLES 1-4 (PDF)
Joao A Paulo, Vivek Kadiyala, Scott Brizard, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 13, No 4 (2012): July – p. 330-469 Highlights on the First Line Treatment of Metastatic Pancreatic Cancer ABSTRACT  HTML  PDF
Krishna S Gunturu, Jamie Jarboe, Muhammad Wasif Saif
Vol 14, No 2 (2013): March – p. 109-220 Pancreatic Cancer: Updates on Translational Research and Future Applications ABSTRACT  HTML  PDF
Evangelos G Sarris, Konstantinos N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474 Pancreatic Cancer: What About Screening and Detection? ABSTRACT  HTML  PDF
Froso Konstantinou, Kostas N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474 Diabetes and Pancreatic Cancer ABSTRACT  HTML  PDF
Najla Hatem El-Jurdi, Muhammad Wasif Saif
Vol 13, No 5 (2012): September – p. 470-547 Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 1: Basic Studies ABSTRACT  HTML  PDF
Murat Saruc, Fumiaki Nozawa, Mehmet Yalniz, Atsushi Itami, Parviz M Pour
Vol 14, No 2 (2013): March – p. 109-220 Analysis of Endoscopic Pancreatic Function Test (ePFT)-Collected Pancreatic Fluid Proteins Precipitated Via Ultracentrifugation ABSTRACT  HTML  PDF  SUPPL.(XLS)  SUPPL.(PDF)
Joao A Paulo, Vivek Kadiyala, Aleksandr Gaun, John F K Sauld, Ali Ghoulidi, Peter A Banks, Hanno Steen, Darwin L Conwell
Vol 16, No 1 (2015): January – p. 1-99 Regulation Mechanisms of the Hedgehog Pathway in Pancreatic Cancer: A Review ABSTRACT  HTML  PDF
Kim Christin Honselmann, Moritz Pross, Carlo Maria Felix Jung, Ulrich Friedrich Wellner, Steffen Deichmann, Tobias Keck, Dirk Bausch
Vol 14, No 5S (2013): September (Suppl.) – p. 528-602 History of Previous Cancer in Patients Undergoing Resection for Pancreatic Adenocarcinoma ABSTRACT  PDF
Francesca Gavazzi, Maria Rachele Angiolini, Cristina Ridolfi, Maria Carla Tinti, Marco Madonini, Marco Montorsi, Alessandro Zerbi
Vol 13, No 4 (2012): July – p. 330-469 Molecular Biology of Pancreatic Cancer: How Useful Is It in Clinical Practice? ABSTRACT  HTML  PDF
George H Sakorafas, Vasileios Smyrniotis
Vol 13, No 4 (2012): July – p. 330-469 Endoscopic Findings of Upper Gastrointestinal Lesions in Patients with Pancreatic Cancer ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Hiroyuki Watanabe, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Seiji Yano
Vol 13, No 5 (2012): September – p. 470-547 Two Avirulent, Lentogenic Strains of Newcastle Disease Virus Are Cytotoxic for Some Human Pancreatic Tumor Lines In Vitro ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Megan Delimata, Sooraj Tejaswi
Vol 14, No 3 (2013): May – p. 221-303 Duration of Diabetes and Pancreatic Cancer in a Case-Control Study in the Midwest and the Iowa Women’s Health Study (IWHS) Cohort ABSTRACT  HTML  PDF
Sarah A Henry, Anna E Prizment, Kristin E Anderson
Vol 16, No 1 (2015): January – p. 1-99 Endoscopic Management of Pain in Pancreatic Cancer ABSTRACT  HTML  PDF
Parit Mekaroonkamol, Field F Willingham, Saurabh Chawla
Vol 14, No 2 (2013): March – p. 109-220 Advancements in the Management of Pancreatic Cancer: 2013 ABSTRACT  HTML  PDF
Muhammad Wasif Saif
Vol 15, No 5 (2014): September – p. 413-540 New-onset Diabetes: A Clue to the Early Diagnosis of Pancreatic Cancer ABSTRACT  HTML  PDF
Suresh T Chari
Vol 13, No 5 (2012): September – p. 470-547 Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies ABSTRACT  HTML  PDF
Fumiaki Nozawa, Mehmet Yalniz, Murat Saruc, Jens Standop, Hiroshi Egami, Parviz M Pour
Vol 14, No 5 (2013): September – p. 475-527 Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency ABSTRACT  HTML  PDF
Koushiro Ohtsubo, Daisuke Ishikawa, Shigeki Nanjo, Shinji Takeuchi, Tadaaki Yamada, Hisatsugu Mouri, Kaname Yamashita, Kazuo Yasumoto, Toshifumi Gabata, Osamu Matsui, Hiroko Ikeda, Yasushi Takamatsu, Sakae Iwakami, Seiji Yano
Vol 13, No 1 (2012): January – p. 1-123 Newcastle Disease Virus LaSota Strain Kills Human Pancreatic Cancer Cells in Vitro with High Selectivity ABSTRACT  HTML  PDF
Robert J Walter, Bashar M Attar, Asad Rafiq, Sooraj Tejaswi, Megan Delimata
Vol 13, No 3 (2012): May – p. 252-329 Rare Solid Tumors of the Pancreas as Differential Diagnosis of Pancreatic Adenocarcinoma ABSTRACT  HTML  PDF
Sabine Kersting, Monika S Janot, Johanna Munding, Dominique Suelberg, Andrea Tannapfel, Ansgar M Chromik, Waldemar Uhl, Uwe Bergmann
Vol 14, No 4 (2013): July – p. 304-474 A Proteomic Comparison of Formalin-Fixed Paraffin-Embedded Pancreatic Tissue from Autoimmune Pancreatitis, Chronic Pancreatitis, and Pancreatic Cancer ABSTRACT  HTML  PDF  SUPPL. TABLES 1-4 (PDF)
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Evangelos G Sarris, Konstantinos N Syrigos, Muhammad Wasif Saif
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Froso Konstantinou, Kostas N Syrigos, Muhammad Wasif Saif
Vol 14, No 4 (2013): July – p. 304-474 Diabetes and Pancreatic Cancer ABSTRACT  HTML  PDF
Najla Hatem El-Jurdi, Muhammad Wasif Saif
Vol 13, No 5 (2012): September – p. 470-547 Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 1: Basic Studies ABSTRACT  HTML  PDF
Murat Saruc, Fumiaki Nozawa, Mehmet Yalniz, Atsushi Itami, Parviz M Pour
Vol 14, No 2 (2013): March – p. 109-220 Analysis of Endoscopic Pancreatic Function Test (ePFT)-Collected Pancreatic Fluid Proteins Precipitated Via Ultracentrifugation ABSTRACT  HTML  PDF  SUPPL.(XLS)  SUPPL.(PDF)
Joao A Paulo, Vivek Kadiyala, Aleksandr Gaun, John F K Sauld, Ali Ghoulidi, Peter A Banks, Hanno Steen, Darwin L Conwell
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Kim Christin Honselmann, Moritz Pross, Carlo Maria Felix Jung, Ulrich Friedrich Wellner, Steffen Deichmann, Tobias Keck, Dirk Bausch
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Francesca Gavazzi, Maria Rachele Angiolini, Cristina Ridolfi, Maria Carla Tinti, Marco Madonini, Marco Montorsi, Alessandro Zerbi

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Voluntary and Involuntary S- Insufficiency

Writer and Curator: Larry H Bernstein, MD, FCAP 

Transthyretin and the Stressful Condition

Introduction

This article is written among a series of articles concerned with stress, obesity, diet and exercise, as well as altitude and deep water diving for extended periods, and their effects.  There is a reason that I focus on transthyretin (TTR), although much can be said about micronutients and vitamins, and fat soluble vitamins in particular, and iron intake during pregnancy.    While the importance of vitamins and iron are well accepted, the metabolic basis for their activities is not fully understood.  In the case of a single amino acid, methionine, it is hugely important because of the role it plays in sulfur metabolism, the sulfhydryl group being essential for coenzyme A, cytochrome c, and for disulfide bonds.  The distribution of sulfur, like the distribution of iodine, is not uniform across geographic regions.  In addition, the content of sulfur found in plant sources is not comparable to that in animal protein.  There have been previous articles at this site on TTR, amyloid and sepsis.

Transthyretin and Lean Body Mass in Stable and Stressed State

https://pharmaceuticalintelligence.com/2013/12/01/transthyretin-and-lean-body-mass-in-stable-and-stressed-state/

A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/

Stabilizers that prevent transthyretin-mediated cardiomyocyte amyloidotic toxicity

https://pharmaceuticalintelligence.com/2013/12/02/stabilizers-that-prevent-transthyretin-mediated-cardiomyocyte-amyloidotic-toxicity/

Thyroid Function and Disorders

https://pharmaceuticalintelligence.com/2015/02/05/thyroid-function-and-disorders/

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com

https://pharmaceuticalintelligence.com/2014/09/01/compilation-of-references-in-leaders-in-pharmaceutical-intelligence-about-proteomics-metabolomics-signaling-pathways-and-cell-regulation-2/

Malnutrition in India, high newborn death rate and stunting of children age under five years

https://pharmaceuticalintelligence.com/2014/07/15/malnutrition-in-india-high-newborn-death-rate-and-stunting-of-children-age-under-five-years/

Vegan Diet is Sulfur Deficient and Heart Unhealthy

https://pharmaceuticalintelligence.com/2013/11/17/vegan-diet-is-sulfur-deficient-and-heart-unhealthy/

How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

https://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-leads_to_hyperhomocysteinemia/

Amyloidosis with Cardiomyopathy

https://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/

Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

https://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control

https://pharmaceuticalintelligence.com/2012/10/13/sepsis-multi-organ-dysfunction-syndrome-and-septic-shock-a-conundrum-of-signaling-pathways-cascading-out-of-control/

Automated Inferential Diagnosis of SIRS, sepsis, septic shock

https://pharmaceuticalintelligence.com/2012/08/01/automated-inferential-diagnosis-of-sirs-sepsis-septic-shock/

Transthyretin and the Systemic Inflammatory Response 

Transthyretin has been widely used as a biomarker for identifying protein-energy malnutrition (PEM) and for monitoring the improvement of nutritional status after implementing a nutritional intervention by enteral feeding or by parenteral infusion. This has occurred because transthyretin (TTR) has a rapid removal from the circulation in 48 hours and it is readily measured by immunometric assay. Nevertheless, concerns have been raised about the use of TTR in the ICU setting, which prompts a review of the actual benefit of using this test in a number of settings. TTR is easily followed in the underweight and the high risk populations in an ambulatory setting, which has a significant background risk of chronic diseases.  It is sensitive to the systemic inflammatory response syndrom (SIRS), and needs to be understood in the context of acute illness to be used effectively. There are a number of physiologic changes associated with SIRS and the injury/repair process that will affect TTR and will be put in context in this review. The most important point is that in the context of an ICU setting, the contribution of TTR is significant in a complex milieu.  copyright @ Bentham Publishers Ltd. 2009.

Transthyretin as a marker to predict outcome in critically ill patients.
Arun Devakonda, Liziamma George, Suhail Raoof, Adebayo Esan, Anthony Saleh, Larry H. Bernstein.
Clin Biochem Oct 2008; 41(14-15): 1126-1130

A determination of TTR level is an objective method od measuring protein catabolic loss of severly ill patients and numerous studies show that TTR levels correlate with patient outcomes of non-critically ill patients. We evaluated whether TTR level correlates with the prevalence of PEM in the ICUand evaluated serum TTR level as an indicator of the effectiveness of nutrition support and the prognosis in critically ill patients.

TTR showed excellent concordance with patients classified with PEM or at high malnutrition risk, and followed for 7 days, it is a measure of the metabolic burden. TTR levels did not respond early to nutrition support because of the delayed return to anabolic status. It is particularly helpful in removing interpretation bias, and it is an excellent measure of the systemic inflammatory response concurrent with a preexisting state of chronic inanition.

 The Stressful Condition as a Nutritionally Dependent Adaptive Dichotomy

Yves Ingenbleek and Larry Bernstein
Nutrition 1999;15(4):305-320 PII S0899-9007(99)00009-X

The injured body manifests a cascade of cytokine-induced metabolic events aimed at developing defense mechanisms and tissue repair. Rising concentrations of counterregulatory hormones work in concert with cytokines to generate overall insulin and insulin-like growth factor 1 (IGF-1), postreceptor resistance and energy requirements grounded on lipid dependency. Dalient features are self-sustained hypercortisolemia persisting as long as cytokines are oversecreted and down-regulation of the hypothalamo-pituitary-thyroid axis stabilized at low basal levels. Inhibition of thyroxine 5’deiodinating activity (5’DA) accounts for the depressed T3 values associated with the sparing of both N and energy-consuming processes. Both the liver and damaged territories adapt to stressful signals along up-regulated pathways disconnected from the central and peripheral control systems. Cytokines stimulate 5’DA and suppress the synthesis of TTR, causing the drop of retinol-binding protein (RBP) and the leakage of increased amounts of T4 and retinol in free form. TTR and RBP thus work as prohormonal reservoirs of precursor molecules which need to be converted into bioactive derivatives (T3 and retinoic acids) to reach transcriptional efficiency. The converting steps (5’DA and cellular retinol-binding protein-1) are activated to T4 and retinol, themselves operating as limiting factors to positive feedback loops. …The suicidal behavior of TBG, CBG, and IGFBP-3 allows the occurrence of peak endocrine and mitogenic influences at the site of inflammation. The production rate of TTR by the liver is the main determinant of both the hepatic release and blood transport of holoRBP, which explains why poor nutritional status concomitantly impairs thyroid- and retinoid-dependent acute phase responses, hindering the stressed body to appropriately face the survival crisis.  …
abbreviations: TBG, thyroxine-binding globulain; CBG, cortisol-binding globulin; IGFBP-3, insulin growth factor binding protein-3; TTR, transthyretin; RBP, retionol-binding protein.

Why Should Plasma Transthyretin Become a Routine Screening Tool in Elderly Persons? 

Yves Ingenbleek.
J Nutrition, Health & Aging 2009.

The homotetrameric TTR molecule (55 kDa as MM) was first identified in cerebrospinal fluid (CSF).  The initial name of prealbumin (PA)  was assigned based on the electrophoretic migration anodal to albumin. PA was soon recognized as a specific binding protein for thyroid hormone. and also of plasma retinol through the mediation of the small retinol-binding protein (RBP, 21 kDa as MM), which has a circulating half-life half that of TTR (24 h vs 48 h).

There exist at least 3 goos reasons why TTR should become a routine medical screening test in elderly persons.  The first id grounded on the assessment of protein nutritional status that is frequently compromized and may become a life threatening condition.  TTR was proposed as a marker of protein-energy malnutrition (PEM) in 1972. As a result of protein and energy deprivation, TTR hepatic synthesis is suppressed whereas all plasma indispensable amino acids (IAAs) manifest declining trends with the sole exception of methionine (Met) whose concentration usually remains unmodified. By comparison with ALB and transferrin (TF) plasma values, TTR did reveal a much higher degree of reactivity to changes in protein status that has been attributed to its shorter biological half-life and to its unusual tryptophan richness. The predictive ability of outcome offered by TTR is independent of that provided by ALB and TF. Uncomplicated PEM primarily affects the size of body nitrogen (N) pools, allowing reduced protein syntheses to levels compatible with survival.  These adaptiver changes are faithfully identified by the serial measurement of TTR whose reliability has never been disputed in protein-depleted states. On the contrary, the nutritional relevance of TTR has been controverted in acute and chronic inflammatory conditions due to the cytokine-induced transcriptional blockade of liver synthesis which is an obligatory step occurring independently from the prevailing nutritional status. Although PEM and stress ful disorders refer to distinct pathogenic mechanisms, their combined inhibitory effects on TTR liber production fueled a long-lasting strife regarding a poor specificity.  Recent body compositional studies have contributed to disentagling these intermingled morbidities, showing that evolutionary patterns displayed by plasma TTR are closely correlated with the fluctuations of lean body mass (LBM).

The second reason follows from advances describing the unexpected relationship established between TTR and homocysteine (Hcy), a S-containing AA not found in customary diets but resulting from the endogenous transmethylation of dietary methionine.  Hcy may be recycled to Met along a remethylation pathway (RM) or irreversibly degraded throughout the transsulfuration (TS) cascade to relase sulfaturia as end-product. Hcy is thus situated at the crossrad of RM and TS pathways which are in equilibrium keeping plasma Met values unaltered.  Three dietary water soluble B viatamins are implicated in the regulation of the Hcy-Met cycle. Folates (vit B9) are the most powerful agent, working as a supplier of the methyl group required for the RM process whereas cobalamines (vit B12) and pyridoxine (vit B6) operate as cofactors of Met-synthase and cystathionine-β-synthase.  Met synthase promotes the RM pathway whereas the rate-limiting CβS governs the TS degradative cascade. Dietary deficiency in any of the 3 vitamins may upregulate Hcy plasma values, an acquied biochemiucal anomaly increasingly encountered in aged populations.

The third reason refers to recent and fascinating data recorded in neurobiology and emphasizing the specific properties of TTR in the prevention of brain deterioration. TTR participates directly in the maintenance of memory and normal cognitive processes during the aging process by acting on the retinoid signaling pathway.  Moreover, TTR may bind amyloid β peptide in vitro, preventing its transformation into toxic amyloid fibrils and amyloid plaques.  TTR works as a limiting factor for the plasma transport of retinoid, which in turn operates as a limiting determinant of both physiologically active retinoic acid (RA) derivatives, implying that any fluctuation in protein status might well entail corresponding  alterations in cellular bioavailability of retinoid compounds.  Under normal aging circumstances, the concentration of retinoid compounds declines in cerebral tissues together with the downregulation of RA receptor expression. In animal models, depletion of RAs causes the deposition of amyloid-β peptides, favoring the formation of amyloid plaques.

Prealbumin and Nutritional Evaluation

Larry Bernstein, Walter Pleban
Nutrition Apr 1996; 12(4):255-259.
http://nutritionjrnl.com/article/S0899-9007(96)90852-7

We compressed 16-test-pattern classes of albumin (ALB), cholesterol (CHOL), and total protein (TPR) in 545 chemistry profiles to 4 classes by conveerting decision values to a number code to separate malnourished (1 or 2) from nonmalnourished (NM)(0) patients using as cutoff values for NM (0), mild (1), and moderate (2): ALB 35, 27 g/L; TPR 63, 53 g/L; CHOL 3.9, 2.8 mmol/L; and BUN 9.3, 3.6 mmol/L. The BUN was found to have  to have too low an S-value to make a contribution to the compressed classification. The cutoff values for classifying the data were assigned prior to statistical analysis, after examining information in the structured data. The data was obtained by a natural experiment in which the test profiles routinely done by the laboratory were randomly extracted. The analysis identifies the values used that best classify the data and are not dependent on distributional assumptions. The data were converted to 0, 1, or 2 as outcomes, to create a ternary truth table (eaxch row in nnn, the n value is 0 to 2). This allows for 3(81) possible patterns, without the inclusion of prealbumin (TTR). The emerging system has much fewer patterns in the information-rich truth table formed (a purposeful, far from random event). We added TTR, coded, and examined the data from 129 patients. The classes are a compressed truth table of n-coded patterns with outcomes of 0, 1, or 2 with protein-energy malnutrition (PEM) increasing from an all-0 to all-2 pattern.  Pattern class (F=154), PAB (F=35), ALB (F=56), and CHOL (F=18) were different across PEM class and predicted PEM class (R-sq. = 0.7864, F=119, p < E-5). Kruskall-Wallis analysis of class by ranks was significant for pattern class E-18), TTR (6.1E-15) ALB (E-16), CHOL (9E-10), and TPR (5E-13). The medians and standard error (SEM) for TTR, ALB, and CHOL of four TTR classes (NM, mild, mod, severe) are: TTR = 209, 8.7; 159, 9.3; 137, 10.4; 72, 11.1 mg/L. ALB – 36, 0.7; 30.5, 0.8; 25.0, 0.8; 24.5, 0.8 g/L. CHOL = 4.43, 0.17; 4.04, 0.20; 3.11, 0.21; 2.54, 0.22 mmol/L. TTR and CHOL values show the effect of nutrition support on TTR and CHOL in PEM. Moderately malnourished patients receiving nutrition support have TTR values in the normal range at 137 mg/L and at 159 mg/L when the ALB is at 25 g/L or at 30.5 g/L.

An Informational Approach to Likelihood of Malnutrition 

Larry Bernstein, Thomas Shaw-Stiffel, Lisa Zarney, Walter Pleban.
Nutrition Nov 1996;12(11):772-776.  PII: S0899-9007(96)00222-5.
http://dx.doi.org:/nutritionjrnl.com/article/S0899-9007(96)00222-5

Unidentified protein-energy malnutrition (PEM) is associated with comorbidities and increased hospital length of stay. We developed a model for identifying severe metabolic stress and likelihood of malnutrition using test patterns of albumin (ALB), cholesterol (CHOL), and total protein (TP) in 545 chemistry profiles…They were compressed to four pattern classes. ALB (F=170), CHOL (F = 21), and TP (F = 5.6) predicted PEM class (R-SQ = 0.806, F= 214; p < E^-6), but pattern class was the best predictor (R-SQ = 0.900, F= 1200, p< E^-10). Ktuskal-Wallis analysis of class by ranks was significant for pattern class (E^18), ALB (E^-18), CHOL (E^-14), TP (@E^-16). The means and SEM for tests in the three PEM classes (mild, mod, severe) were; ALB – 35.7, 0.8; 30.9, 0.5; 24.2, 0.5 g/L. CHOL – 3.93, 0.26; 3.98, 0.16; 3.03, 0.18 µmol/L, and TP – 68.8, 1.7; 60.0, 1.0; 50.6, 1.1 g/L. We classified patients at risk of malnutrition using truth table comprehension.

Downsizing of Lean Body Mass is a Key Determinant of Alzheimer’s Disease

Yves Ingenbleek, Larry Bernstein
J Alzheimer’s Dis 2015; 44: 745-754.
http://dx.doi.org:/10.3233/JAD-141950

Lean body mass (LBM) encompasses all metabolically active organs distributed into visceral and structural tissue compartments and collecting the bulk of N and K stores of the human body. Transthyretin (TTR)  is a plasma protein mainly secreted by the liver within a trimolecular TTR-RBP-retinol complex revealing from birth to old age strikingly similar evolutionary patterns with LBM in health and disease. TTR is also synthesized by the choroid plexus along distinct regulatory pathways. Chronic dietary methionine (Met) deprivation or cytokine-induced inflammatory disorders generates LBM downsizing following differentiated physiopathological processes. Met-restricted regimens downregulate the transsulfuration cascade causing upstream elevation of homocysteine (Hcy) safeguarding Met homeostasis and downstream drop of hydrogen sulfide (H2S) impairing anti-oxidative capacities. Elderly persons constitute a vulnerable population group exposed to increasing Hcy burden and declining H2S protection, notably in plant-eating communities or in the course of inflammatory illnesses. Appropriate correction of defective protein status and eradication of inflammatory processes may restore an appropriate LBM size allowing the hepatic production of the retinol circulating complex to resume, in contrast with the refractory choroidal TTR secretory process. As a result of improved health status, augmented concentrations of plasma-derived TTR and retinol may reach the cerebrospinal fluid and dismantle senile amyloid plaques, contributing to the prevention or the delay of the onset of neurodegenerative events in elderly subjects at risk of Alzheimer’s disease.

Amyloidogenic and non-amyloidogenic transthyretin variants interact differently with human cardiomyocytes: insights into early events of non-fibrillar tissue damage

Pallavi Manral and Natalia Reixach
Biosci.Rep.(2015)/35/art:e00172 http://dx.doi.org:/10.1042/BSR20140155

TTR (transthyretin) amyloidosis are diseases characterized by the aggregation and extracellular deposition of the normally soluble plasma protein TTR. Ex vivo and tissue culture studies suggest that tissue damage precedes TTR fibril deposition, indicating that early events in the amyloidogenic cascade have an impact on disease development. We used a human cardiomyocyte tissue culture model system to define these events. We previously described that the amyloidogenic V122I TTR variant is cytotoxic to human cardiac cells, whereas the naturally occurring, stable and non-amyloidogenic T119M TTR variant is not. We show that most of the V122I TTR interacting with the cells is extracellular and this interaction is mediated by a membraneprotein(s). In contrast, most of the non-amyloidogenic T119M TTR associated with the cells is intracellular where it undergoes lysosomal degradation. The TTR internalization process is highly dependent on membrane cholesterol content. Using a fluorescent labelled V122I TTR variant that has the same aggregation and cytotoxic potential as the native V122I TTR, we determined that its association with human cardiomyocytes is saturable with a KD near 650nM. Only amyloidogenic V122I TTR compete with fluorescent V122I force ll-binding sites. Finally, incubation of the human cardiomyocytes with V122I TTR but not with T119M TTR, generates superoxide species and activates caspase3/7. In summary, our results show that the interaction of the amyloidogenic V122I TTR is distinct from that of a non-amyloidogenic TTR variant and is characterized by its retention at the cell membrane, where it initiates the cytotoxic cascade.

Emerging roles for retinoids in regeneration and differentiation in normal and disease states

Lorraine J. Gudas
Biochimica et Biophysica Acta 1821 (2012) 213–221
http://dx.doi.org:/10.1016/j.bbalip.2011.08.002

The vitamin (retinol) metabolite, all-transretinoic acid (RA), is a signaling molecule that plays key roles in the development of the body plan and induces the differentiation of many types of cells. In this review the physiological and pathophysiological roles of retinoids (retinol and related metabolites) in mature animals are discussed. Both in the developing embryo and in the adult, RA signaling via combinatorial Hoxgene expression is important for cell positional memory. The genes that require RA for the maturation/differentiation of T cells are only beginning to be cataloged, but it is clear that retinoids play a major role in expression of key genes in the immune system. An exciting, recent publication in regeneration research shows that ALDH1a2(RALDH2), which is the rate-limiting enzyme in the production of RA from retinaldehyde, is highly induced shortly after amputation in the regenerating heart, adult fin, and larval fin in zebrafish. Thus, local generation of RA presumably plays a key role in fin formation during both embryogenesis and in fin regeneration. HIV transgenic mice and human patients with HIV-associated kidney disease exhibit a profound reduction in the level of RARβ protein in the glomeruli, and HIV transgenic mice show reduced retinol dehydrogenase levels, concomitant with a greater than 3-fold reduction in endogenous RA levels in the glomeruli. Levels of endogenous retinoids (those synthesized from retinol within cells) are altered in many different diseases in the lung, kidney, and central nervous system, contributing to pathophysiology.

The Membrane Receptor for Plasma Retinol-Binding Protein, A New Type of Cell-Surface Receptor

Hui Sun and Riki Kawaguchi
Intl Review Cell and Molec Biol, 2011; 288:Chap 1. Pp 1:34
http://dx.doi.org:/10.1016/B978-0-12-386041-5.00001-7

Vitamin A is essential for diverse aspects of life ranging from embryogenesis to the proper functioning of most adul torgans. Its derivatives (retinoids) have potent biological activities such as regulating cell growth and differentiation. Plasma retinol-binding protein (RBP) is the specific vitamin A carrier protein in the blood that binds to vitamin A with high affinity and delivers it to target organs. A large amount of evidence has accumulated over the past decades supporting the existence of a cell-surface receptor for RBP that mediates cellular vitamin A uptake. Using an unbiased strategy, this specific cell-surface RBP receptor has been identified as STRA6, a multi-transmembrane domain protein with previously unknown function. STRA6 is not homologous to any protein of known function and represents a new type of cell-surface receptor. Consistent with the diverse functions of vitamin A, STRA6 is widely expressed in embryonic development and in adult organ systems. Mutations in human STRA6 are associated with severe pathological phenotypes in many organs
such as the eye, brain, heart, and lung. STRA6 binds to RBP with high affinity and mediates vitamin A uptake into cells. This review summarizes the history of the RBP receptor research, its expression in the context of known functions of vitamin A in distinct human organs, structure/function analysis of this new type of membrane receptor, pertinent questions regarding its very existence, and its potential implication in treating human diseases.

Choroid plexus dysfunction impairs beta-amyloid clearance in a triple transgenic mouse model of Alzheimer’s disease

Ibrahim González-Marrero, Lydia Giménez-Llort, Conrad E. Johanson, et al.
Front Cell Neurosc  Feb2015; 9(17): 1-10
http://dx.doi.org:/10.3389/fncel.2015.00017

Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Aβ) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer’s disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: β-amyloid (Aβ) plaques and neurofibrillary tangles (NFT) with a temporal-and regional-specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Aβ in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Aβ42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Aβ transporters: the low density lipoprotein receptor-related protein1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin(TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Aβ burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Aβ) and diminished secretion of TTR (less neuroprotection against cortical Aβ toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD.

Endoplasmic reticulum: The unfolded protein response is tangled In neurodegeneration

Jeroen J.M. Hoozemans, Wiep Scheper
Intl J Biochem & Cell Biology 44 (2012) 1295–1298
http://dx.doi.org/10.1016/j.biocel.2012.04.023

Organelle facts•The ER is involved in the folding and maturation ofmembrane-bound and secreted proteins.•The ER exerts protein quality control to ensure correct folding and to detect and remove misfolded proteins.•Disturbance of ER homeostasis leads to protein misfolding and induces the UPR.•Activation of the UPR is aimed to restore proteostasis via an intricate transcriptional and (post)translational signaling network.•In neurodegenerative diseases classified as tauopathies the activation of the UPR coincides with the pathogenic accumulation of the microtubule associated protein tau.•The involvement of the UPR in tauopathies makes it a potential therapeutic target.

The endoplasmic reticulum (ER) is involved in the folding and maturation of membrane-bound and secreted proteins. Disturbed homeostasis in the ER can lead to accumulation of misfolded proteins, which trigger a stress response called the unfolded protein response (UPR). In neurodegenerative diseases that are classified as tauopathies, activation of the UPR coincides with the pathogenic accumulation of the microtubule associated protein tau. Several lines of evidence indicate that UPR activation contributes to increased levels of phosphorylated tau, a prerequisite for the formation of tau aggregates. Increased understanding of the crosstalk between signaling pathways involved in protein quality control in the ERand tau phosphorylation will support the development of new therapeutic targets that promote neuronal survival.

Chemical and/or biological therapeutic strategies to ameliorate protein misfolding diseases

Derrick Sek Tong Ong and Jeffery W Kelly
Current Opin Cell Biol 2011; 23:231–238
http://dx.doi.org:/10.1016/j.ceb.2010.11.002

Inheriting a mutant misfolding-prone protein that cannot be efficiently folded in a given cell type(s) results in a spectrum of human loss-of-function misfolding diseases. The inability of the biological protein maturation pathways to adapt to a specific misfolding-prone protein also contributes to pathology. Chemical and biological therapeutic strategies are presented that restore protein homeostasis, or proteostasis, either by enhancing the biological capacity of the proteostasis network or through small molecule stabilization of a specific misfolding-prone protein. Herein, we review the recent literature on therapeutic strategies to ameliorate protein misfolding diseases that function through either of these mechanisms, or a combination thereof, and provide our perspective on the promise of alleviating protein misfolding diseases by taking advantage of proteostasis adaptation.

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