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Archive for the ‘Cancer – General’ Category


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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Live Coverage: MedCity Converge 2018 Philadelphia: AI in Cancer and Keynote Address

Reporter: Stephen J. Williams, PhD

8:30 AM -9:15

Practical Applications of AI in Cancer

We are far from machine learning dictating clinical decision making, but AI has important niche applications in oncology. Hear from a panel of innovative startups and established life science players about how machine learning and AI can transform different aspects in healthcare, be it in patient recruitment, data analysis, drug discovery or care delivery.

Moderator: Ayan Bhattacharya, Advanced Analytics Specialist Leader, Deloitte Consulting LLP
Speakers:
Wout Brusselaers, CEO and Co-Founder, Deep 6 AI @woutbrusselaers ‏
Tufia Haddad, M.D., Chair of Breast Medical Oncology and Department of Oncology Chair of IT, Mayo Clinic
Carla Leibowitz, Head of Corporate Development, Arterys @carlaleibowitz
John Quackenbush, Ph.D., Professor and Director of the Center for Cancer Computational Biology, Dana-Farber Cancer Institute

Ayan: working at IBM and Thompon Rueters with structured datasets and having gone through his own cancer battle, he is now working in healthcare AI which has an unstructured dataset(s)

Carla: collecting medical images over the world, mainly tumor and calculating tumor volumetrics

Tufia: drug resistant breast cancer clinician but interested in AI and healthcareIT at Mayo

John: taking large scale datasets but a machine learning skeptic

moderator: how has imaging evolved?

Carla: ten times images but not ten times radiologists so stressed field needs help with image analysis; they have seen measuring lung tumor volumetrics as a therapeutic diagnostic has worked

moderator: how has AI affected patient recruitment?

Tufia: majority of patients are receiving great care but AI can offer profiles and determine which patients can benefit from tertiary care;

John: 1980 paper on no free lunch theorem; great enthusiasm about optimization algortihisms fell short in application; can extract great information from e.g. images

moderator: how is AI for healthcare delivery working at mayo?

Tufia: for every hour with patient two hours of data mining. for care delivery hope to use the systems to leverage the cognitive systems to do the data mining

John: problem with irreproducible research which makes a poor dataset:  also these care packages are based on population data not personalized datasets; challenges to AI is moving correlation to causation

Carla: algorithisms from on healthcare network is not good enough, Google tried and it failed

John: curation very important; good annotation is needed; needed to go in and develop, with curators, a systematic way to curate medial records; need standardization and reproducibility; applications in radiometrics can be different based on different data collection machines; developed a machine learning model site where investigators can compare models on a hub; also need to communicate with patients on healthcare information and quality information

Ayan: Australia and Canada has done the most concerning AI and lifescience, healthcare space; AI in most cases is cognitive learning: really two types of companies 1) the Microsofts, Googles, and 2) the startups that may be more pure AI

 

Final Notes: We are at a point where collecting massive amounts of healthcare related data is simple, rapid, and shareable.  However challenges exist in quality of datasets, proper curation and annotation, need for collaboration across all healthcare stakeholders including patients, and dissemination of useful and accurate information

 

9:15 AM–9:45 AM

Opening Keynote: Dr. Joshua Brody, Medical Oncologist, Mount Sinai Health System

The Promise and Hype of Immunotherapy

Immunotherapy is revolutionizing oncology care across various types of cancers, but it is also necessary to sort the hype from the reality. In his keynote, Dr. Brody will delve into the history of this new therapy mode and how it has transformed the treatment of lymphoma and other diseases. He will address the hype surrounding it, why so many still don’t respond to the treatment regimen and chart the way forward—one that can lead to more elegant immunotherapy combination paths and better outcomes for patients.

Speaker:
Joshua Brody, M.D., Assistant Professor, Mount Sinai School of Medicine @joshuabrodyMD

Director Lymphoma therapy at Mt. Sinai

  • lymphoma a cancer with high PD-L1 expression
  • hodgkin’s lymphoma best responder to PD1 therapy (nivolumab) but hepatic adverse effects
  • CAR-T (chimeric BCR and TCR); a long process which includes apheresis, selection CD3/CD28 cells; viral transfection of the chimeric; purification
  • complete remissions of B cell lymphomas (NCI trial) and long term remissions past 18 months
  • side effects like cytokine release (has been controlled); encephalopathy (he uses a hand writing test to see progression of adverse effect)

Vaccines

  •  teaching the immune cells as PD1 inhibition exhausting T cells so a vaccine boost could be an adjuvant to PD1 or checkpoint therapy
  • using Flt3L primed in-situ vaccine (using a Toll like receptor agonist can recruit the dendritic cells to the tumor and then activation of T cell response);  therefore vaccine does not need to be produced ex vivo; months after the vaccine the tumor still in remission
  • versus rituximab, which can target many healthy B cells this in-situ vaccine strategy is very specific for the tumorigenic B cells
  • HoWEVER they did see resistant tumor cells which did not overexpress PD-L1 but they did discover a novel checkpoint (cannot be disclosed at this point)

 

 

 

 

 

 

 

 

 

Please follow on Twitter using the following #hashtags and @pharma_BI

#MCConverge

#AI

#cancertreatment

#immunotherapy

#healthIT

#innovation

#precisionmedicine

#healthcaremodels

#personalizedmedicine

#healthcaredata

And at the following handles:

@pharma_BI

@medcitynews

 

Please see related articles on Live Coverage of Previous Meetings on this Open Access Journal

LIVE – Real Time – 16th Annual Cancer Research Symposium, Koch Institute, Friday, June 16, 9AM – 5PM, Kresge Auditorium, MIT

Real Time Coverage and eProceedings of Presentations on 11/16 – 11/17, 2016, The 12th Annual Personalized Medicine Conference, HARVARD MEDICAL SCHOOL, Joseph B. Martin Conference Center, 77 Avenue Louis Pasteur, Boston

Tweets Impression Analytics, Re-Tweets, Tweets and Likes by @AVIVA1950 and @pharma_BI for 2018 BioIT, Boston, 5/15 – 5/17, 2018

BIO 2018! June 4-7, 2018 at Boston Convention & Exhibition Center

https://pharmaceuticalintelligence.com/press-coverage/

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

 

The CRISPR-Cas9 system has proven to be a powerful tool for genome editing allowing for the precise modification of specific DNA sequences within a cell. Many efforts are currently underway to use the CRISPR-Cas9 system for the therapeutic correction of human genetic diseases. CRISPR/Cas9 has revolutionized our ability to engineer genomes and conduct genome-wide screens in human cells.

 

CRISPR–Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9.

 

Whereas some cell types are amenable to genome engineering, genomes of human pluripotent stem cells (hPSCs) have been difficult to engineer, with reduced efficiencies relative to tumour cell lines or mouse embryonic stem cells. Using hPSC lines with stable integration of Cas9 or transient delivery of Cas9-ribonucleoproteins (RNPs), an average insertion or deletion (indel) efficiency greater than 80% was achieved. This high efficiency of insertion or deletion generation revealed that double-strand breaks (DSBs) induced by Cas9 are toxic and kill most hPSCs.

 

The toxic response to DSBs was P53/TP53-dependent, such that the efficiency of precise genome engineering in hPSCs with a wild-type P53 gene was severely reduced. These results indicate that Cas9 toxicity creates an obstacle to the high-throughput use of CRISPR/Cas9 for genome engineering and screening in hPSCs. As hPSCs can acquire P53 mutations, cell replacement therapies using CRISPR/Cas9-enginereed hPSCs should proceed with caution, and such engineered hPSCs should be monitored for P53 function.

 

CRISPR-based editing of T cells to treat cancer, as scientists at the University of Pennsylvania are studying in a clinical trial, should also not have a p53 problem. Nor should any therapy developed with CRISPR base editing, which does not make the double-stranded breaks that trigger p53. But, there are pre-existing humoral and cell-mediated adaptive immune responses to Cas9 in humans, a factor which must be taken into account as the CRISPR-Cas9 system moves forward into clinical trials.

 

References:

 

https://techonomy.com/2018/06/new-cancer-concerns-shake-crispr-prognosis/

 

https://www.statnews.com/2018/06/11/crispr-hurdle-edited-cells-might-cause-cancer/

 

https://www.biorxiv.org/content/early/2017/07/26/168443

 

https://www.nature.com/articles/s41591-018-0049-z.epdf?referrer_access_token=s92jDP_yPBmDmi-USafzK9RgN0jAjWel9jnR3ZoTv0MRjuB3dEnTctGtoy16n3DDbmISsvbln9SCISHVDd73tdQRNS7LB8qBlX1vpbLE0nK_CwKThDGcf344KR6RAm9k3wZiwyu-Kb1f2Dl7pArs5yYSiSLSdgeH7gst7lOBEh9qIc6kDpsytWLHqX_tyggu&tracking_referrer=www.statnews.com

 

https://www.nature.com/articles/s41591-018-0050-6.epdf?referrer_access_token=2KJ0L-tmvjtQdzqlkVXWVNRgN0jAjWel9jnR3ZoTv0Phq6GCpDlJx7lIwhCzBRjHJv0mv4zO0wzJJCeuxJjzoUWLeemH8T4I3i61ftUBkYkETi6qnweELRYMj4v0kLk7naHF-ujuz4WUf75mXsIRJ3HH0kQGq1TNYg7tk3kamoelcgGp4M7UTiTmG8j0oog_&tracking_referrer=www.statnews.com

 

https://www.biorxiv.org/content/early/2018/01/05/243345

 

https://www.nature.com/articles/nmeth.4293.epdf

 

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Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Curator: Stephen J. Williams, PhD 

Below is a series of posts and articles related to the role of G protein coupled receptors (GPCR) in various chronic diseases.  This is only a cursory collection and by no means represents the complete extensive literature on pathogenesis related to G protein function or alteration thereof.  However it is important to note that, although we think of G protein signaling as rather short lived, quick, their chronic activation may lead to progression of various disease. As to whether disease onset, via GPCR, is a result of sustained signal, loss of desensitization mechanisms, or alterations of transduction systems is an area to be investigated.

From:

Molecular Pathogenesis of Progressive Lung Diseases

Author: Larry H. Bernstein, MD, FCAP

 

Chronic Obstructive Lung Disease (COPD)

Inflammatory and infectious factors are present in diseased airways that interact with G-protein coupled receptors (GPCRs), such as purinergic receptors and bradykinin (BK) receptors, to stimulate phospholipase C [PLC]. This is followed by the activation of inositol 1,4,5-trisphosphate (IP3)-dependent activation of IP3 channel receptors in the ER, which results in channel opening and release of stored Ca2+ into the cytoplasm. When ER Ca2+ stores are depleted a pathway for Ca2+ influx across the plasma membrane is activated. This has been referred to as “capacitative Ca2+ entry”, and “store-operated calcium entry” (3). In the next step PLC mediated Ca2+ i is mobilized as a result of GPCR activation by inflammatory mediators, which triggers cytokine production by Ca2+ i-dependent activation of the transcription factor nuclear factor kB (NF-kB) in airway epithelia.

 

 

 

In Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator discusses findings from a research team at University of California at San Diego (UCSD) which the neuropeptide hormone corticotropin-releasing factor (CRF) as having an important role in the etiology of Alzheimer’s Disease (AD). CRF activates the CRF receptor (a G stimulatory receptor).  It was found inhibition of the CRF receptor prevented cognitive impairment in a mouse model of AD.  Furthermore researchers at the Flanders Interuniversity Institute for Biotechnology found the loss of a protein called G protein-coupled receptor 3 (GPR3) may lower the amyloid plaque aggregation, resulting in improved cognitive function.  Additionally inhibition of several G-protein coupled receptors alter amyloid precursor processing, providing a further mechanism of the role of GPCR in AD (see references in The role of G protein-coupled receptors in the pathology of Alzheimer’s disease by Amantha Thathiah and Bart De Strooper Nature Reviews Feb 2011; 12: 73-87 and read post).

 

In Cardiovascular and Thrombotic Disease

 

Adenosine Receptor Agonist Increases Plasma Homocysteine

 

and read related articles in curation on effects of hormones on the cardiovascular system at

Action of Hormones on the Circulation

 

In Cancer

A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial

 

Further curations and references of G proteins and chronic disease can be found at the Open Access journal https://pharmaceuticalintelligence.com using the search terms “GCPR” and “disease” in the Search box in the upper right of the home page.

 

 

 

 

 

 

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Lesson 9 Cell Signaling:  Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBiol3373

Stephen J. Wiilliams, Ph.D: Curator

The following contain curations of scientific articles from the site https://pharmaceuticalintelligence.com  intended as additional reference material  to supplement material presented in the lecture.

Wnts are a family of lipid-modified secreted glycoproteins which are involved in:

Normal physiological processes including

A. Development:

– Osteogenesis and adipogenesis (Loss of wnt/β‐catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes)

  – embryogenesis including body axis patterning, cell fate specification, cell proliferation and cell migration

B. tissue regeneration in adult tissue

read: Wnt signaling in the intestinal epithelium: from endoderm to cancer

And in pathologic processes such as oncogenesis (refer to Wnt/β-catenin Signaling [7.10]) and to your Powerpoint presentation

 

The curation Wnt/β-catenin Signaling is a comprehensive review of canonical and noncanonical Wnt signaling pathways

 

To review:

 

 

 

 

 

 

 

 

 

 

 

Activating the canonical Wnt pathway frees B-catenin from the degradation complex, resulting in B-catenin translocating to the nucleus and resultant transcription of B-catenin/TCF/LEF target genes.

Fig. 1 Canonical Wnt/FZD signaling pathway. (A) In the absence of Wnt signaling, soluble β-catenin is phosphorylated by a degradation complex consisting of the kinases GSK3β and CK1α and the scaffolding proteins APC and Axin1. Phosphorylated β-catenin is targeted for proteasomal degradation after ubiquitination by the SCF protein complex. In the nucleus and in the absence of β-catenin, TCF/LEF transcription factor activity is repressed by TLE-1; (B) activation of the canonical Wnt/FZD signaling leads to phosphorylation of Dvl/Dsh, which in turn recruits Axin1 and GSK3β adjacent to the plasma membrane, thus preventing the formation of the degradation complex. As a result, β-catenin accumulates in the cytoplasm and translocates into the nucleus, where it promotes the expression of target genes via interaction with TCF/LEF transcription factors and other proteins such as CBP, Bcl9, and Pygo.

NOTE: In the canonical signaling, the Wnt signal is transmitted via the Frizzled/LRP5/6 activated receptor to INACTIVATE the degradation complex thus allowing free B-catenin to act as the ultimate transducer of the signal.

Remember, as we discussed, the most frequent cancer-related mutations of WNT pathway constituents is in APC.

This shows how important the degradation complex is in controlling canonical WNT signaling.

Other cell signaling systems are controlled by protein degradation:

A.  The Forkhead family of transcription factors

Read: Regulation of FoxO protein stability via ubiquitination and proteasome degradation

B. Tumor necrosis factor α/NF κB signaling

Read: NF-κB, the first quarter-century: remarkable progress and outstanding questions

1.            Question: In cell involving G-proteins, the signal can be terminated by desensitization mechanisms.  How is both the canonical and noncanonical Wnt signal eventually terminated/desensitized?

We also discussed the noncanonical Wnt signaling pathway (independent of B-catenin induced transcriptional activity).  Note that the canonical and noncanonical involve different transducers of the signal.

Noncanonical WNT Signaling

Note: In noncanonical signaling the transducer is a G-protein and second messenger system is IP3/DAG/Ca++ and/or kinases such as MAPK, JNK.

Depending on the different combinations of WNT ligands and the receptors, WNT signaling activates several different intracellular pathways  (i.e. canonical versus noncanonical)

 

In addition different Wnt ligands are expressed at different times (temporally) and different cell types in development and in the process of oncogenesis. 

The following paper on Wnt signaling in ovarian oncogenesis shows how certain Wnt ligands are expressed in normal epithelial cells but the Wnt expression pattern changes upon transformation and ovarian oncogenesis. In addition, differential expression of canonical versus noncanonical WNT ligands occur during the process of oncogenesis (for example below the authors describe the noncanonical WNT5a is expressed in normal ovarian  epithelia yet WNT5a expression in ovarian cancer is lower than the underlying normal epithelium. However the canonical WNT10a, overexpressed in ovarian cancer cells, serves as an oncogene, promoting oncogenesis and tumor growth.

Wnt5a Suppresses Epithelial Ovarian Cancer by Promoting Cellular Senescence

Benjamin G. Bitler,1 Jasmine P. Nicodemus,1 Hua Li,1 Qi Cai,2 Hong Wu,3 Xiang Hua,4 Tianyu Li,5 Michael J. Birrer,6Andrew K. Godwin,7 Paul Cairns,8 and Rugang Zhang1,*

A.           Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy in the US. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a non-canonical Wnt ligand that plays a context-dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We demonstrate that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; p = 0.039) or fallopian tube epithelium (n = 28; p < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (p = 0.003) and predicts shorter overall survival in EOC patients (p = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/β-catenin signaling and induces cellular senescence by activating the histone repressor A (HIRA)/promyelocytic leukemia (PML) senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy.

Oncol Lett. 2017 Dec;14(6):6611-6617. doi: 10.3892/ol.2017.7062. Epub 2017 Sep 26.

Clinical significance and biological role of Wnt10a in ovarian cancer. 

Li P1Liu W1Xu Q1Wang C1.

Ovarian cancer is one of the five most malignant types of cancer in females, and the only currently effective therapy is surgical resection combined with chemotherapy. Wnt family member 10A (Wnt10a) has previously been identified to serve an oncogenic function in several tumor types, and was revealed to have clinical significance in renal cell carcinoma; however, there is still only limited information regarding the function of Wnt10a in the carcinogenesis of ovarian cancer. The present study identified increased expression levels of Wnt10a in two cell lines, SKOV3 and A2780, using reverse transcription-polymerase chain reaction. Functional analysis indicated that the viability rate and migratory ability of SKOV3 cells was significantly inhibited following Wnt10a knockdown using short interfering RNA (siRNA) technology. The viability rate of SKOV3 cells decreased by ~60% compared with the control and the migratory ability was only ~30% of that in the control. Furthermore, the expression levels of β-catenin, transcription factor 4, lymphoid enhancer binding factor 1 and cyclin D1 were significantly downregulated in SKOV3 cells treated with Wnt10a-siRNA3 or LGK-974, a specific inhibitor of the canonical Wnt signaling pathway. However, there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974, which indicated that Wnt10a activated the Wnt/β-catenin signaling pathway in SKOV3 cells. In addition, using quantitative PCR, Wnt10a was overexpressed in the tumor tissue samples obtained from 86 patients with ovarian cancer when compared with matching paratumoral tissues. Clinicopathological association analysis revealed that Wnt10a was significantly associated with high-grade (grade III, P=0.031) and late-stage (T4, P=0.008) ovarian cancer. Furthermore, the estimated 5-year survival rate was 18.4% for patients with low Wnt10a expression levels (n=38), whereas for patients with high Wnt10a expression (n=48) the rate was 6.3%. The results of the present study suggested that Wnt10a serves an oncogenic role during the carcinogenesis and progression of ovarian cancer via the Wnt/β-catenin signaling pathway.

Targeting the Wnt Pathway includes curations of articles related to the clinical development of Wnt signaling inhibitors as a therapeutic target in various cancers including hepatocellular carcinoma, colon, breast and potentially ovarian cancer.

 

2.         Question: Given that different Wnt ligands and receptors activate different signaling pathways, AND  WNT ligands  can be deferentially and temporally expressed  in various tumor types and the process of oncogenesis, how would you approach a personalized therapy targeting the WNT signaling pathway?

3.         Question: What are the potential mechanisms of either intrinsic or acquired resistance to Wnt ligand antagonists being developed?

 

Other related articles published in this Open Access Online Scientific Journal include the following:

Targeting the Wnt Pathway [7.11]

Wnt/β-catenin Signaling [7.10]

Cancer Signaling Pathways and Tumor Progression: Images of Biological Processes in the Voice of a Pathologist Cancer Expert

e-Scientific Publishing: The Competitive Advantage of a Powerhouse for Curation of Scientific Findings and Methodology Development for e-Scientific Publishing – LPBI Group, A Case in Point 

Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies

 

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Energy dysfunction detected in skin cells a possible additional explanation of the Alzheimer’s disease’s hallmark Dementia

Reporter: Aviva Lev-Ari, PhD, RN

A team at Harvard-affiliated McLean Hospital tested the cells of late-onset Alzheimer’s patients and found malfunctions in their energy production, including problems with the health of their mitochondria, the cellular power plants that provide most of their energy.

The brain, because it is the body’s most energy-hungry organ, demanding as much as 20 times the energy of other tissues. Such a malfunction, he said, could damage or kill nerve cells and help explain the cognitive decline associated with the disease.

McLean researchers detect dysfunction in cells’ energy production in late-onset patients

“Although people hope with a lot of these conditions we study — normal or abnormal — that there are going to be simple answers … it’s never simple, it’s always all kinds of factors interacting to determine whether you get lucky or not, whether you get sick or not,” Cohen said.

The next step, Cohen said, will be to do a similar study on the neurons and other brain cells of Alzheimer’s patients, to see whether the energy dysfunction detected in skin cells is replicated there. Even if medical understanding of the disease remains imperfect, Cohen said the ultimate hope is to find an intervention that interrupts Alzheimer’s most devastating effects.

“You don’t have to fix everything to keep somebody from getting sick,” Cohen said. “The reason somebody gets sick is you’re unlucky five different ways and it all combines to tip you over the edge. Maybe you only need to fix one of them and you don’t tip over the edge anymore.”

SOURCE

https://news.harvard.edu/gazette/story/2017/11/new-clues-to-alzheimers-disease/

Other related articles on Mitochondria’s functions published in this Open Access Online Scientific Journal include the following:

Search all +5,200 Journal articles for “Mitochondria”

https://pharmaceuticalintelligence.com/?s=Mitochondria

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation – Articles of Note, LPBI Group’s Scientists @ http://pharmaceuticalintelligence.com

https://www.linkedin.com/pulse/proteomics-metabolomics-signaling-pathways-cell-lev-ari-phd-rn/

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

 

A mutated gene called RAS gives rise to a signalling protein Ral which is involved in tumour growth in the bladder. Many researchers tried and failed to target and stop this wayward gene. Signalling proteins such as Ral usually shift between active and inactive states.

 

So, researchers next tried to stop Ral to get into active state. In inacvtive state Ral exposes a pocket which gets closed when active. After five years, the researchers found a small molecule dubbed BQU57 that can wedge itself into the pocket to prevent Ral from closing and becoming active. Now, BQU57 has been licensed for further development.

 

Researchers have a growing genetic data on bladder cancer, some of which threaten to overturn the supposed causes of bladder cancer. Genetics has also allowed bladder cancer to be reclassified from two categories into five distinct subtypes, each with different characteristics and weak spots. All these advances bode well for drug development and for improved diagnosis and prognosis.

 

Among the groups studying the genetics of bladder cancer are two large international teams: Uromol (named for urology and molecular biology), which is based at Aarhus University Hospital in Denmark, and The Cancer Genome Atlas (TCGA), based at institutions in Texas and Boston. Each team tackled a different type of cancer, based on the traditional classification of whether or not a tumour has grown into the muscle wall of the bladder. Uromol worked on the more common, earlier form, non-muscle-invasive bladder cancer, whereas TCGA is looking at muscle-invasive bladder cancer, which has a lower survival rate.

 

The Uromol team sought to identify people whose non-invasive tumours might return after treatment, becoming invasive or even metastatic. Bladder cancer has a high risk of recurrence, so people whose non-invasive cancer has been treated need to be monitored for many years, undergoing cystoscopy every few months. They looked for predictive genetic footprints in the transcriptome of the cancer, which contains all of a cell’s RNA and can tell researchers which genes are turned on or off.

 

They found three subgroups with distinct basal and luminal features, as proposed by other groups, each with different clinical outcomes in early-stage bladder cancer. These features sort bladder cancer into genetic categories that can help predict whether the cancer will return. The researchers also identified mutations that are linked to tumour progression. Mutations in the so-called APOBEC genes, which code for enzymes that modify RNA or DNA molecules. This effect could lead to cancer and cause it to be aggressive.

 

The second major research group, TCGA, led by the National Cancer Institute and the National Human Genome Research Institute, that involves thousands of researchers across USA. The project has already mapped genomic changes in 33 cancer types, including breast, skin and lung cancers. The TCGA researchers, who study muscle-invasive bladder cancer, have looked at tumours that were already identified as fast-growing and invasive.

 

The work by Uromol, TCGA and other labs has provided a clearer view of the genetic landscape of early- and late-stage bladder cancer. There are five subtypes for the muscle-invasive form: luminal, luminal–papillary, luminal–infiltrated, basal–squamous, and neuronal, each of which is genetically distinct and might require different therapeutic approaches.

 

Bladder cancer has the third-highest mutation rate of any cancer, behind only lung cancer and melanoma. The TCGA team has confirmed Uromol research showing that most bladder-cancer mutations occur in the APOBEC genes. It is not yet clear why APOBEC mutations are so common in bladder cancer, but studies of the mutations have yielded one startling implication. The APOBEC enzyme causes mutations early during the development of bladder cancer, and independent of cigarette smoke or other known exposures.

 

The TCGA researchers found a subset of bladder-cancer patients, those with the greatest number of APOBEC mutations, had an extremely high five-year survival rate of about 75%. Other patients with fewer APOBEC mutations fared less well which is pretty surprising.

 

This detailed knowledge of bladder-cancer genetics may help to pinpoint the specific vulnerabilities of cancer cells in different people. Over the past decade, Broad Institute researchers have identified more than 760 genes that cancer needs to grow and survive. Their genetic map might take another ten years to finish, but it will list every genetic vulnerability that can be exploited. The goal of cancer precision medicine is to take the patient’s tumour and decode the genetics, so the clinician can make a decision based on that information.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/29117162

 

https://www.ncbi.nlm.nih.gov/pubmed/27321955

 

https://www.ncbi.nlm.nih.gov/pubmed/28583312

 

https://www.ncbi.nlm.nih.gov/pubmed/24476821

 

https://www.ncbi.nlm.nih.gov/pubmed/28988769

 

https://www.ncbi.nlm.nih.gov/pubmed/28753430

 

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