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Archive for the ‘Calmodulin Kinase and Contraction’ Category


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

Stephen J. Wiilliams, Ph.D: Curator

UPDATED 4/23/2019

This has an updated lesson on WNT signaling.  Please click on the following and look at the slides labeled under lesson 10

cell motility 9b lesson_2018_sjw

Remember our lessons on the importance of signal termination.  The CANONICAL WNT signaling (that is the β-catenin dependent signaling)

is terminated by the APC-driven degradation complex.  This leads to the signal messenger  β-catenin being degraded by the proteosome.  Other examples of growth factor signaling that is terminated by a proteosome-directed include the Hedgehog signaling system, which is involved in growth and differentiation as well as WNTs and is implicated in various cancers.

A good article on the Hedgehog signaling pathway is found here:

The Voice of a Pathologist, Cancer Expert: Scientific Interpretation of Images: Cancer Signaling Pathways and Tumor Progression

All images in use for this article are under copyrights with Shutterstock.com

Cancer is expressed through a series of transformations equally involving metabolic enzymes and glucose, fat, and protein metabolism, and gene transcription, as a result of altered gene regulatory and transcription pathways, and also as a result of changes in cell-cell interactions.  These are embodied in the following series of graphics.

Figure 1: Sonic_hedgehog_pathwaySonic_hedgehog_pathway

The Voice of Dr. Larry

The figure shows a modification of nuclear translocation by Sonic hedgehog pathway. The hedgehog proteins have since been implicated in the development of internal organs, midline neurological structures, and the hematopoietic system in humans. The Hh signaling pathway consists of three main components: the receptor patched 1 (PTCH1), the seven transmembrane G-protein coupled receptor smoothened (SMO), and the intracellular glioma-associated oncogene homolog (GLI) family of transcription factors.5The GLI family is composed of three members, including GLI1 (gene activating), GLI2 (gene activating and repressive), and GLI3 (gene repressive).6 In the absence of an activating signal from either Shh, Ihh or Dhh, PTCH1 exerts an inhibitory effect on the signal transducer SMO, preventing any downstream signaling from occurring.7 When Hh ligands bind and activate PTCH1, the inhibition on SMO is released, allowing the translocation of SMO into the cytoplasm and its subsequent activation of the GLI family of transcription factors.

 

And from the review of  Elaine Y. C. HsiaYirui Gui, and Xiaoyan Zheng   Regulation of Hedgehog Signaling by Ubiquitination  Front Biol (Beijing). 2015 Jun; 10(3): 203–220.

the authors state:

Finally, termination of Hh signaling is also important for controlling the duration of pathway activity. Hh induced ubiquitination and degradation of Ci/Gli is the most well-established mechanism for limiting signal duration, and inhibiting this process can lead to cell patterning disruption and excessive cell proliferation (). In addition to Ci/Gli, a growing body of evidence suggests that ubiquitination also plays critical roles in regulating other Hh signaling components including Ptc, Smo, and Sufu. Thus, ubiquitination serves as a general mechanism in the dynamic regulation of the Hh pathway.

Overview of Hedgehog signaling showing the signal termination by ubiquitnation and subsequent degradation of the Gli transcriptional factors. obtained from Oncotarget 5(10):2881-911 · May 2014. GSK-3B as a Therapeutic Intervention in Cancer

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Note that in absence of Hedgehog ligands Ptch inhibits Smo accumulation and activation but upon binding of Hedgehog ligands (by an autocrine or paracrine fashion) Ptch is now unable to inhibit Smo (evidence exists that Ptch is now targeted for degradation) and Smo can now inhibit Sufu-dependent and GSK-3B dependent induced degradation of Gli factors Gli1 and Gli2.  Also note the Gli1 and Gli2 are transcriptional activators while Gli3 is a transcriptional repressor.

UPDATED 4/16/2019

Please click on the following links for the Powerpoint presentation for lesson 9.  In addition click on the mp4 links to download the movies so you can view them in Powerpoint slide 22:

cell motility 9 lesson_SJW 2019

movie file 1:

Tumorigenic but noninvasive MCF-7 cells motility on an extracellular matrix derived from normal (3DCntrol) or tumor associated (TA) fibroblasts.  Note that TA ECM is “soft” and not organized and tumor cells appear to move randomly if  much at all.

Movie 2:

 

Note that these tumorigenic and invasive MDA-MB-231 breast cancer cells move in organized patterns on organized ECM derived from Tumor Associated (TA) fibroblasts than from the ‘soft’ or unorganized ECM derived from normal  (3DCntrl) fibroblasts

 

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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Control Heartbeats using Light

Curator: Larry H. Bernstein, MD, FCAP

 

 

How to control heartbeats more precisely, using light

October 20, 2015

http://www.kurzweilai.net/how-to-control-heartbeats-more-precisely-using-light?utm_source=KurzweilAI+Weekly+Newsletter_147a5a48c1-9a20162408-282099089

 

Using computer-generated light patterns, researchers were able to control the direction of spiraling electrical waves in heart cells. (credit: Eana Park)

http://www.kurzweilai.net/images/Excitation-Waves-362×512.jpg

 

Researchers from Oxford and Stony Brook universities has found a way to precisely control the electrical waves that regulate the rhythm of our heartbeat — using light. Their results are published in the journal Nature Photonics.

Cardiac cells in the heart and neurons in the brain communicate by electrical signals, and these messages of communication travel fast from cell to cell as “excitation waves.”

For heart patients there are currently two options to keep these waves in check: electrical devices (pacemakers or defibrillators) or drugs (e.g., beta blockers). However, these methods are relatively crude: they can stop or start waves but cannot provide fine control over the wave speed and direction.

Gil Bub, from Oxford University explained: ‘When there is scar tissue in the heart or fibrosis, this can cause part of the wave to slow down. That can cause re-entrant waves which spiral back around the tissue, causing the heart to beat much too quickly, which can be fatal. If we can control these spirals, we could prevent that.

The optogenetics solution

The solution the researchers found was optogenetics, which uses genetic modification to alter cells so that they can be activated by light. Until now, it has mainly been used to activate individual cells or to trigger excitation waves in tissue, especially in neuroscience research. “We wanted to use it to very precisely control the activity of millions of cells,” said Bub.

A light-activated protein called channelrhodopsin was delivered to heart cells using gene therapy techniques so that they could be controlled by light. Then, using a computer-controlled light projector, the team was able to control the speed of the cardiac waves, their direction and even the orientation of spirals in real time — something that never been shown for waves in a living system before.

In the short term, the ability to provide fine control means that researchers are able to carry out experiments at a level of detail previously only available using computer models. They can now compare those models to experiments with real cells, potentially improving our understanding of how the heart works. The research can also be applied to the physics of such waves in other processes. In the long run, it might be possible to develop precise treatments for heart conditions.

“Precise control of the direction, speed and shape of such excitation waves would mean unprecedented direct control of organ-level function, in the heart or brain, without having to focus on manipulating each cell individually,” said Stony Brook University scientist Emilia Entcheva.

The team stresses that there are significant hurdles before this could offer new treatments; a key issue is being able to alter the heart to be light-sensitized and being able to get the light to desired locations. However, as gene therapy moves into the clinic and with miniaturization of optical devices, use of this all-optical technology may become possible.

In the meantime, the research enables scientists to look into the physics behind many biological processes, including those in our own brains and hearts.

https://youtu.be/CvY-K8of3-I

 

University of Oxford | Controlling heart tissue with light


Abstract of Optical control of excitation waves in cardiac tissue

In nature, macroscopic excitation waves are found in a diverse range of settings including chemical reactions, metal rust, yeast, amoeba and the heart and brain. In the case of living biological tissue, the spatiotemporal patterns formed by these excitation waves are different in healthy and diseased states. Current electrical and pharmacological methods for wave modulation lack the spatiotemporal precision needed to control these patterns. Optical methods have the potential to overcome these limitations, but to date have only been demonstrated in simple systems, such as the Belousov–Zhabotinsky chemical reaction. Here, we combine dye-free optical imaging with optogenetic actuation to achieve dynamic control of cardiac excitation waves. Illumination with patterned light is demonstrated to optically control the direction, speed and spiral chirality of such waves in cardiac tissue. This all-optical approach offers a new experimental platform for the study and control of pattern formation in complex biological excitable systems.

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Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle


Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle

Reporter: Stephen S Williams, PhD

 

Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series D:

Metabolic Genomics & Pharmaceutics, Vol. I

SACHS FLYER 2014 Metabolomics SeriesDindividualred-page2

which is now available on Amazon Kindle at

http://www.amazon.com/dp/B012BB0ZF0.

This e-Book is a comprehensive review of recent Original Research on  METABOLOMICS and related opportunities for Targeted Therapy written by Experts, Authors, Writers. This is the first volume of the Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases.  It is written for comprehension at the third year medical student level, or as a reference for licensing board exams, but it is also written for the education of a first time baccalaureate degree reader in the biological sciences.  Hopefully, it can be read with great interest by the undergraduate student who is undecided in the choice of a career. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012.  All new articles on this subject, will continue to be incorporated, as published with periodical updates.

We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon.

All forthcoming BioMed e-Book Titles can be viewed at:

https://pharmaceuticalintelligence.com/biomed-e-books/

Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of  life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.

Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:

  • delivering curation and summary interpretations of latest findings and innovations on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
  • providing a social platform for scientists and clinicians to enter into discussion using social media
  • compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform

This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.

Table of Contents for Metabolic Genomics & Pharmaceutics, Vol. I

Chapter 1: Metabolic Pathways

Chapter 2: Lipid Metabolism

Chapter 3: Cell Signaling

Chapter 4: Protein Synthesis and Degradation

Chapter 5: Sub-cellular Structure

Chapter 6: Proteomics

Chapter 7: Metabolomics

Chapter 8:  Impairments in Pathological States: Endocrine Disorders; Stress

                   Hypermetabolism and Cancer

Chapter 9: Genomic Expression in Health and Disease 

 

Summary 

Epilogue

 

 

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Archives of Medicine (AOM) to Publish from “Leaders in Pharmaceutical Business Intelligence (LPBI)” Open Access On-Line Scientific Journal http://pharmaceuticalintelligence.com

Reporter: Aviva Lev-Ari, PhD, RN

From our series on Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

AOM Editor-in Chief’s Article Selection and Assignment of manuscript number: iMedPub Journals includes the following and is updated as soon as additional selections are made

Part I:

Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

  

Part II: has been been assigned the following manuscript number: iMedPub Journals-15-472

Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

 

Part III:

Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN

  

Part IV: has been been assigned the following manuscript number: iMedPub Journals-15-471

The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, ArterialSmooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

 

Part V: has been been assigned the following manuscript number: iMedPub Journals-15-516

Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

 

Part VI:

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

 

Part VII:

Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

  

Part VIII

Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism – Part VIII

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part IX

Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor – Part IX

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part X – has been been assigned the following manuscript number: iMedPub Journals-15-517

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission – Part X

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Part XI

Sensors and Signaling in Oxidative Stress – Part XI

Larry H. Bernstein, MD, FCAP

 

Part XII

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD)) – Part XII

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part XIII has been been assigned the following manuscript number: iMedPub Journals-15-471

Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

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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

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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.

 pc9

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.

pc10

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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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)
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

Read Full Post »


Heart-Lung-Kidney: Essential Ties

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

 

Introduction

The basic functioning of the heart, and the kidney have been covered in depth elsewhere, and pulmonary function less, except in this series.  The relationship between them on the basis of endocrine, signaling, and metabolic balance is the focus in this piece.

Other elated articles can be found in http://pharmaceuticalintelligence.com:

The Amazing Structure and Adaptive Functioning of the Kidneys: Nitric Oxide – Part I
https://pharmaceuticalintelligence.com/2012/11/26/the-amazing-structure-and-adaptive-functioning-of-the-kidneys/

Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II
https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease
https://pharmaceuticalintelligence.com/2012/08/16/stroke-and-bleeding-in-atrial-fibrillation-with-chronic-kidney-disease/

Risks of Hypoglycemia in Diabetics with Chronic Kidney Disease (CKD)
https://pharmaceuticalintelligence.com/2012/08/01/risks-of-hypoglycemia-in-diabetics-with-ckd/

Acute Lung Injury
https://pharmaceuticalintelligence.com/2015/02/26/acute-lung-injury/

Neonatal Pathophysiology
https://pharmaceuticalintelligence.com/2015/02/22/neonatal-pathophysiology/

Altitude Adaptation
https://pharmaceuticalintelligence.com/2015/02/24/altitude-adaptation/

Action of Hormones on the Circulation
https://pharmaceuticalintelligence.com/2015/02/17/action-of-hormones-on-the-circulation/

Innervation of Heart and Heart Rate
https://pharmaceuticalintelligence.com/2015/02/15/innervation-of-heart-and-heart-rate/

Neural Activity Regulating Endocrine Response
https://pharmaceuticalintelligence.com/2015/02/13/neural-activity-regulating-endocrine-response/

Adrenal Cortex
https://pharmaceuticalintelligence.com/2015/02/07/adrenal-cortex/

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

Highlights in the History of Physiology
https://pharmaceuticalintelligence.com/2014/12/28/highlights-in-the-history-of-physiology/

The Evolution of Clinical Chemistry in the 20th Century
https://pharmaceuticalintelligence.com/2014/12/13/the-evolution-of-clinical-chemistry-in-the-20th-century/

Complex Models of Signaling: Therapeutic Implications
https://pharmaceuticalintelligence.com/2014/10/31/complex-models-of-signaling-therapeutic-implications/

Cholesterol and Regulation of Liver Synthetic Pathways
https://pharmaceuticalintelligence.com/2014/10/25/cholesterol-and-regulation-of-liver-synthetic-pathways/

A Brief Curation of Proteomics, Metabolomics, and Metabolism
https://pharmaceuticalintelligence.com/2014/10/03/a-brief-curation-of-proteomics-metabolomics-and-metabolism/

Natriuretic Peptides in Evaluating Dyspnea and Congestive Heart Failure
https://pharmaceuticalintelligence.com/2014/09/08/natriuretic-peptides-in-evaluating-dyspnea-and-congestive-heart-failure/

Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease
https://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-in-renal-disease/

Summary – Volume 4, Part 2: Translational Medicine in Cardiovascular Diseases
https://pharmaceuticalintelligence.com/2014/05/10/summary-part-2-volume-4-translational-medicine-in-cardiovascular-diseases/

More on the Performance of High Sensitivity Troponin T and with Amino Terminal Pro BNP in Diabetes
https://pharmaceuticalintelligence.com/2014/01/20/more-on-the-performance-of-high-sensitivity-troponin-t-and-with-amino-terminal-pro-bnp-in-diabetes/

Diagnostic Value of Cardiac Biomarkers
https://pharmaceuticalintelligence.com/2014/01/04/diagnostic-value-of-cardiac-biomarkers/

Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker
https://pharmaceuticalintelligence.com/2013/12/10/epo-as-therapeutics-for-anemia-in-chf/

The Young Surgeon and The Retired Pathologist: On Science, Medicine and HealthCare Policy – Best writers Among the WRITERS
https://pharmaceuticalintelligence.com/2013/12/10/the-young-surgeon-and-the-retired-pathologist-on-science-medicine-and-healthcare-policy-best-writers-among-the-writers/

Renal Function Biomarker, β-trace protein (BTP) as a Novel Biomarker for Cardiac Risk Diagnosis in Patients with Atrial Fibrillation
https://pharmaceuticalintelligence.com/2013/11/13/renal-function-biomarker-%CE%B2-trace-protein-btp-as-a-novel-biomarker-for-cardiac-risk-diagnosis-in-patients-with-atrial-fibrilation/

Leptin signaling in mediating the cardiac hypertrophy associated with obesity
https://pharmaceuticalintelligence.com/2013/11/03/leptin-signaling-in-mediating-the-cardiac-hypertrophy-associated-with-obesity/

The Role of Tight Junction Proteins in Water and Electrolyte Transport
https://pharmaceuticalintelligence.com/2013/10/07/the-role-of-tight-junction-proteins-in-water-and-electrolyte-transport/

Selective Ion Conduction
https://pharmaceuticalintelligence.com/2013/10/07/selective-ion-conduction/

Translational Research on the Mechanism of Water and Electrolyte Movements into the Cell
https://pharmaceuticalintelligence.com/2013/10/07/translational-research-on-the-mechanism-of-water-and-electrolyte-movements-into-the-cell/

Landscape of Cardiac Biomarkers for Improved Clinical Utilization
https://pharmaceuticalintelligence.com/2013/09/22/landscape-of-cardiac-biomarkers-for-improved-clinical-utilization/

Calcium-Channel Blocker, Calcium as Neurotransmitter Sensor and Calcium Release-related Contractile Dysfunction (Ryanopathy)
https://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism
https://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease
https://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Cardiac Contractility & Myocardium Performance: Therapeutic Implications for Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
https://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

Advanced Topics in Sepsis and the Cardiovascular System at its End Stage
https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-sepsis-and-the-cardiovascular-system-at-its-end-stage/

The Cardio-Renal Syndrome (CRS) in Heart Failure (HF)
https://pharmaceuticalintelligence.com/2013/06/30/the-cardiorenal-syndrome-in-heart-failure/

More…

Sodium homeostasis

Icariin attenuates angiotensin IIinduced hypertrophy and apoptosis in H9c2 cardiomyocytes by inhibiting reactive oxygen speciesdependent JNK and p38 pathways

H Zhou, Y Yuan, Y Liu, Wei Deng, Jing Zong, Zhou‑Yan Bian, Jia Dai and Qi‑Zhu Tang
Exper and Therapeutic Med 7: 1116-1122, 2014
http://dx.doi.org:/10.3892/etm.2014.1598

Icariin, the major active component isolated from plants of the Epimedium family, has been reported to have potential protective effects on the cardiovascular system. However, it is not known whether icariin has a direct effect on angiotensin II (Ang II)‑induced cardiomyocyte enlargement and apoptosis. In the present study, embryonic rat heart‑derived H9c2 cells were stimulated by Ang II, with or without icariin administration. Icariin treatment was found to attenuate the Ang II‑induced increase in mRNA expression levels of hypertrophic markers, including atrial natriuretic peptide and B‑type natriuretic peptide, in a concentration‑dependent manner. The cell surface area of Ang II‑treated H9c2 cells also decreased with icariin administration. Furthermore, icariin repressed Ang II‑induced cell apoptosis and protein expression levels of Bax and cleaved‑caspase 3, while the expression of Bcl‑2 was increased by icariin. In addition, 2′,7’‑dichlorofluorescein diacetate incubation revealed that icariin inhibited the production of intracellular reactive oxygen species (ROS), which were stimulated by Ang II. Phosphorylation of c‑Jun N‑terminal kinase (JNK) and p38 in Ang II‑treated H9c2 cells was blocked by icariin. Therefore, the results of the present study indicated that icariin protected H9c2 cardiomyocytes from Ang II‑induced hypertrophy and apoptosis by inhibiting the ROS‑dependent JNK and p38 pathways.

Short-term add-on therapy with angiotensin receptor blocker for end-stage inotrope-dependent heart failure patients: B-type natriuretic peptide reduction in a randomized clinical trial

Marcelo E. Ochiai, ECO Brancalhao, RSN Puig, KRN Vieira, et al.
Clinics. 2014; 69(5):308-313
http://dx.doi.org:/10.6061/clinics/2014(05)02

OBJECTIVE: We aimed to evaluate angiotensin receptor blocker add-on therapy in patients with low cardiac output during decompensated heart failure. METHODS: We selected patients with decompensated heart failure, low cardiac output, dobutamine dependence, and an ejection fraction ,0.45 who were receiving an angiotensin-converting enzyme inhibitor. The patients were randomized to losartan or placebo and underwent invasive hemodynamic and B-type natriuretic peptide measurements at baseline and on the seventh day after intervention. ClinicalTrials.gov: NCT01857999. RESULTS: We studied 10 patients in the losartan group and 11 patients in the placebo group. The patient characteristics were as follows: age 52.7 years, ejection fraction 21.3%, dobutamine infusion 8.5 mcg/kg.min, indexed systemic vascular resistance 1918.0 dynes.sec/cm5.m2, cardiac index 2.8 L/min.m2, and B-type natriuretic peptide 1,403 pg/mL. After 7 days of intervention, there was a 37.4% reduction in the B-type natriuretic peptide levels in the losartan group compared with an 11.9% increase in the placebo group (mean difference, – 49.1%; 95% confidence interval: -88.1 to -9.8%, p = 0.018). No significant difference was observed in the hemodynamic measurements. CONCLUSION: Short-term add-on therapy with losartan reduced B-type natriuretic peptide levels in patients hospitalized for decompensated severe heart failure and low cardiac output with inotrope dependence.

Development of a Novel Heart Failure Risk Tool: The Barcelona Bio-Heart Failure Risk Calculator (BCN Bio-HF Calculator)

Josep Lupon, Marta de Antonio, Joan Vila, Judith Penafiel, et al.
PLoS ONE 9(1): e85466. http://dx.doi.org:/10.1371/journal.pone.0085466

Background: A combination of clinical and routine laboratory data with biomarkers reflecting different pathophysiological pathways may help to refine risk stratification in heart failure (HF). A novel calculator (BCN Bio-HF calculator) incorporating N-terminal pro B-type natriuretic peptide (NT-proBNP, a marker of myocardial stretch), high-sensitivity cardiac troponin T (hs-cTnT, a marker of myocyte injury), and high-sensitivity soluble ST2 (ST2), (reflective of myocardial fibrosis and remodeling) was developed. Methods: Model performance was evaluated using discrimination, calibration, and reclassi-fication tools for 1-, 2-, and 3-year mortality. Ten-fold cross-validation with 1000 bootstrapping was used. Results: The BCN Bio-HF calculator was derived from 864 consecutive outpatients (72% men) with mean age 68.2612 years (73%/27% New York Heart Association (NYHA) class I-II/III-IV, LVEF 36%, ischemic etiology 52.2%) and followed for a median of 3.4 years (305 deaths). After an initial evaluation of 23 variables, eight independent models were developed. The variables included in these models were age, sex, NYHA functional class, left ventricular ejection fraction, serum sodium, estimated glomerular filtration rate, hemoglobin, loop diuretic dose, β-blocker, Angiotensin converting enzyme inhibitor/Angiotensin-2 receptor blocker and statin treatments, and hs-cTnT, ST2, and NT-proBNP levels. The calculator may run with the availability of none, one, two, or the three biomarkers. The calculated risk of death was significantly changed by additive biomarker data. The average C-statistic in cross-validation analysis was 0.79. Conclusions: A new HF risk-calculator that incorporates available biomarkers reflecting different pathophysiological pathways better allowed individual prediction of death at 1, 2, and 3 years.

TNF and angiotensin type 1 receptors interact in the brain control of blood pressure in heart failure

Tymoteusz Zera, Marcin Ufnal, Ewa Szczepanska-Sadowska
Cytokine 71 (2015) 272–277
http://dx.doi.org/10.1016/j.cyto.2014.10.019

Accumulating evidence suggests that the brain renin-angiotensin system and proinflammatory cytokines, such as TNF-α, play a key role in the neuro-hormonal activation in chronic heart failure (HF). In this study we tested the involvement of TNF-α and angiotensin type 1 receptors (AT1Rs) in the central control of the cardiovascular system in HF rats. Methods: we carried out the study on male Sprague–Dawley rats subjected to the left coronary artery ligation (HF rats) or to sham surgery (sham-operated rats). The rats were pretreated for four weeks with intracerebroventricular (ICV) infusion of either saline (0.25 µl/h) or TNF-α inhibitor etanercept (0.25 µg/0.25 µl/h). At the end of the pretreatment period, we measured mean arterial blood pressure (MABP) and heart rate (HR) at baseline and during 60 min of ICV administration of either saline (5 µl/h) or AT1Rs antagonist losartan (10 µg/5 µl/h). After the experiments, we measured the left ventricle end-diastolic pressure (LVEDP) and the size of myocardial scar. Results: MABP and HR of sham-operated and HF rats were not affected by pretreatments with etanercept or saline alone. In sham-operated rats the ICV infusion of losartan did not affect MABP either in saline or in etanercept pretreated rats. In contrast, in HF rats the ICV infusion of losartan significantly decreased MABP in rats pretreated with saline, but not in those pretreated with etanercept. LVEDP was significantly elevated in HF rats but not in sham-operated ones. Surface of the infarct scar exceeded 30% of the left ventricle in HF groups, whereas sham-operated rats did not manifest evidence of cardiac scarring. Conclusions: our study provides evidence that in rats with post-infarction heart failure the regulation of blood pressure by AT1Rs depends on centrally acting endogenous TNF-α.

Statins in heart failure—With preserved and reduced ejection fraction. An update

Dimitris Tousoulis , E Oikonomou, G Siasos, C Stefanadis
Pharmacology & Therapeutics 141 (2014) 79–91
http://dx.doi.org/10.1016/j.pharmthera.2013.09.001

HMG-CoA reductase inhibitors or statins beyond their lipid lowering properties and mevalonate inhibition exert also their actions through a multiplicity of mechanisms. In heart failure (HF) the inhibition of isoprenoid intermediates and small GTPases, which control cellular function such as cell shape, secretion and proliferation, is of clinical significance. Statins share also the peroxisome proliferator-activated receptor pathway and inactivate extracellular-signal-regulated kinase phosphorylation suppressing inflammatory cascade. By down-regulating Rho/Rho kinase signaling pathways, statins increase the stability of eNOS mRNA and induce activation of eNOS through phosphatidylinositol 3-kinase/Akt/eNOS pathway restoring endothelial function. Statins change also myocardial action potential plateau by modulation of Kv1.5 and Kv4.3 channel activity and inhibit sympathetic nerve activity suppressing arrhythmogenesis. Less documented evidence proposes also that statins have antihypertrophic effects – through p21ras/mitogen activated protein kinase pathway – which modulate synthesis of matrix metalloproteinases and procollagen 1 expression affecting interstitial fibrosis and diastolic dysfunction. Clinical studies have partly confirmed the experimental findings and despite current guidelines new evidence supports the notion that statins can be beneficial in some cases of HF. In subjects with diastolic HF, moderately impaired systolic function, low B-type natriuretic peptide levels, exacerbated inflammatory response and mild interstitial fibrosis evidence supports that statins can favorably affect the outcome. Under the lights of this evidence in this review article we discuss the current knowledge on the mechanisms of statins’ actions and we link current experimental and clinical data to further understand the possible impact of statins’ treatment on HF syndrome.

Since 1980 when the first 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor or statin was introduced in clinical practice, statins have been extensively used in the treatment of patients with dyslipidemia as well as of those with coronary artery disease (CAD). Importantly, large scale trials and metanalysis have documented their significant benefits in terms of primary and secondary CAD prevention which out-weigh any potential side effects. Statins’ benefits extend, according to recent studies, even in patients with normal or low cholesterol levels and beyond their lipid lowering effects, indicating their multiple protective mechanisms.

Heart failure (HF) is a complex syndrome with different definitions and its diagnosis is based on a combination of symptoms, clinical signs and imaging or laboratory data. different categorization schemes have been used dividing HF in acute or chronic, in systolic or diastolic, and in ischemic or dilated simply reflecting the complexity of the syndrome and the multiplicity of the pathophysiologic mechanisms implicated in the disease development and progression. In addition to the diverse pathophysiology of HF the syndrome is also characterized by high morbidity and mortality. Recent treatment advantages such as angiotensin converting enzyme inhibitors and beta blockers have not yet proven their clinical benefit in subjects with diastolic HF.

As the most common cause of HF is CAD and statins have proven their benefits in a wide spectrum of diseases directly or indirectly associated with atherosclerotic cardiovascular disease, HMG-CoA reductase inhibitors have been tested in subjects with HF. Interestingly, non-randomized, observational and retrospective early studies in subjects with HF of ischemic and non-ischemic etiology have suggested that statins are associated with improved outcomes. Thereafter, two large scale randomized control trials failed to demonstrate any benefits in mortality of HF patients treated with rosuvastatin and subsequently current HF guidelines do not include recommendations for statin use except from when they are indicated for comorbidities, such as established CAD.

Statins inhibit HMG-CoA reductase. This enzyme catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to L-mevalonic acid, which is the rate-limiting step in the cholesterol synthesis pathway. Inhibition of the mevalonate pathway and of cholesterol synthesis triggers an increase in LDL receptor activity by stimulating production of mRNA for LDL receptor in liver. The induction of LDL receptors is responsible for the observed increase in plasma clearance of LDL cholesterol. CAD is the cause of approximately two-thirds of cases of systolic HF. The beneficial effects of statins-induced LDL reduction are well established in patients with atherosclerosis and CAD. Nevertheless, the results from statin treatment, even in ischemic HF cases, are not straightforward and several mechanisms have been proposed for this paradox.

multiplicity of HMG CoA reductase inhibitors mechanisms and their effects

multiplicity of HMG CoA reductase inhibitors mechanisms and their effects

The figure demonstrates the multiplicity of HMG CoA reductase inhibitors mechanisms and their effects. ↓: decrease; ↑ increase; FPP: farnesyl pyrophosphate: GGPP: geranylgeranyl pyrophosphate; Ras, Rac, Rho; small GTPases; eNOS: endothelial nitric oxide synthase; ATP: adenosine triphosphate; PI-3 kinase: phosphatidylinositol 3-kinase; AMPK: AMP activated protein kinase; GTP: Guanosine triphosphate; NADPH: Nicotinamide adenine dinucleotide phosphate; ERK: extracellular-signal-regulated kinase; Shadow box represents adverse mechanism and actions of HGM CoA reductase inhibitors.

The anti-inflammatory effects of HMG CoA reductase inhibitors in atherosclerosis have been early recognized. Statins also have a potent anti-inflammatory effect in HF models. Importantly, there is a link between inflammation and HF pathogenesis and is now widely accepted that pro-inflammatory cytokines cause systolic dysfunction, myocardial hypertrophy, activate a fetal gene program in cardiac myocytes, disturb extracellular matrix structure, cause cardiac cachexia etc. In addition, data from the Vesnarinone trial (VEST) in 384 patients with HF demonstrate a decline in survival with increasing TNFα levels confirming the notion that circulating cytokines are associated with adverse prognosis of HF patients.

The proposed, by the aforementioned mechanisms, anti-inflammatory effects of statins have been confirmed experimentally. Indeed, in a rat HF model with preserved ejection fraction (EF), treatment with rosuvastatin resulted in a significant additional improvement in HF and cardiac remodeling, partly due to decreased myocardial inflammation. In rats after acute myocardial infarction simvastatin treatment for 4 weeks beneficially modified the levels of TNFα, interleukin (IL)-1, 6 and 10 in the infarct regions. Importantly, in 446 patients with systolic HF, followed up for a period of 24 months, statins’ treatment was associated with a decrease in serum levels of C-reactive protein (CRP), IL-6 and tumor necrosis factor-alpha receptor II. Recently, in a randomized study of 22 subjects with ischemic HF short term atorvastatin treatment achieved a significant decrease in serum levels of intracellular adhesion molecule-1.

Taken together we can conclude that HMG CoA reductase inhibitors can modify inflammatory status by modulation of PRAP and ERK pathways by down regulating Toll like receptor 4 mRNA expressions and LDL oxidation and by reducing soluble lipoprotein-associated phospholipase A2 mass and activity. Importantly, the theoretical anti-inflammatory properties were confirmed in experimental and clinical HF models.

Endothelial dysfunction contributes to the pathogenesis of HF and can enhance adverse left ventricle (LV) remodeling and increase afterload in subjects with HF. Interestingly, statins have been constantly associated with improved endothelial function in subjects with a variety of cardiovascular diseases. Endothelium derived nitric oxide (NO) is an important determinant of endothelial function and HMG-CoA reductase inhibitors can up regulate endothelial NO synthase (eNOS) by different mechanisms.

Statins induce down regulation of Rho/Rho kinase signaling pathways, increasing the stability of eNOS mRNA and its expression . In addition, in human endothelial cells the Rho-kinase inhibitor, hydroxyfasudil leads to the activation of the phosphatidylinositol 3-kinase/Akt/eNOS pathway. Statins also induce activation of eNOS through the rapid activation of the serine–threonine protein kinase Akt. The beneficial effects of Akt activation are not limited to eNOS phoshorylation but extend to the promotion of new blood vessels growth. HMG CoA reductase inhibitors can further affect endothelial function through their effect on caveolin-1. Caveolin-1 binds to eNOS inhibiting NO production. Incubation of endothelial cells with atorvastatin promotes NO production by decreasing caveolin-1 expression, regardless of the level of extracellular LDL-cholesterol. These effects were reversed with mevalonate highlighting the therapeutic potential of inhibiting cholesterol synthesis in peripheral cells to correct NO-dependent endothelial dysfunction associated with hypercholesterolemia and possibly other diseases.

Although the experimentally confirmed benefits of HMG CoA reductase inhibitors in diastolic dysfunction and left ventricle stiffness, few data exist concerning the underlying mechanisms. As diastolic dysfunction precedes myocardial hypertrophy the anti-hypertrophic pathways mentioned in the previous section (inhibition of RhoA/Ras/ERK, PRAPγ pathways, inhibition of a large G(h) protein-coupled pathway etc.), may also contribute to the restoration of diastolic function. Moreover, in angiotensin II induced diastolic dysfunction in hypertensive mice, pravastatin not only improved diastolic function but also down-regulated collagen I, transforming growth factor-beta, matrix metalloproteinases (MMPs)-2 and -3, atrial natriuretic factor, IL-6 TNFα, Rho kinase 1 gene expression, and upregulated eNOS gene expression. These findings suggest the potential involvement of Rho kinase 1 in the beneficial effects of pravastatin in diastolic HF. Taken together data suggest that HMG CoA reductase inhibitors might be beneficial in patients with diastolic HF, a hypothesis that remains to be confirmed by clinical studies. Nevertheless, mechanistic studies have not fully explored the pathways affecting diastolic function and most data until now are indirect. Therefore efforts should be focus on the underline mechanisms affecting collagen synthesis, MMPs activity extracellular matrix synthesis and overall diastolic function in HF subjects under statin treatment.

Statins through inhibition of small GTPases can modulate MMPs activity in several cell types such as endothelial cells and human macrophages. In rat and human cardiac fibroblasts, stimulated with either transforming growth factor β1 or angiotensin II, atorvastatin reduced collagen synthesis and α1-procollagen mRNA as well as gene expression of the profibrotic peptide connective tissue growth factor 4. This antifibrotic action may contribute to the anti-remodelling effect of statins. In mouse cardiac fibroblasts treated with angiotensin II, the combination of pravastatin and pioglitazone blocked angiotensin II p38 MAPK and p44/42 MAPK activation and procollagen expression-1.

Several studies have documented the impact of statin treatment on arrhythmia potential. The arrhythmic protective effects of statins can be attributed not only to anti-inflammatory properties but also to changes in myocardial action potential plateau by modulation of Kv1.5 and Kv4.3 channel activity. Atorvastatin and simvastatin block Kv1.5 and Kv4.3 channels shifting the inactivation curve to more negative potentials following a complex mechanism that does not imply the binding of the drug to the channel pore. Moreover, in hypertrophied neonatal rat ventricular myocytes simvastatin alleviated the reduction of Kv4.3 expression, I(to) currents in subepicardial myocardium from the hypertrophied left ventricle. Furthermore, pravastatin in an animal model attenuated reperfusion induced lethal ventricular arrhythmias by inhibition of calcium overload.

Taking together experimental and cellular evidence supporting an effect of statin treatment in myocardial contractility is spare and for the time being we cannot definitively conclude on the clinical impact of HMG CoA reductase inhibitors in myocardial systolic performance.

Half of the cases of HF are attributed to diastolic dysfunction and the prognosis of HF with preserved EF is as ominous as the prognosis of HF with systolic dysfunction. Unfortunately, no treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HF and preserved EF, while this group of patients is usually excluded from large prospective randomized trials and accordingly few data exist for the role of statins in this heterogeneous population.

As there is substantially lack of evidence concerning the effects of HMG CoA reductase inhibitors in subjects with HF and preserved EF the first indirect hypothesis was extrapolated from observational prospective studies in subjects with ischemic heart disease and no evidence of congestive HF. Indeed, in a cohort of 430 consecutive patients with ischemic heart disease and a mean EF of 57% Okura et al. observed that subjects under HMG CoA reductase inhibitors treatment had decreased E/E′ ratio—corresponding to a better diastolic function—and a significantly higher survival rate (Okura et al., 2007). According to the authors those beneficially effects can be attributed to improved endothelial function and vasodilatory response to reactive hyperemia, attenuation of myocardial hypertrophy, and interstitial fibrosis.

Despite the positive results from mechanistic and experimental studies clinical studies have failed to confirm a definitive role of HMG CoA reductase inhibitors in HF. Nevertheless, by extrapolating experimental and mechanistic data in clinical settings we further understand how HMG-CoA reductase inhibitors can beneficially affect subgroups of HF subjects such as those with preserved EF, low B-type natriuretic peptide levels, exacerbated inflammatory response and limited interstitial fibrosis. Nevertheless, as a definitive mechanism is lacking, there is uncertainty about the decisive mode of action and further mechanistic studies are needed to reveal how HMG-CoA reductase inhibitors act in HF substrate.

Pro- A-Type Natriuretic Peptide, Proadrenomedullin, and N-Terminal Pro-B-Type Natriuretic Peptide Used in a Multimarker Strategy in Primary Health Care in Risk Assessment of Patients with Symptoms of Heart Failure

Urban Alehagen, Ulf Dahlstr€Om,  Jens F. Rehfeld, And Jens P. Goetze
J Cardiac Fail 2013; 19(1):31-39. http://dx.doi.org/10.1016/j.cardfail.2012.11.002

Use of new biomarkers in the handling of heart failure patients has been advocated in the literature, but most often in hospital-based populations. Therefore, we wanted to evaluate whether plasma measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional pro-A-type  atriuretic peptide (MR-proANP), and midregional proadrenomedullin (MR-proADM), individually or combined, gives prognostic information regarding cardiovascular and all-cause mortality that could motivate use in elderly patients presenting with symptoms suggestive of heart failure in primary health care. Methods and Results: The study included 470 elderly patients (mean age 73 years) with symptoms of heart failure in primary health care. All participants underwent clinical examination, 2-dimenstional echocardiography, and plasma measurement of the 3 propeptides and were followed for 13 years. All mortality was registered during the follow-up period. The 4th quartiles of the biomarkers were applied as cutoff values. NT-proBNP exhibited the strongest prognostic information with 4-fold increased risk for cardiovascular mortality within 5 years. For all-cause mortality MR-proADM exhibited almost 2-fold and NTproBNP 3-fold increased risk within 5 years. In the 5e13-year perspective, NT-proBNP and MR-proANP showed significant and independent cardiovascular prognostic information. NT-proBNP and MR-proADM showed significant prognostic information regarding all-cause mortality during the same time. In those with ejection fraction (EF) !40%, MR-proADM exhibited almost 5-fold increased risk of cardiovascular mortality with 5 years, whereas in those with EF O50% NT-proBNP exhibited 3-fold increased risk if analyzed as the only biomarker in the model. If instead the biomarkers were all below the cutoff value, the patients had a highly reduced mortality risk, which also could influence the handling of patients. Conclusions: The 3 biomarkers could be integrated in a multimarker strategy for use in primary health care.

Novel Biomarkers in Heart Failure with Preserved Ejection Fraction

Kevin S. Shah, Alan S. Maisel
Heart Failure Clin 10 (2014) 471–479
http://dx.doi.org/10.1016/j.hfc.2014.04.005

KEY POINTS

  • Heart failure with preserved ejection fraction (HFPEF) is a common subtype of congestive heart failure for which therapies to improve morbidity and mortality have been limited thus far.
  • Numerous biomarkers have emerged over the past decade demonstrating prognostic significance in HFPEF, including natriuretic peptides, galectin-3, soluble ST2, and high-sensitivity troponins.
  • These markers reflect the multiple mechanisms implicated in the pathogenesis of HFPEF, and future research will likely use these markers to not only help determine heart failure phenotypes but also target specific therapies.

Heart failure (HF) is a global epidemic, defined as an abnormality of cardiac function leading to the inability to deliver oxygen at a rate adequate to meet the requirements of tissues. It is truly a clinical syndrome of symptoms and signs resulting from this cardiac abnormality. Over the past decade, further characterization into 2 entities has occurred: HF with preserved ejection fraction (HFPEF) and HF with reduced ejection fraction (HFREF). HFPEF, previously termed diastolic HF, encompasses the syndrome of HF with a preserved ejection fraction. Cutoffs for this ejection fraction typically are from 45% to 50%. The prevalence of HF is upward of 1% to 2% of the adult population, with an increased prevalence found in elderly and female patients. Multiple studies have shown that the prevalence of HFPEF is actually comparable with the number of patients with HFREF. As expected, most deaths from HFPEF are cardiovascular, comprising 51% to 70% of mortality.

The pathophysiology of HFPEF is controversial and remains poorly understood. Originally, HFPEF was thought to be a primary manifestation of diastolic dysfunction of the left ventricle. However, patients with HFREF are known to also commonly have impaired ventricular relaxation. The primary mechanism of left ventricular (LV) dysfunction is based on structural remodeling and endothelial dysfunction, lending itself to LV stiffness, and increased left atrial pressure. This pressure change is what drives pulmonary venous congestion and subsequent symptomatology. The ventricular stiffness commonly seen in HFPEF is attributed to multiple mechanisms, including fibrosis, excessive collagen deposition, cardiomyocyte stiffness, and slow LV relaxation.

The natriuretic peptides (NPs) are the cornerstone biomarker in congestive HF (CHF). Many of the details of the role of NPs are covered in an article – Florea VG, Anand IS. Biomarkers. Heart Fail Clin 2012;8(2):207–24. The Breathing Not Properly trial originally helped establish the role of B-type natriuretic peptide (BNP) in the diagnosis of CHF. BNP and the N-terminal prohormone BNP (NT-proBNP) have been shown in numerous trials to be an excellent tool for ruling out CHF as a cause of acute dyspnea. Aside from a strong negative predictive value, NPs correlate with HF severity, prognostication, outpatient CHF management, and screening. When attempting to use NPs specifically to distinguish between HFPEF and HFREF, results have shown that NPs do not have a particular cutoff, but are typically elevated in HFPEF in comparison with patients without HF. These levels of NPs in HFPEF are typically lower than levels in patients with HFREF.

Although the role of novel renal biomarkers has not been fully explored specifically in HFPEF, they likely have an impactful role in the assessment and management of acute kidney injury (AKI) and the cardiorenal syndrome. Two biomarkers are briefly discussed here: neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C. NGAL is a 25-kDa protein in the lipocalin family of proteins with a role in inflammation and immune modulation.

The future of biomarkers and their utility in HF is very promising, starting with the potential for using biomarkers as end points in trials. Biomarkers serve as surrogates for various pathophysiologic mechanisms, and there are potential benefits in using them as trial end points. Advantages include the ability to obtain quick and early data, as well as possibly better understand the nature of the disease. However, the counterargument against using biomarkers as trial end points includes whether treatment effects on a biomarker reliably predict effects on a clinically meaningful end point.
Reduced cGMP signaling activates NF-κB in hypertrophied hearts of mice lacking natriuretic peptide receptor-A

Elangovan Vellaichamy, Naveen K. Sommana, Kailash N. Pandey
Biochemical and Biophysical Research Communications 327 (2005) 106–111
http://dx.doi.org:/10.1016/j.bbrc.2004.11.153

Mice lacking natriuretic peptide receptor-A (NPRA) develop progressive cardiac hypertrophy and congestive heart failure. However, the mechanisms responsible for cardiac hypertrophic growth in the absence of NPRA signaling are not yet known. We sought to determine the activation of nuclear factor-κB (NF-κB) in Npr1 (coding for NPRA) gene-knockout (Npr1-/-) mice exhibiting cardiac hypertrophy and fibrosis. NF-κB binding activity was 4-fold greater in the nuclear extract of Npr1-/-mutant mice hearts as compared with wild-type (Npr1+/+) mice hearts. In parallel, inhibitory κB kinase-b activity and IκB-α protein phosphorylation were also increased 3- and 4-fold, respectively, in hypertrophied hearts of mutant mice. cGMP levels were significantly reduced 5-fold in plasma and 10-fold in ventricular tissues of mutant mice hearts  relative to wild-type controls. The present findings provide direct evidence that ablation of NPRA/cGMP signaling activates NF-κB binding activity associated with hypertrophic growth of mutant mice hearts.

Regulation of guanylyl cyclase/natriuretic peptide receptor-A gene expression

Renu Garg, Kailash N. Pandey
Peptides 26 (2005) 1009–1023
http://dx.doi.org:/10.1016/j.peptides.2004.09.022

Natriuretic peptide receptor-A (NPRA) is the biological receptor of the peptide hormones atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). The level and activity of this receptor determines the biological effects of ANP and BNP in different tissues mainly directed towards the maintenance of salt and water homeostasis. The core transcriptional machinery of the TATA-less Npr1 gene, which encodes NPRA, consists of three SP1 binding sites and the inverted CCAAT box. This promoter region of Npr1 gene has been shown to contain several putative binding sites for the known transcription factors, but the functional significance of most of these regulatory sequences is yet to be elucidated. The present review discusses the current knowledge of the functional significance of the promoter region of Npr1 gene and its transcriptional regulation by a number of factors including different hormones, growth factors, changes in extracellular osmolarity, and certain physiological and patho-physiological conditions.

Atrial natriuretic peptide (ANP), a member of natriuretic peptide family is a polypeptide consisting of 28 amino acids and was discovered as a potent vasodilator and diuretic hormone produced in granules of the atrium. The natriuretic peptide family consists of the peptide hormones ANP, brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), each of which is derived from a separate gene. ANP and BNP are cardiac derived peptides, which are secreted and up-regulated in myocardium in response to different patho-physiological stimuli, while CNP is an endothelium-derived mediator that plays an important paracrine role in the vasculature. All of these natriuretic peptides elicit a number of vascular, renal, and endocrine effects mainly directed towards the maintenance of blood pressure and extracellular fluid volume by binding to their specific cell surface receptors. ANP exerts its effects at a number of sites including the kidney, where it produces natriuretic and diuretic responses; the adrenal gland, where it inhibits aldosterone synthesis and secretion; vascular smooth muscle cells, where it produces vasorelaxation; the endothelial cells, where it may regulate vascular permeability; gonadal cells, where it affects synthesis of androgen and estradiol. Each of these target sites of ANP activity has been shown to possess specific high affinity receptors for ANP. To date, three different subtypes of natriuretic peptide receptors have been characterized, purified, and cloned, i.e. natriuretic peptide receptors A, B, and C also designated as NPRA, NPRB, and NPRC, respectively. ANP and BNP specifically bind to NPRA, which contains guanylyl cyclase catalytic activity and produces intracellular secondary messenger cGMP in response to hormone binding.

NPRA is considered the biological receptor of ANP and BNP because most of the physiological effects of these hormones are triggered by generation of cGMP or its cell permeable analogs. Recent studies with mice lacking the Npr1 gene, demonstrated that genetic disruption of NPRA increases the blood pressure and causes hypertension in these animals. On the other hand, the effect of ANP was found to be increased linearly in Npr1 gene-duplicated mice
in a manner consistent with gene copy number. All this clearly indicates that the level of NPRA expression determines the extent of the biological effects of ANP and BNP. But the intervention strategies aimed at controlling NPRA expression are limited by the paucity of studies in this area. The cDNA and gene encoding NPRA designated as Npr1 has been cloned and characterized in mouse, rat, bull frog, euryhaline eel, and medaka fish. The primary structure of this gene is essentially same in all the different species and contains 22 exons interrupted by 21 introns.  The Npr1 gene sequence has been found to be interspersed with a number of repetitive elements including (SINES), (MER2), and tandem repeat elements in all the different species.

Although the Npr1 gene transcriptional regulation is only poorly understood, the activity and expression of NPRA assessed primarily through ANP stimulated cGMP accumulation are found to be regulated by a number of factors including auto-regulation by natriuretic peptides themselves, other hormones such as endothelin, glucocorticoids, and angiotensin II (ANG II), growth factors, changes in extracellular ion composition, and certain physiological and patho-physiological conditions.

The core molecular machinery of the TATA-less Npr1 gene consisting of SP1 binding sites and the inverted CCAAT box has been authenticated to be indeed functional in rat promoter element. It has been shown that the molecular machinery that regulates the basal expression of Npr1 gene consists of three SP1 binding sites in conjunction with an inverted CCAAT box present in the proximal promoter region. Mutation in any of these SP1 binding sites which
are located within 350 bp upstream of transcription start site in rat Npr1 promoter inhibited SP1 and SP3 binding and decreased the promoter activity by 50–75%, while simultaneous mutation of all the three led to a >90% reduction in promoter activity. The proximal SP1 binding site was much more effective than the distal sites in inducing the expression implying that the proximity to the core transcriptional machinery contributes to the magnitude of the observed effect. The over-expression of either SP1 or SP3 resulted in the induction of the wild type Npr1 promoter, confirming that these transcription factors serve as positive regulators of the Npr1 gene expression.

A number of natriuretic peptides such as ANP, BNP, CNP, and urodilatin (i.e. ANP95–126) can down-regulate ligand dependent NPRA activity after as little as 2 h prior exposure to the ligand, which remains suppressed until 48 h of exposure in cultured cells. The early reduction of NPRA activity is independent of changes in Npr1 gene expression as the pretreatment of cultured cells with actinomycin D (an inhibitor of transcription) for 1 h failed to block the response to ANP implying that ligand acts, at least early on, through a post transcriptional mechanism in reducing NPRA activity. The sustained reduction of NPRA activity, on the other hand, has been shown in fact due to reduction in NPRA mRNA levels (∼50%) by treatment with 100nM ANP for 48 h. This reduction could also be affected by treatment of cultured cells with 8-Br-cGMP with similar kinetic response and was amplified by phosphodiesterase inhibitors, but was not shared by NPRC-selective ligand cANF, suggesting that the down regulation of Npr1 gene expression is mediated by elevations of intracellular cGMP involving either NPRA or NPRB. .. The cGMP regulatory region was pinpointed to position−1372 to−1354 bp from the transcription start site of Npr1 by gel shift assays and footprinting analysis, which indicated its interaction with transcriptional factor(s). Further cross-competition experiments with mutated oligonucleotides led to the definition of a consensus sequence (−1372 bp AaAtRKaNTTCaAcAKTY −1354 bp) for the novel cGMP-RE, which is conserved in the human (75% identity) and mouse (95% identity) Npr1 promoters. The combination of these transcriptional and post-transcriptional ligand-dependent regulatory mechanisms provides the cells with greater flexibility in both initiating and maintaining the suppression of NPRA activity.

The peptide hormone Ang II is an important component of renin-angiotensin system (RAS) and exerts its biological effects such as blood pressure regulation, vasoconstriction, and cell proliferation in many tissues including the kidney, adrenal glands, brain, and vasculature. The two vasoactive peptide hormones, Ang II (vasoconstrictive) and ANP (vasodilatory), interact and mutually antagonize the biological effects of each other at various levels. ANP has been shown to inhibit Ang II-induced contraction of isolated glomeruli and cultured mesangial cells, as well as Ang II-stimulated activation of protein kinase C and mitogen activated protein kinase in vascular smooth muscle cells in a cGMP-dependent manner. Inversely, Ang II has been shown to down-regulate guanylyl cyclase activity of the biological receptor of ANP, NPRA, by activating protein kinase C and/or by stimulating protein tyrosine phosphatase activity, thereby inhibiting the ANP stimulated cGMP accumulation. Ang II also reduces the ANP dependent cGMP levels by stimulating cGMP hydrolysis, apparently
via a calcium dependent cGMP phosphodiesterase.

Endothelin is a vasoconstrictor peptide that was originally isolated from porcine endothelial cells. It is produced as three isoforms (ET1-3) that bind to two receptor subtypes (ETA and ETB). ET is produced in the kidney and subject to regulation by a number of local and systemic factors including immune cytokines and extracellular tonicity. Since, endothelin is avidly expressed in the nephron segment, where NPRA is up-regulated by osmotic stimulus, it was investigated whether endothelin plays a role in the control of basal or osmotically regulated Npr1 gene expression in these cells. The endogenous endothelin and not the exogeneously administered endothelin inhibit the basal but not osmotically stimulated expression of Npr1. The type A (BQ610) and type B (IRL 1038) endothelin receptor antagonists increased the level of NPRA mRNA by two to three-fold, whereas co-administration of exogenous endothelin resulted in partial reversal of this stimulatory effect of receptor antagonists. The increase in extracellular tonicity reduces the endothelin mRNA accumulation (∼15% of control levels) in inner medullary collecting duct cells but this reduction is not found to be linked to the stimulation of NPRA activity/expression in response to osmotic stress.

Glucocorticoids influence the cardiovascular system and induce a rapid increase in blood pressure. Glucocorticoids are known to regulate
transcription in many systems, possibly by interacting with glucocorticoid responsive elements and associated chromatin proteins. These have been shown to affect the atrial endocrine system by regulating both the synthesis and secretion of ANP in vitro and in vivo. Thus, it seems plausible that glucocorticoid may also interact with the atrial endocrine system by modulating ANP receptor levels. The stimulation of vascular smooth muscle cells from rat mesenteric artery with dexa-methasone (a highly specific synthetic glucocorticoid agonist) caused an increase in NPRA mRNA levels in a time dependent manner which reached a plateau after 48 h of glucocorticoid administration. This mRNA increase was mimicked by cortisol and inhibited by glucocorticoid receptor antagonists RU38486. Also cGMP generated by NPRA in dexamethasone treated cells was higher than in control cells and this production was mimicked by cortisol and blocked by RU 38486. These results suggest that glucocorticoids exert a positive effect on NPRA transcription in rat mesenteric arteries.

Previous studies have shown that guanylyl cyclase activity of NPRA is either activated, or inhibited by an increase in extracellular tonicity. Though none of these studies were definitive in terms of elucidating the mechanisms involved, they suggested that the activation predominates with longer exposure (∼24 h), while the inhibition with short-term exposure (minutes) to the osmotic stimulus. More recently, the mechanism(s) underlying the activation of NPRA expression by osmotic stimulus has been investigated. The NaCl (75 mM) or sucrose (150 mM), but not osmotically inert solute, urea (150 mM) increased NPRA activity, gene expression, and promoter activity after as early as 4 h reaching a maximum at 24 h in inner medullary collecting duct cells. The osmotic stimulus also activated extracellular signal regulated kinase (ERK), c-Jun-NH2-terminal kinase (JNK), and p38 mitogen activated protein kinase- (p38 MAPK-β). The inhibition of p38 MAPK-βwith SB20580 completely  blocked the osmotic stimulation of receptor activity and expression, and caused a dose-dependent reduction in promoter activity, whereas inhibition of ERK with PD98059 had no effect.

The expression of NPRB, the biological receptor of CNP, has been shown to be regulated by a number of factors including natriuretic peptide ligands, intracellular cAMP levels, water deprivation, TGF-1, dexamethasone treatment, as well as renal sodium status, as its mRNA levels were upregulated in the renal cortex of sodium depleted animals. NPRB expression has also been found to be regulated by alternative splicing. Three isoforms of NPRB have been identified of which NPRB1 is the full length form and responds maximally to CNP, NPRB2 isoform contains a 25 amino acid deletion in protein kinase homology domain and NPRB3 contains a partial extracellular ligand binding domain and fails to bind the ligand. The relative expression levels of the three isoforms vary across different tissues. Since, the smaller splice variants of NPRB act as dominant negative isoforms by blocking formation of active NPRB1 homodimers, these isoforms might play important role in the tissue specific regulation of receptor, NPRB.

The NPRC expression has also been found to be down-regulated by its ligands and their secondary messenger, cGMP, hormones, growth factors, dietary salt supplementation, β-adrenergic blocker, and physiological as well as patho-physiological conditions. On the other hand, NPRC expression gets augmented by TGF-β1, 1,25-dihydroxy VitaminD3 and during conditions like chronic heart failure.

Hypertension is the leading cause of human deaths in today’s world. The natriuretic peptide system plays a well defined role in the regulation of blood pressure and fluid volume. The cellular and physiological effects of natriuretic peptides (ANP, BNP, and CNP) are mediated by their specific receptors NPRA, NPRB, and NPRC. The transcriptional regulation of these receptors has been studied since their identification, but still remains poorly understood. Better understanding and the elucidation of different molecular mechanisms responsible for the regulation of NPRA expression would provide us the framework to develop the therapeutic strategies to manipulate the expression levels of this receptor and to control the biological actions of ANP and BNP during different patho-physiological conditions.

Inhibition of Heat Shock Protein 90 (Hsp90) in Proliferating Endothelial Cells Uncouples Endothelial Nitric Oxide Synthase Activity

Jingsong Ou, Zhijun Ou, AW Ackerman, KT Oldham, & KA Pritchard, Jr.
Free Radical Biol Med 2003; 34(2):269–276
PII S0891-5849(02)01299-6

Dual increases in nitric oxide (•NO) and superoxide anion (O2•-) production are one of the hallmarks of endothelial cell proliferation. Increased expression of endothelial nitric oxide synthase (eNOS) has been shown to play an important role in maintaining high levels of •NO generation to offset the increase in O2•- that occurs during proliferation. Although recent reports indicate that heat shock protein 90 (hsp90) associates with eNOS to increase •NO generation, the role of hsp90 association with eNOS during endothelial cell proliferation remains unknown. In this report, we examine the effects of endothelial cell proliferation on eNOS expression, hsp90 association with eNOS, and the mechanisms governing eNOS generation of •NO and O2•-. Western analysis revealed that endothelial cells not only increased eNOS expression during proliferation but also hsp90 interactions with the enzyme. Pretreatment of cultures with radicicol (RAD, 20 µM), a specific inhibitor that does not redox cycle, decreased A23187-stimulated •NO production and increased Lω-nitroargininemethylester (L-NAME)-inhibitable O2•-generation. In contrast, A23187 stimulation of controls in the presence of L-NAME increased O2•- generation, confirming that during proliferation eNOS generates •NO. Our findings demonstrate that hsp90 plays an important role in maintaining •NO generation during proliferation. Inhibition of hsp90 in vascular endothelium provides a convenient mechanism for uncoupling eNOS activity to inhibit •NO production. This study provides new understanding of the mechanisms by which ansamycin antibiotics inhibit endothelial cell proliferation. Such information may be useful in the development and design of new antineoplastic agents in the future.

Natriuretic Peptides, Ejection Fraction, and Prognosis – Parsing the Phenotypes of Heart Failure

James L. Januzzi, JR
J Amer Coll Cardiol 2013; 61(14): 1507-9
http://dx.doi.org/10.1016/j.jacc.2013.01.039

Since the first pivotal studies introduced the natriuretic peptides as biomarkers for the diagnosis of heart failure (HF), use of both B-type natriuretic peptide (BNP) and its N-terminal equivalent (NT-proBNP) has grown not only for this indication, but also for establishing HF prognosis as well. Indeed, a vast array of studies has established the natriuretic peptides as the biomarker gold standard to prognosticate risk for a wide array of relevant complications in HF (ranging from ventricular arrhythmias to pump failure). In these studies, the prognostic information provided by BNP and NT-proBNP in HF was independent of a number of relevant covariates, including left ventricular ejection fraction (LVEF).

It has been known for quite a while that patients with heart failure and preserved ejection fraction (HFpEF) typically have lower natriuretic peptide values than do those with heart failure and reduced ejection fraction (HFrEF). A conundrum is thus present: whereas both BNP and NTproBNP tend to be lower in HFpEF, when these peptides are elevated in this setting, they remain prognostic; this intriguing circumstance has been relatively poorly studied. It is in this setting that van Veldhuisen et al. examined the impact of LVEF on the prognostic merits of BNP in the COACH (Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure) study in the present issue of the Journal. The investigators found—as expected—that BNP levels were lower in HFpEF, but for a given BNP concentration, prognosis of those with HFpEF in COACH was just as poor as those with HFrEF at matched BNP values. Stated differently, a high BNP in a patient with HFpEF imparted similar prognostic information as it would in someone with HFrEF. Actually, whereas LVEF was not obviously prognostically impactful, when considered across the range of ventricular function, an elevated BNP concentration in the most normal range of LVEF seemed to be associated with a higher risk than at the lower ranges of pump function. Although it is previously established that BNP or NT-proBNP are prognostic independently of LVEF, the well-executed analysis by van Veldhuisen et al. (van Veldhuisen DJ, Linssen GCM, Jaarsma T, et al. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013;61:1498–506.) allows for a more in-depth examination of this phenomenon and raises some important questions.

Phenotypic Definition of the Patient With Heart Failure

Phenotypic Definition of the Patient With Heart Failure

Phenotypic Definition of the Patient With Heart Failure

Natriuretic Peptides in Heart Failure with Preserved Ejection Fraction

Mark Richards, James L. Januzzi Jr, Richard W. Troughton
Heart Failure Clin 10 (2014) 453–470
http://dx.doi.org/10.1016/j.hfc.2014.04.006

KEY POINTS

  • Threshold values of B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) validated for diagnosis of undifferentiated acutely decompensated heart failure (ADHF) remain useful in patients with heart failure with preserved ejection fraction (HFPEF), with minor loss of diagnostic performance.
  • BNP and NT-proBNP measured on admission with ADHF are powerfully predictive of in-hospital mortality in both HFPEF and heart failure with reduced EF (HFREF), with similar or greater risk in HFPEF as in HFREF associated with any given level of either peptide.
  • In stable treated heart failure, plasma natriuretic peptide concentrations often fall below cut-point values used for the diagnosis of ADHF in the emergency department; in HFPEF, levels average approximately half those in HFREF.
  • BNP and NT-proBNP are powerful independent prognostic markers in both chronic HFREF and chronic HFPEF, and the risk of important clinical adverse outcomes for a given peptide level is similar regardless of left ventricular ejection fraction.
  • Serial measurement of BNP or NT-proBNP to monitor status and guide treatment in chronic heart failure may be more applicable in HFREF than in HFPEF.

 

The bioactivity of atrial NP (ANP) and B-type NP (BNP) encompasses short-term and longterm hemodynamic, renal, neurohormonal, and trophic effects. The relationship between cardiac hemodynamic load, plasma concentrations of ANP and BNP, and the cardioprotective profile of NP bioactivity have led to investigation of both biomarker and therapeutic potential of

NPs in HF.

PlasmaBNPandNT-proBNP thresholds (100pg/mL and 300 pg/mL, respectively) used in the diagnosis of undifferentiated ADHF retain good diagnosticperformance for acute HFPEF

 

Plasma NPs are related to multiple echo indicators of cardiac structure and function in both HFREF and HFPEF.
Box 1Causes of increased plasma cardiac natriuretic peptides

Cardiac

Heart failure, acute and chronic

Acute coronary syndromes

Atrial fibrillation

Valvular heart disease

Cardiomyopathies

Myocarditis

Cardioversion

Left ventricular hypertrophy

Noncardiac

Age

Female sex

Renal impairment

Pulmonary embolism

Pneumonia (severe)

Obstructive sleep apnea

Critical illness

Bacterial sepsis

Severe burns

Cancer chemotherapy

Toxic and metabolic insults

 

BNP and NT-proBNP fall below ADHF thresholds in stable HFREF in approximately 50% and 20% of cases, respectively. Levels in stable HFPEF are even lower, approximately half those in HFREF.
Whereas BNPs have 90% sensitivity for asymptomatic LVEF of less than 40% in the community (a precursor state for HFREF), they offer no clear guide to the presence of early community based HFPEF.
Guidelines recommend BNP and NT-proBNP as adjuncts to the diagnosis of acute and chronic HF and for risk stratification. Refinements for application to HFPEF are needed.
The prognostic power of NPs is similar in HFREF and HFPEF. Defined levels of BNP and NT-proBNP correlate with similar short-term and long-term risks of important clinical adverse outcomes in both HFREF and HFPEF.
Diagnostic algorithm for suspected heart failure presenting either acutely or nonacutely

Diagnostic algorithm for suspected heart failure presenting either acutely or nonacutely

Diagnostic algorithm for suspected heart failure presenting either acutely or nonacutely. a In the acute setting, mid-regional pro–atrial natriuretic peptide may also be used (cutoff point 120 pmol/L; ie, <120 pmol/L 5 heart failure unlikely). b Other causes of elevated natriuretic peptide levels in the acute setting are an acute coronary syndrome, atrial or ventricular arrhythmias, pulmonary embolism, and severe chronic obstructive pulmonary disease with elevated right heart pressures, renal failure, and sepsis. Other causes of an elevated natriuretic level in the nonacute setting are old age (>75 years), atrial arrhythmias, left ventricular hypertrophy, chronic obstructive pulmonary disease, and chronic kidney disease. c Exclusion cutoff points for natriuretic peptides are chosen to minimize the false-negative rate while reducing unnecessary referrals for echocardiography. d Treatment may reduce natriuretic peptide concentration, and natriuretic peptide concentrations may not be markedly elevated in patients with heart failure with preserved ejection fraction. BNP, B-type natriuretic peptide; ECG, electrocardiogram; NT-proBNP, N-terminal prohormone of B-type natriuretic peptide. (From McMurray JJ, Adamopoulos S, Anker SD, et al. The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012;33:1787–847; with permission.)

Natriuretic Peptide Receptor-A Negatively Regulates Mitogen-Activated Protein Kinase and Proliferation of Mesangial Cells: Role of cGMP-Dependent Protein Kinase

Kailash N. Pandey, Houng T. Nguyen, Ming Li, and John W. Boyle
Biochem Biophys Res Commun 271, 374–379 (2000)
http://dx.doi.org:/10.1006/bbrc.2000.2627

peptide (ANP) and its guanylyl cyclase/natriuretic peptide receptor-A (NPRA) on mitogen-activated protein kinase/extracellular signal-regulated kinase 2 (MAPK/ERK2) activity in rat mesangial cells overexpressing NPRA. Agonist hormones such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiotensin II (ANG II), and endothelin-1 (ET-1) stimulated 2.5- to 3.5-fold immunoreactive MAPK/ERK2 activity in these cells. ANP inhibited agonist-stimulated activity of MAPK/ERK2 by 65–75% in cells overexpressing NPRA, whereas in vector transfected cells, its inhibitory effect was only 18–20%. NPRA antagonist A71915 and KT5823, a specific inhibitor of cGMP-dependent protein kinase (PKG) completely reversed the inhibitory effect of ANP on MAPK/ERK2 activity. ANP also inhibited the PDGF stimulated [3H]thymidine uptake by almost 70% in cells overexpressing NPRA, as compared with only 20–25% inhibition in vector-transfected cells. These
results demonstrate that ANP/NPRA system negatively regulates MAPK/ERK2 activity and proliferation of mesangial cells in a PKG-dependent manner.

 

Regulation of lipoprotein lipase by Angptl4

Wieneke Dijk and Sander Kersten
Trends in Endocrin and Metab, Mar2014; 25(3):146-155
http://dx.doi.org/10.1016/j.tem.2013.12.005

Triglyceride (TG)-rich chylomicrons and very low density lipoproteins (VLDL) distribute fatty acids (FA) to various tissues by interacting with the enzyme lipoprotein lipase (LPL). The protein angiopoietin-like 4 (Angptl4) is under sensitive transcriptional control by FA and the FA-activated peroxisome proliferator activated receptors (PPARs), and its tissue expression largely overlaps with that of LPL. Growing evidence indicates that Angptl4 mediates the physiological fluctuations in LPL activity, including the decrease in
adipose tissue LPL activity during fasting. This review focuses on the major ambiguities concerning the mechanism of LPL inhibition by Angptl4, as well as on the physiological role of Angptl4 in lipid metabolism, highlighting its function in a variety of tissues, and uses this information to make suggestions for further research.

Box 1. LPL and TG metabolism

LPL belongs to a family of lipases that also includes hepatic lipase, pancreatic lipase, and endothelial lipase. Because LPL is essential in the lipolytic processing of chylomicrons and VLDL, LPL is primarily expressed in tissues that either require large amounts of FA as fuel or are responsible for TG storage, which include heart, skeletal muscle, and adipose tissue. Upon production by the underlying parenchymal cells, LPL is released into the subendothelial space and is transported to the luminal side of the capillary endothelium by the GPI-anchored protein GPIHBP1, which after transport continues to anchor LPL to the capillary endothelium. The essential role for LPL in the clearance of plasma TG is well-demonstrated by the severe hypertriglyceridemia of patients carrying homozygous mutations in the LPL gene. Generalized deletion of LPL in mice results in severe hypertriglycer-idemia, resulting in the premature death of pups within 24 h after birth. Analogous to the deletion of LPL, the mislocalization of LPL to the subendothelial spaces due the absence or misfolding of GPIHBP1 also results in severe chylomicronemia and hypertriglyceridemia. The LPL enzyme is catalytically active as a non-covalent head-to-tail dimer with a catalytic N-terminal domain and a non-catalytic C terminal domain. Folding of LPL into its dimer conformation occurs in the endoplasmic reticulum, chaperoned by lipase maturation factor 1, calreticulin, and calnexin. In its active 3D conformation, the catalytic site of LPL is postulated to be covered by a lid, which can be opened by the binding of chylomicrons and VLDL to the C terminus. The active LPL dimers rapidly exchange subunits, indicating that a dynamic equilibrium exists between LPL dimers and dimerization-competent monomers. Dimerization-competent monomers have, however, not yet been isolated, and it is unclear whether this monomer is catalytically active. The enzymatic activity of LPL is lost when the LPL dimer is converted into inactive, folded monomers. This conversion to inactive monomers is mainly regulated via post-translational mechanisms and is dependent on nutritional state. Enzymatic activity of inactive monomers can be regained in vitro by the addition of calcium, indicating that inactivation of LPL is a reversible process.

One of the key questions is whether (patho)physiological variations in LPL activity are mediated via regulation of Angptl4 cleavage and/or oligomerization, and which factors are involved in modulating Angptl4 in vivo. Recent biochemical evidence suggests that FA may be able to promote dissociation of oligomers, which, by destabilizing the protein, would impair its ability to inhibit LPL. Destabilization of Angptl4 by FA is, however, seemingly at odds with the marked stimulatory effect of FA on Angptl4 production observed in vitro and in vivo.

The currently accepted molecular model for the inhibition of LPL by Angptl4 is that Angptl4 stimulates the conversion of catalytically active LPL dimers into inactive monomers – following in vitro studies showing that coincubation of LPL and Angptl4 increases the abundance of LPL monomers. Subsequent studies revealed that the proportion of LPL dimers is reduced in post-heparin plasma of mice that overexpress Angptl4 in favor of LPL monomers, providing in vivo support for the dimer-to monomer conversion. The elucidation of the purported biochemical mechanism has strengthened the status of Angptl4 as a LPL inhibitor, but several questions related to the in vivo mechanism remain unanswered. Whereas the original in vitro experiments favored the hypothesis that Angptl4 enzymatically and irreversibly catalyzes the LPL dimer-to-monomer conversion, an in vivo study of Angptl4 transgenic mice suggested that Angptl4 is physically bound to LPL monomers, thereby driving the LPL dimer–monomer equilibrium towards inactive monomers. The latter study also revealed that the relative decrease in post-heparin plasma LPL activity upon Angptl4 overexpression is much more pronounced than the relative decrease in heparin-releasable LPL dimers, pointing to an additional or alternative mechanism. In support, a recently published study suggests that Angptl4, instead of acting as a catalyst, functions as a conventional, non-competitive inhibitor that binds to LPL to prevent the hydrolysis of substrate LPL and Angptl4 are regulated by changes in nutritional state in a tissue-specific manner, reflecting the different functions of these tissues and the corresponding variations in physiological requirements for lipids. Below, we discuss current knowledge on the regulation of Angptl4 and LPL in response to various physiological stimuli and address the importance of Angptl4 in lipid uptake. An overview of the role of Angptl4 in physiological regulation of lipid metabolism is presented in Figure 2.

model for mechanisms of lipoprotein lipase (LPL) inhibition by Angptl4.

model for mechanisms of lipoprotein lipase (LPL) inhibition by Angptl4.

Figure 1. Hypothetical model for mechanisms of lipoprotein lipase (LPL) inhibition by Angptl4. Angiopoietin-like 4 (Angptl4) and LPL are expressed in the parenchymal cells of muscle, heart, and adipose tissue. Following secretion of LPL and Angptl4 into the subendothelial space, transport of LPL to the capillary lumen is mediated by two mechanisms. The principal transport mechanism (1) relies on GPIHBP1 [glycosylphosphatidylinositol (GPI)-anchored high density lipoprotein-binding protein] picking up LPL from the subendothelial space and transporting it to the capillary lumen. This action by GPIHBP1 is opposed by Angptl4, which is bound to extracellular matrix (ECM) proteins and which retains and inhibits LPL. In the presence of GPIHBP1, high expression levels of Angptl4 are needed to overcome the competition with GPIHBP1. Angptl4 secreted into the capillary lumen, primarily as N-terminal truncation fragment generated by cleavage by proprotein convertases (PCs), inhibits LPL activity on the endothelium by promoting the irreversible conversion of LPL dimers into inactive monomers and/or via a reversible mechanism that requires binding of Angptl4 to LPL. The second transport mechanism involves a so far unidentified carrier and can be disrupted by Angptl4. In the absence of GPIHBP1, Angptl4 fully retains LPL in the subendothelial space (a). The additional loss of Angptl4 liberates LPL and allows it to be transported to the endothelial surface via the unidentified carrier (b). This model suggests that Angptl4 and LPL start interacting before arrival in the capillary lumen, either in the parenchymal cells or in the subendothelial space. Abbreviation: HSPG, heparan sulfate proteoglycan.

Regulation and role of angiopoietin-like 4 (Angptl4)

Regulation and role of angiopoietin-like 4 (Angptl4)

Figure 2. Regulation and role of angiopoietin-like 4 (Angptl4) in lipid metabolism. Angptl4 is expressed in parenchymal cells of white adipose tissue (WAT), liver, intestine, heart and muscle, as well as in macrophages, where it is subject to cell- and tissue-specific regulation. Angptl4 is a sensitive target of peroxisome proliferator-activated receptor (PPAR) transcription factors in several tissues. In WAT the expression of Angptl4 is induced during fasting and by the transcription factors PPARg, glucocorticoid receptor (GR), and hypoxia inducible factor 1a (HIF1a). In WAT Angptl4 stimulates lipolysis of stored triglycerides (TG) and inhibits lipoprotein lipase (LPL) activity. Expression of Angptl4 in liver is stimulated by PPARa, PPARd, and GR. Because the liver does not express LPL, Angptl4 is mainly released into the blood, affecting LPL activity in peripheral tissues. Angptl4 may also impact upon hepatic lipase activity in liver. Expression of Angptl4 in heart and skeletal muscle is potently induced by fatty acids (FA) via PPARd activation. Angptl4 inhibits LPL activities in cardiac and likely skeletal muscle. FA also stimulate Angptl4 expression in macrophages via PPARd, leading to local inhibition of LPL activity. We hypothesize that macrophage LPL enables uptake of remnant particles containing lipid antigens, which are subsequently presented to natural killer T cells. In the intestine, FA stimulate Angptl4 expression via one of the PPARs. Angptl4 produced by enterocytes may be released towards the lumen and inhibit pancreatic lipase activity. Angptl4 produced by enteroendocrine cells is released towards the blood and may inhibit LPL in distant tissues.

Box 2. Outstanding questions

  1. What is the importance of Angptl4 cleavage and oligomerization to Angptl4 function in vivo?
  2. What is the precise biochemical mechanism behind the inhibition of LPL activity by Angptl4?
  3. At which cellular location(s) does the inhibition of LPL by Angptl4 occur and, if at multiple locations, what is the relative contribution of both tissue-produced Angptl4 compared to circulating Angptl4 with respect to inhibition of tissue LPL activity.
  4. What is the interplay between GPIHBP1 and Angptl4 in the regulation of LPL activity?
  5. What is the protein structure of Angptl4 and LPL?
  6. Does Angptl4 also regulate LPL activity in brown adipose tissue and skeletal muscle and, if so, how is the expression of Angptl4 regulated in these tissues?
  7. What is the potential of Angptl4 as a biomarker in the context of disorders of lipid metabolism?

In the past decade, angiopoietin-like proteins have been demonstrated to regulate plasma TG levels powerfully in mice and humans. The elucidation of these proteins as inhibitors of LPL activity has led to a paradigm shift in how clearance of circulating TG and thereby tissue uptake of FA are regulated. Most of our understanding of angiopoietin-like proteins has resulted from detailed study of Angptl4.

A major portion of the physiological variation in LPL activity in various tissues can be attributed to regulation of Angptl4 production. We predict that Angptl4 will turn out to be equally important for governing LPL activity in muscle during exercise, in brown adipose tissue during cold, and in several tissues during fasting.

Besides the increasing recognition of the pivotal role of Angptl4 in lipid metabolism as an inhibitor of LPL, major insight has been gained into the molecular mechanism of action of Angptl4. Key questions remain, however, especially related to the interaction between LPL, GPIHBP1, and Angptl4 on the endothelium and in the subendothelial space. Several points of interest have been highlighted throughout the text; these include the elucidation of the molecular structure for LPL and Angptl4 by X-ray crystallography and the clarification of in vivo Angptl4 cleavage and oligomerization.

Native Low-Density Lipoprotein Induces Endothelial Nitric Oxide Synthase Dysfunction: Role of Heat Shock Protein 90 And Caveolin-1

Kirkwood A. Pritchard, Jr., Allan W. Ackerman, Jingsong Ou, et al.
Free Radical Biol & Med 2002; 33(1):52–62 PII S0891-5849(02)00851-1

Although native LDL (n-LDL) is well recognized for inducing endothelial cell (EC) dysfunction, the mechanisms remain unclear. One hypothesis is n-LDL increases caveolin-1 (Cav-1), which decreases nitric oxide (•NO) production by binding endothelial nitric oxide synthase (eNOS) in an inactive state. Another is n-LDL increases superoxide anion (O2•-), which inactivates •NO. To test these hypotheses, EC were incubated with n-LDL and then analyzed for •NO, O2•-, phospho-eNOS (S1179), eNOS, Cav-1, calmodulin (CaM), and heat shock protein 90 (hsp90). n-LDL increased NOx by more than 4-fold while having little effect on A23187-stimulated nitrite production. In contrast, n-LDL decreased cGMP under basal and A23187-stimulated conditions and increased O2•-by a mechanism that could be inhibited by L-nitroargininemethylester (L-NAME) and BAPTA/AM. n-LDL increased phospho-eNOS by 149%, eNOS by [1]34%, and Cav-1 by 28%, and decreased the association of hsp90 with eNOS by 49%. n-LDL did not appear to alter eNOS distribution between membrane fractions (-85%) and cytosol (-15%). Only 3–6% of eNOS in membrane fractions was associated with Cav-1. These data support the hypothesis that n-LDL increases O2•-, which scavenges •NO, and suggest that n-LDL uncouples eNOS activity by decreasing the association of hsp90 as an initial step in signaling eNOS to generate O2•-.

In conclusion, n-LDL decreases the association of hsp90 with eNOS, increases phospho-eNOS levels, and increases eNOS-dependent O2•-generation. These findings suggest that activation of eNOS without adequate levels of hsp90 may signal eNOS to switch from •NO to O2•-generation. Such changes in eNOS radical product generation may play an important role in impairing endothelial and vascular function.

New insights into IGF-1 signaling in the heart

Rodrigo Troncoso, C Ibarra, JM Vicencio, E Jaimovich, and S Lavandero
Trends in Endocrin and Metab, Mar 2014; 25(3):128-131
http://dx.doi.org/10.1016/j.tem.2013.12.002

Insulin-like growth factor 1 (IGF-1) signaling regulates contractility, metabolism, hypertrophy, autophagy, senescence, and apoptosis in the heart. IGF-1 deficiency is associated with an increased risk of cardiovascular disease, whereas cardiac activation of IGF-1 receptor (IGF-1R) protects from the detrimental effects of a high-fat diet and myocardial infarction. IGF-1R activates multiple pathways through its intrinsic tyrosine kinase activity and through coupling to heterotrimeric G protein. These pathways involve classic second messengers, phosphorylation cascades, lipid signaling, Ca2+ transients, and gene expression. In addition, IGF-1R triggers signaling in different subcellular locations including the plasma membrane, perinuclear T tubules, and also in internalized vesicles. In this review, we provide a fresh and updated view of the complex IGF-1 scenario in the heart, including a critical focus on therapeutic strategies.

The hormone insulin-like growth factor 1 (IGF-1) is a small peptide of 7.6 kDa, which is composed of 70 amino acids and shares 50% homology with insulin. IGF-1 plays key roles in regulating proliferation, differentiation, metabolism, and cell survival. It is mainly synthesized and secreted by the liver in response to hypothalamic growth hormone (GH); its plasma concentration is finely regulated (Box 1). However, other tissues also produce IGF-1, which acts locally as an autocrine and paracrine hormone. IGF-1 exhibits pleiotropic effects in many organs and is also involved in the development of several pathologies.

Box 1. IGF-1 synthesis and biodisponibilityInsulin-like growth factor 1 (IGF-1) is a 70 amino acid peptide

hormone with endocrine, paracrine, and autocrine effects. It shares

>60% structure homology with IGF-2 and 50% with pro-insulin. IGF-

1 is mainly synthesized in the liver in response to hypothalamic

growth hormone (GH). In the peripheral circulation it exerts negative

feedback on the somatotrophic axis suppressing pituitary GH

release. IGF-1 can also be generated in almost all tissues, but liver

synthesis accounts for nearly 75% of circulating IGF-1 levels. As a

hormone with a wide range of physiological roles, IGF-1 circulating

levels must be strictly controlled. Around 98% of circulating IGF-1 is

bound to insulin-like growth factor binding protein (IGFBP). Six

forms of high affinity IGFBP have been described, with IGFBP3

binding approximately 90% of circulating IGF-1. Also, IGFBP1–6 and

their fragments have significant intrinsic biological activity independent

of IGF-1 interaction.

Canonical and noncanonical IGF-1 signaling pathways Activation of IGF-1R requires the sequential phosphorylation of three conserved tyrosine residues within the activation loop of the catalytic domain. From these phosphorylated motifs, tyrosine 950 contained in an NPXY motif provides a docking site for the recruitment of adaptor proteins, such as insulin receptor substrate-1 (IRS-1) and Shc, as an obligatory step to initiate signaling cascades. Two canonical pathways are activated by IGF-1R in cardiomyocytes – the phosphatidylinositol-3 kinase (PI3K)/Akt pathway and the extracellular signal-regulated kinase (ERK) pathway. Both pathways have been extensively studied, and their involvement in the pro-hypertrophic and pro-survival actions in cardiomyocytes is well established. Interestingly, a noncanonical signaling mechanism for IGF-1R in cardiomyocytes has been described in several recent studies. These studies show that some of the effects of IGF-1 are inhibited by the heterotrimeric Gi protein blocker Pertussis toxin (PTX) in several cell lines, suggesting that IGF-1R is a dual-activity receptor that triggers tyrosine-kinase-dependent responses as well as Gi-protein-dependent pathways. This duality has been reported in cultured neonatal cardiomyocytes; IGF-1R can activate ERK and Akt but also phospholipase C (PLC), which increases inositol 1,4,5 triphosphate (InsP3; IP3) leading to nuclear Ca2+ signals.

The cardiac effects of IGF-1 are mediated by activation of the plasma membrane IGF-1R, which belongs to the receptor tyrosine kinase (RTK) family. IGF-1R comprises a α2β2 heterotetrameric complex of approximately 400 kDa. Structurally, IGF-1R has two extracellular a-subunits that contain the ligand-binding sites. Each α-subunit couples to one of two membrane-spanning β-subunits, which contain an intracellular domain with intrinsic tyrosine kinase activity. Both subunits of IGF-1R are the product of one single gene, which is synthesized as a 180 kDa precursor. The immature IGF-1R full peptide is further glycosylated, dimerized, and proteolytically processed for assembly of the mature receptor isoforms a and b. In neonatal and adult rat cardiomyocytes, the IGF-1R precursor peptide and the processed α and β receptor subunits have been detected. Binding of IGF-1 to its receptor initiates a complex signaling cascade in cardiomyocytes.

Figure 1. not shown. Canonical and noncanonical signaling pathways activated by insulin-like growth factor 1 (IGF-1) in cardiomyocytes. Binding of IGF-1 to plasma membrane IGF-1 receptor (IGF-1R) leads to receptor autophosphorylation in the intracellular β-subunits. Docking of Grβ2 to the phosphorylated IGF-1Rβ subunits leads to extracellular signal-regulated kinase (ERK) phosphorylation through the Ras/Raf/Mitogen-activated protein kinase (MEK) axis. Phosphorylated ERK can translocate to the nucleus to control gene expression. Phosphorylated β-subunits also provide docking sites for insulin receptor substrate-1 (IRS-1), which mediates phosphatidylinositol-3 kinase (PI3K) activation and Akt phosphorylation. Downstream targets of activated Akt are mechanistic target of rapamycin (mTOR), which suppresses autophagy and promotes protein synthesis by activating S6K and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). Akt also phosphorylates and inactivates Bad, thus inhibiting apoptosis. IGF-1R activation also promotes its interaction with a Pertussis-toxin-sensitive heterotrimeric Gi protein, which mediates the activation of phospholipase C (PLC) and hydrolysis of plasma membrane phosphatidylinositol 4,5 biphosphate (PIP2) to form inositol 1,4,5 triphosphate (InsP3; IP3) which activates InsP3 receptors located at the endoplasmin reticulum (ER)/nuclear envelope Ca2+ store, producing nucleoplasmic and cytoplasmic Ca2+ increases. The former is involved in the regulation of specific target genes and the latter promotes mitochondrial Ca2+ uptake, which increases mitochondrial respiration and metabolism, further preventing apoptosis and regulating autophagy. Canonical signaling pathways include the ERK and Akt axes, and are shown in red, whereas the noncanonical G protein pathway is shown in blue. Both pathways interact as Ca2+ contributes to ERK activation and additionally both Akt and ERK can compensate each other’s activation. Abbreviations: MEK, Mitogen-activated protein kinase; mTOR, mechanistic target of rapamycin; 4EBP1, eukaryotic translation initiation factor 4E binding protein 1; PIP2, phosphatidylinositol 4,5 biphosphate.

Figure 2. not shown. Classical versus proposed models of nuclear Ca2+ signaling in cardiomyocytes. The insulin-like growth factor 1 receptor (IGF-1R) can specifically regulate nuclear Ca2+ signaling independently of the role of Ca2+ on excitation–contraction coupling. On the classic model, inositol 1,4,5 triphosphate (InsP3; IP3) produced after IGF-1R activation travels from the peripheral plasma membrane to the nucleus, where it activates InsP3 receptors. In this model InsP3 bypasses its receptors present on the sarcoplasmic reticulum, which would lead to cytosolic Ca2+ signals. The novel model that we propose is based on recent findings, where the IGF-1R signaling complex is present in T-tubule invaginations toward the nucleus. In these compartments, IGF-1R activation leads to locally restricted InsP3 production that allows nuclear Ca2+ signals to regulate gene expression of genes associated with the development of cardiomyocyte hypertrophy. Abbreviations: RyR, ryanodine receptor; ECC, excitation–contraction coupling; PLC, phospholipase C; DHPR, dihydropyridine receptor.

The beneficial roles of IGF-1 in the cardiovascular system largely explain the interest in the development of new IGF-1-based treatments for cardiovascular disease. So far the FDA has approved two drugs for the treatment of IGF-1 deficiency: mecasermin (Increlex1), a human recombinant IGF-1 analog; and mecasermin rinfabate (IPLEX1), a binary protein complex of human recombinant IGF-1 and human recombinant IGBP-3. The safety of a chronic systemic IGF-1 therapy is open to question because it could promote severe adverse effects, such as an increased risk of cancer. To avoid these problems, several researchers have selectively overexpressed IGF-1 and IGF-1R in the heart.

Box 2. Outstanding questionsInsulin-like growth factor 1 (IGF-1) is an old friend of the heart. Despite the well-known protective effects of IGF-1 on cardiac function and the antiapoptotic effects of this peptide, novel evidence opens new questions to this longstanding relationship.

·       How do the multiple signaling pathways triggered by IGF-1 receptor (IGF-1R) interact with each other?

·       What lies further than extracellular signal-regulated kinase (ERK)/Akt/Ca2+ activation toward heart function?

·       Do these signaling pathways regulate cardiac fibroblast or endothelial cell function?

·       Which are the specific downstream signaling pathways of the different pools of IGF-1R and their role in regulating cardiomyocyte survival, hypertrophy, metabolism, proliferation?

·       What drives IGF-1R to such specific subcellular compartments?

·       What is the relevance of the hybrid IGF-1R/insulin receptors on cardiovascular disease?

·       Does a crosstalk exist between insulin receptor and IGF-1R in the heart under physiological and pathological conditions?

·       Is one pathway more beneficial than the other?

·       Will stem cell therapy of cardiac progenitors be able to provide concrete treatment opportunities?

·       Is IGF-1 a key regulator of this outcome?

Abundant evidence supports the key physiological roles of IGF-1 in the heart. In cardiomyocytes, IGF-1 activates multiple downstream signaling pathways for controlling cell death, metabolism, autophagy, differentiation, transcription, and protein synthesis (Figure 1). Of great interest are the findings that the entire IGF-1R complex is strategically located in perinuclear sarcolemmal invaginations that locally control nuclear Ca2+ signaling and transcriptional upregulation (Figure 2). This novel evidence changesmthe classical paradigm of IGF-1 signaling and adds a new level of complexity that may be relevant for other signaling receptors in the heart: interorganelle communication between plasma membrane invaginations and the nucleus.
The strategic localization of IGF-1R in these structures and the association with heterotrimeric G proteins may explain the differences in the phenotypic response induced by IGF-1 and others agonists, like endothelin-1 and angiotensin II, that also signal through intracellular Ca2+. By activating a noncanonical, selective mechanism of nuclear Ca2+ release, IGF-1 can regulate the expression of a specific set of cardiac genes via the generation of a particular signal-encoding pattern, leading to adaptive cardiac hypertrophy, antiapoptotic effects, and metabolic adaptation.

Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction – any Pathophysiological Role of Mitral Regurgitation

Marco Guazzi
http://dx.doi.org:/10.1016/j.jacc.2009.04.088

read with interest the study by Lam et al. (1) as an important contribution to the pathophysiological and clinical impact of pulmonary hypertension (PH) in hypertensive patients with heart failure and preserved left ventricular ejection fraction (HFpEF). Recent guidelines on arterial PH recognize HFpEF as a growing cause of left-sided PH, but a definitive appreciation of its true prevalence and prognostic relevance is lacking. The present study provides some new important information on this subject.

It is noteworthy that HFpEF was associated, in a high rate of cases (83%), with a typical hemodynamic pattern of precapillary PH, and a strong correlation was found between pulmonary artery systolic pressure and pulmonary capillary wedge pressure. Most important, pulmonary artery systolic pressure, rather than other echocardiography-derived measures of diastolic dysfunction, was the only significant multivariate predictor of mortality, a finding that was confirmed even when combined comorbid diseases potentially contributing to PH development, such as chronic obstructive pulmonary disease, were taken into account.

In patients with systolic heart failure, a major determinant of PH development is mitral regurgitation. Whether mitral regurgitation could be a putative factor in the pathogenesis of PH in HFpEF patients remains an open and intriguing question.

Accordingly, it would be of interest if the authors could provide some details on how many HFpEF patients exhibited mitral regurgitation, especially in comparison with control hypertensive patients without HFpEF.

Lam CSP, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009; 53:1119–23.

Midregion Prohormone Adrenomedullin and Prognosis in Patients Presenting with Acute Dyspnea Results from the BACH (Biomarkers in Acute Heart Failure) Trial

Alan Maisel, MD, Christian Mueller, Richard M. Nowak,W. Frank Peacock, et al.
J Am Coll Cardiol 2011; 58(10):1057–67
http://dx.doi.org:/10.1016/j.jacc.2011.06.006

Objectives The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath.
Background
The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p < 0.001) in acute heart failure.
Methods The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission.
Results Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 90-day all-cause mortality in patients presenting with acute dyspnea (c index = 0.755, p < 0.0001). Furthermore, MR-proADM added significantly to all clinical variables (all adjusted hazard ratios: HR=3.28), and it was also superior to all other biomarkers. MRproADM added significantly to the best clinical model (bootstrap-corrected c index increase: 0.775 to 0.807; adjusted standardized hazard ratio: 2.59; 95% confidence interval: 1.91 to 3.50; p < 0.0001). Within the model, MR-proADM was the biggest contributor to the predictive performance, with a net reclassification improvement of 8.9%. Serial evaluation of MR-proADM performed in patients admitted provided a significant added value compared with a model with admission values only (p< 0.0005). More than one-third of patients originally at high risk could be identified by the biomarker evaluation at discharge as low-risk patients. Conclusions MR-proADM identifies patients with high 90-day mortality and adds prognostic value to natriuretic peptides in patients presenting with acute shortness of breath. Serial measurement of this biomarker may also prove useful for monitoring, although further studies will be required. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628)

Invasive Hemodynamic Characterization of Heart Failure with Preserved Ejection Fraction

Mads J. Andersen, Barry A. Borlaug
Heart Failure Clin 10 (2014) 435–444
http://dx.doi.org/10.1016/j.hfc.2014.03.001

KEY POINTS

  • Invasive hemodynamic assessment in heart failure with preserved ejection fraction (HFpEF) was originally a primary research tool to advance the understanding of the pathophysiology of HFpEF.
  • The role of invasive hemodynamic assessment in HFpEF is expanding to the diagnostic arena where invasive assessment offers a robust, sensitive, and specific way to diagnose or exclude HFpEF in patients with unexplained dyspnea and normal ejection fraction.
  • In future years, invasive hemodynamic profiling may more rigorously phenotype patients to individualized therapy and, potentially, deliver novel device-based structural interventions.

The circulatory system serves to deliver substrates to the body via the bloodstream while removing the byproducts of cellular metabolism. Hemodynamics broadly refers to the study of the forces involved in the circulation of blood, which are governed by to the physical properties of the heart and vasculature and their dynamic regulation by the autonomic nervous system.

Afterload represents the forces opposing ventricular ejection and can be quantified by systolic left ventricular (LV) wall stress and aortic input impedance or its individual components (resistance, compliance, characteristic impedance). Wall stress is inconvenient because it depends on heart size and geometry, whereas impedance is cumbersome because it is a frequency-domain parameter that cannot be easily coupled with time-domain measures of ventricular function. Effective arterial elastance (Ea), defined by the ratio of LV end-systolic pressure (ESP) to stroke volume, provides a robust measure of total arterial load. Ea is not a directly measured parameter but, instead, a net or lumped stiffness of the vasculature that incorporates both mean and oscillatory components of afterload (Fig. 1). Preload reflects the degree of myofiber stretch before the onset of contraction, which, in turn, dictates the force and velocity of contraction according to the Frank-Starling principle. In everyday practice, preload is often conceptualized as equivalent to LV filling pressures. However, in fact, preload is most accurately reflected by the LV volume at end-diastole volume (EDV). Filling pressures are related to EDV by the LV diastolic chamber stiffness, which differs in healthy volunteers and subjects with HFpEF.

Fig. 1. Not shown. Ventricular-arterial coupling in the pressure-volume plane. Pressure volume loop at steady state is shown in dark black. The area subtended by the loop (shaded) represents the stroke work. Stroke volume is the difference between end-diastolic volume (EDV) and end-systolic volume (ESV). Ea is defined by the negative slope connecting the ESP and ESV coordinates with EDV and pressure = 0. With acute preload reduction (dotted line loops) there is progressive reduction in EDV, ESV, and ESP. The linear slope of the endsystolic pressure volume relationship (ESPVR) is LV end-systolic elastance (Ees). The curvilinear slope of the end diastolic pressure–volume relationship (EDVPR) is derived by fitting pressure volume coordinates measured during diastasis to the equation shown. The exponential power or stiffness constant (b) obtained is a measure of LV diastolic stiffness. (Adapted from Borlaug BA, Kass DA. Invasive hemodynamic assessment in heart failure. Heart Fail Clin 2009;5(2):217–28; with permission.)

Fig. 3. Not shown. Left ventricular diastolic reserve in HFpEF. In the normal healthy adult, the rate of LV pressure decay during isovolumic contraction (t) is rapid and increases markedly during exercise in association with a reduction in LVmin, allowing for suction of blood into the LV, with no increase in left atrial pressure or LV end-diastolic pressure (LVEDP) despite an increase in LV end-diastolic volume and marked shortening of the cycle length. In HFpEF, relaxation is prolonged at baseline (increased t) with inadequate hastening (shortening of t) during exercise, contributing to an inability to reduce LVmin and, consequently, a complete lack of suction effects. LV filling then completely depends on left atrial hypertension, which develops in tandem with marked elevation in LVEDP. (Data from Borlaug BA, Jaber WA, Ommen SR, et al. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart 2011;97(12):964–9.)

Fig. 4. Preload and filling pressures in HFpEF. (A) Cumulative distribution plot shows that acute changes in stroke volume with nitroprusside infusion are lower in HFpEF (black) compared with HFrEF (red). Because afterload (Ea) is lowered, any acute reduction in SV must be related to reduction in preload volume (EDV) and nearly 40% of HFpEF patients experienced stroke volume reduction with nitroprusside, despite high filling pressures (PCWP 20–25 mm Hg), indicating increased reliance on high pressures to achieve adequate EDV. *p<0.0001 compared with HFrEF. (B) LVEDP in a healthy adult (blue) and in a HFpEF patient with increased LV diastolic stiffness (green). At the same preload (EDV), pressure is more than twofold higher in HFpEF. In contrast, at the same LV diastolic pressure (15 mm Hg), LV volume is much lower in HFpEF, indicating decreased LV diastolic capacitance. V15, volume at end-diastolic pressure = 15 mm Hg; LVEDP. (Adapted from Schwartzenberg S, Redfield MM, From AM, et al. Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on response to therapy. J Am Coll Cardiol 2012;59(5):442–51; with permission.)

Updated Clinical Classification of Pulmonary Hypertension

Gérald Simonneau, Ivan M. Robbins, Maurice Beghetti, et al.
J Am Coll of Cardiol   2009; 54(1), Suppl S
http://dx.doi.org:/10.1016/j.jacc.2009.04.012

The aim of a clinical classification of pulmonary hypertension (PH) is to group together different manifestations of disease sharing similarities in pathophysiologic mechanisms, clinical presentation, and therapeutic approaches. In 2003, during the 3rd World Symposium on Pulmonary Hypertension, the clinical classification of PH initially adopted in 1998 during the 2nd World Symposium was slightly modified. During the 4th World Symposium held in 2008, it was decided to maintain the general architecture and philosophy of the previous clinical classifications. The modifications adopted during this meeting principally concern Group 1, pulmonary arterial hypertension (PAH). This subgroup includes patients with PAH with a family history or patients with idiopathic PAH with germline mutations (e.g., bone morphogenetic protein receptor-2, activin receptor-like kinase type 1, and endoglin). In the new classification, schistosomiasis and chronic hemolytic anemia appear as separate entities in the subgroup of PAH associated with identified diseases. Finally, it was decided to place pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis in a separate group, distinct from but very close to Group 1 (now called Group 1=). Thus, Group 1 of PAH is now more homogeneous. (J Am Coll Cardiol 2009; 54: S43–54)
Updated Evidence-Based Treatment Algorithm in Pulmonary Arterial Hypertension

Robyn J. Barst,  J. Simon R. Gibbs, Hossein A. Ghofrani, et al.
J Am Coll Cardiol 2009; 54(1), Suppl S,

Uncontrolled and controlled clinical trials with different compounds and procedures are reviewed to define the risk benefit profiles for therapeutic options in pulmonary arterial hypertension (PAH). A grading system for the level of evidence of treatments based on the controlled clinical trials performed with each compound is used to propose an evidence-based treatment algorithm. The algorithm includes drugs approved by regulatory agencies for the treatment of PAH and/or drugs available for other indications. The different treatments have been evaluated mainly in idiopathic PAH, heritable PAH, and in PAH associated with the scleroderma spectrum of diseases or with anorexigen use. Extrapolation of these recommendations to other PAH subgroups should be done with caution. Oral anticoagulation is proposed for most patients; diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectively. High doses of calcium-channel blockers are indicated only in the minority of patients who respond to acute vasoreactivity testing. Nonresponders to acute vasoreactivity testing or responders who remain in World Health Organization (WHO) functional class III, should be considered candidates for treatment with either an oral phosphodiesterase-5 inhibitor or an oral endothelin-receptor antagonist. Continuous intravenous administration of epoprostenol remains the treatment of choice in WHO functional class IV patients. Combination therapy is recommended for patients treated with PAH monotherapy who remain in WHO functional class III. Atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unavailable. (J Am Coll Cardiol 2009;54:S78–84)

Inhibition and down-regulation of gene transcription and guanylyl cyclase activity of NPRA by angiotensin II involving protein kinase C

Kiran K. Arise, Kailash N. Pandey
Biochem and Biophys Res Commun 349 (2006) 131–135
http://dx.doi.org:/10.1016/j.bbrc.2006.08.003

The objective of this study was to investigate the role of protein kinase C (PKC) in the angiotensin II (Ang II)-dependent repression of Npr1 (coding for natriuretic peptide receptor-A, NPRA) gene transcription. Mouse mesangial cells (MMCs) were transfected with Npr1 gene promoter-luciferase construct and treated with Ang II and PKC agonist or antagonist. The results showed that the treatment of MMCs with 10 nM Ang II produced a 60% reduction in the promoter activity of Npr1 gene. MMCs treated with 10 nM Ang II exhibited 55% reduction in NPRA mRNA levels, and subsequent stimulation with 100 nM ANP resulted in 50% reduction in guanylyl cyclase (GC) activity. Furthermore, the treatment of MMCs with Ang II in the presence of PKC agonist phorbol ester (100 nM) produced an almost 75% reduction in NPRA mRNA and 70% reduction in the intracellular accumulation of cGMP levels. PKC antagonist staurosporine completely reversed the effect of Ang II and phorbol ester. This is the first report to demonstrate that ANG II-dependent transcriptional repression of Npr1 gene promoter activity and down-regulation of GC activity of translated protein, NPRA is regulated by PKC pathways.

Transcriptional regulation of guanylyl cyclase/natriuretic peptide receptor-A gene

Prerna Kumar, Kiran K. Arise, Kailash N. Pandey
peptides 27 (2006) 1762–1769
http://dx.doi.org:/10.1016/j.peptides.2006.01.004

Activation of natriuretic peptide receptor-A (NPRA) produces the second messenger cGMP, which plays a pivotal role in maintaining blood pressure and cardiovascular homeostasis. In the present study, we have examined the role of trans-acting factor Ets-1 in transcriptional regulation of Npr1 gene (coding for NPRA).Using deletional analysis of the Npr1 promoter, we have defined a 400 base pair (bp) region as the core promoter, which contains consensus binding sites for transcription factors including: Ets-1, Lyf-1, and GATA-1/2. Over-expression of Ets-1 in mouse mesangial cells (MMCs) enhanced Npr1 gene transcription by 12-fold. However, overexpression of GATA-1 or Lyf-1 repressed Npr1 basal promoter activity by 50% and 80%, respectively. The constructs having a mutant Ets-1 binding site or lacking this site failed to respond to Ets-1 activation of Npr1 gene transcription. Collectively, the present results demonstrate that Ets-1 greatly stimulates Npr1 gene promoter activity, implicating its critical role in the regulation and function of NPRA at the molecular level.

Several agents that are known to upregulate Ets-1 transcription, include RA, TNF-alpha, VEGF, and TPA. Ets-1 is upregulated at exposure to agonists such as serum in vitro and is expressed in injured vasculature. MAPK-mediated phosphorylation positively regulates the transcriptional activation functions of Ets-1 by recruiting CBP/p300. Not much is known about Ets-1 expression or regulation in mesangial cells. A temporal increase of mesangial cell Ets-1 expression has been reported which correlates with mesangial cell activation
in mesangioproliferative glomerulonephritis suggesting involvement of PDGF-B. There might be a possibility that during glomerulonephritis increased Ets-1 expression upregulates Npr1 gene as a protective mechanism. Npr1 gene has been shown to negatively regulate mitogen-activated protein kinase and proliferation of mesangial cells.

In conclusion, our results demonstrate that the precise control of Npr1 gene transcriptional activity is achieved through a synergy of activators and repressors in which Ets-1 plays an integral role as a transcriptional activator. Comparatively, Lyf-1 and GATA-1 act as repressors, inhibiting and regulating the transcriptional activity of Npr1 gene promoter. The present findings suggest that Ets-1 plays a critical role in enhancing Npr1 gene transcription and may have an important influence in hypertension and cardiovascular homeostasis at the molecular level.

Krüppel-like transcription factor 11 (KLF11) overexpression inhibits cardiac hypertrophy and fibrosis in mice

Yue Zheng, Ye Kong, Feng Li
Biochem and Biophys Res Commun 443 (2014) 683–688
http://dx.doi.org/10.1016/j.bbrc.2013.12.024

The Krüppel-like factors (KLFs) belong to a subclass of Cys2/His2 zinc-finger DNA-binding proteins. The KLF family member KLF11 is originally identified as a transforming growth factor b (TGF-b)-inducible gene and is one of the most studied in this family. KLF11 is expressed ubiquitously and participates  in diabetes and regulates hepatic lipid metabolism. However, the role of KLF11 in cardiovascular system is largely unknown. Here in this study, we reported that KLF11 expression is down-regulated in failing human hearts and hypertrophic murine hearts. To evaluate the roles of KLF11 in cardiac hypertrophy, we generated cardiac-specific KLF11 transgenic mice. KLF11 transgenic mice do not show any difference from their littermates at baseline. However, cardiac-specific KLF11 overexpression protects mice from TAC-induced cardiac hypertrophy, with reduced radios of heart weight (HW)/body weight (BW), lung weight/BW and HW/tibia length, decreased left ventricular wall thickness and increased fractional shortening. We also observe lower expression of hypertrophic fetal genes in TAC-challenged KLF11 transgenic mice compared with WT mice. In addition, KLF11 reduces cardiac fibrosis in mice underwent hypertrophy. The expression of fibrosis markers are also down-regulated when KLF11 is overexpressed in TAC-challenged mice. Taken together, our findings identify a novel anti-hypertrophic and anti-fibrotic role of KLF11, and KLF11 activator may serve as candidate drug for heart failure patients.

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