Archive for the ‘Personalized and Precision Medicine & Genomic Research’ Category

Stomach Cancer Subtypes Methylation-based identified by Singapore-Led Team

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Liver & Digestive Diseases Research, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Technology Transfer: Biotech and Pharmaceutical, tagged Cancer - General, Cancer Genome Atlas, Conditions and Diseases, DNA methylation on October 17, 2012| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Word Cloud By Danielle Smolyar

GASTRIC CANCER

Methylation Subtypes and Large-Scale Epigenetic Alterations in Gastric Cancer

+Author Affiliations

¹Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
²NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
³National Cancer Centre Singapore–Van Andel Research Institute Translational Research Laboratory, Department of Medical Sciences, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.
⁴Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁵Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore.
⁶Neuroscience and Behavioural Disorders, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
⁷Singapore-MIT Alliance, National University of Singapore, Singapore 119074, Singapore.
⁸Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore.
⁹Cancer Science Institute of Singapore, National University of Singapore, Singapore 119074, Singapore.
¹⁰National Cancer Institute Singapore, National University Hospital, Singapore 119228, Singapore.
¹¹Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
¹²Genome Institute of Singapore, 60 Biopolis Street, Genome 02-01, Singapore 138672, Singapore.

+Author Notes

↵* These authors contributed equally to this work.
↵† Present address: LabConnect, LLC, 2910 First Avenue South, Suite 200, Seattle, WA 98134, USA.

↵‡To whom correspondence should be addressed. E-mail: gmstanp@duke-nus.edu.sg

ABSTRACT

Epigenetic alterations are fundamental hallmarks of cancer genomes. We surveyed the landscape of DNA methylation alterations in gastric cancer by analyzing genome-wide CG dinucleotide (CpG) methylation profiles of 240 gastric cancers (203 tumors and 37 cell lines) and 94 matched normal gastric tissues. Cancer-specific epigenetic alterations were observed in 44% of CpGs, comprising both tumor hyper- and hypomethylation. Twenty-five percent of the methylation alterations were significantly associated with changes in tumor gene expression. Whereas most methylation-expression correlations were negative, several positively correlated methylation-expression interactions were also observed, associated with CpG sites exhibiting atypical transcription start site distances and gene body localization. Methylation clustering of the tumors revealed a CpG island methylator phenotype (CIMP) subgroup associated with widespread hypermethylation, young patient age, and adverse patient outcome in a disease stage–independent manner. CIMP cell lines displayed sensitivity to 5-aza-2′-deoxycytidine, a clinically approved demethylating drug. We also identified long-range regions of epigenetic silencing (LRESs) in CIMP tumors. Combined analysis of the methylation, gene expression, and drug treatment data suggests that certain LRESs may silence specific genes within the region, rather than all genes. Finally, we discovered regions of long-range tumor hypomethylation, associated with increased chromosomal instability. Our results provide insights into the epigenetic impact of environmental and biological agents on gastric epithelial cells, which may contribute to cancer.

http://stm.sciencemag.org/content/4/156/156ra140

Sci Transl Med 17 October 2012:
Vol. 4, Issue 156, p. 156ra140
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3004504

Methylation-based Stomach Cancer Subtypes

October 17, 2012

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A new study in Science Translational Medicine is highlighting the epigenetic subtypes that exist within stomach cancer.

“Our results strongly demonstrate that gastric cancer is not one disease but a conglomerate of multiple diseases, each with a different underlying biology and hallmark features,” senior author Patrick Tan, a cancer researcher with the Duke-National University of Singapore Graduate Medical School, said in a statement.

“If gastric cancer is the result of multiple interacting factors, including both environmental factors and host genetic factors, we need better ways to diagnosis and treat it,” added Tan, who is also affiliated with Singapore’s National Cancer Centre and the Genome Institute of Singapore.

Tan and colleagues based in Singapore and the US did array-based DNA methylation analyses on more than 200 gastric tumors and dozens of gastric cancer lines. Their subsequent analyses of these methylation profiles indicated that stomach cancers have many stretches of sequence with higher or lower levels of methylation compared with nearly 100 matched normal stomach samples.

Within the tumor and cell lines, the analysis revealed subsets of gastric cancer with distinct methylation profiles that appear to be prognostically important.

In particular, a group of tumors known as CIMP (CpG island methylator phenotype) tumors, which show excess methylation at some cytosine and guanine-rich regions of the genome, tended to turn up in younger gastric cancer patients and those with poor outcomes.

On the other hand, results of the study also hint that the pronounced methylation shifts in these CIMP gastric cancers could also render them more vulnerable to demethylating compounds.

“Gastric cancer is a heterogenous disease with individual patients often displaying markedly different responses to the same treatment,” Tan said. “Improving gastric cancer clinical outcomes will require molecular approaches capable of subdividing patients into biologically similar subgroups, and designing subtype-specific therapies for each group.”

Previous genomic studies have started to unravel the range of somatic mutations and other genetic alterations that can contribute to gastric adenocarcinoma, the researchers noted. Less is known about the epigenetic features of the often deadly disease, which is especially common in some Asian populations, though some studies have identified specific genes with unusual epigenetic profiles in gastric cancer.

In an effort to more fully understand the epigenetic features of stomach cancer, Tan and his colleagues used Illumina Infinium arrays to profile cytosine methylation patterns in tumor samples from 203 individuals with gastric cancer, along with matched normal stomach tissue samples for 94 of the patients.

Using a similar strategy, the group also measured genome-wide methylation patterns in 37 stomach cancer cell lines.

When they compared methylation profiles across the samples, the researchers saw that some 44 percent of the CpG sites tested had higher- or lower-than-usual cytosine methylation levels that were specific to the stomach cancer. Around a quarter of these seemed to coincide with either jumps or — more frequently — dips in gene expression in the tumors, they reported.

A subset of the tumors had especially high levels of CpG island methylation, the team found. Follow-up analyses indicated that these tumors — which comprise an apparent CIMP sub-group of the stomach cancer — were more commonly found in young patients and/or those with poor survival outcomes.

Over-represented amongst the genes in highly methylated regions of CIMP tumors were genes implicated in stem cell-related processes, researchers noted, as were sites recognized by the histone regulating Polycomb repressive complex.

“Taken collectively,” they wrote, “these results suggest that CIMP tumors may represent a clinically and biologically distinct sub-group of gastric cancers.”

Moreover, in one of its follow-up experiments the team found that it was possible to curb the proliferation of seven gastric cancer-derived cell lines in the CIMP sub-group using a demethylating drug called 5-aza-2′-deoxycytidine, or 5-Aza-dC — an effect they did not see in 10 non-CIMP cell lines treated with the drug.

Based on findings from their methylation and gene expression profiling in gastric cancer so far, the study authors argued that an improved appreciation of the methylome-based sub-types present in the disease might aid future efforts to improve stomach cancer diagnosis and treatment options.

“[A]dditional work will focus on developing simple diagnostic tests to detect gastric cancer at earlier stages, plus drugs and drug targets that might exhibit high potency against different molecular subtypes of disease,” Tan said in a statement.

Congestive Heart Failure & Personalized Medicine: Two-gene Test predicts response to Beta Blocker Bucindolol

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, HTN, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged beta blocker, Cardiology, Gene Regulation, Montreal Heart Institute, pharmacogenomics, vasodilation on October 17, 2012| 7 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Combinatorial Pharmacogenetic Interactions of Bucindolol and β₁, α_2C Adrenergic Receptor Polymorphisms

UPDATED ON 9/4/2019

Beta-Blockers Increase Survival for HF Patients With Renal Impairment

Call for use of the agents in those with heart failure with reduced ejection fraction

Primary Source

European Society of Cardiology

Source Reference: Kotecha D “Beta-blockers in high-risk heart failure patients with reduced ejection fraction and moderately-severe renal dysfunction” ESC 2019.

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/81960?xid=nl_mpt_DHE_2019-09-04&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%202019-09-04&utm_term=NL_Daily_DHE_Active

Christopher M. O’Connor¹^*, Mona Fiuzat¹, Peter E. Carson², Inder S. Anand³, Jonathan F. Plehn⁴, Stephen S. Gottlieb⁵, Marc A. Silver⁶, JoAnn Lindenfeld⁷, Alan B. Miller⁸, Michel White⁹, Ryan Walsh⁷, Penny Nelson⁷, Allen Medway⁷, Gordon Davis¹⁰, Alastair D. Robertson⁷, J. David Port⁷^,¹⁰, James Carr¹⁰, Guinevere A. Murphy¹⁰,Laura C. Lazzeroni¹¹, William T. Abraham¹², Stephen B. Liggett¹³, Michael R. Bristow⁷^,¹⁰

1 Division of Cardiology, Duke University Medical Center/Duke Clinical Research Institute, Durham, North Carolina, United States of America,2 Division of Cardiology, Department of Veterans Affairs, Washington, District of Columbia, United States of America, 3 Division of Cardiology, Department of Veterans Affairs, Minneapolis, Minnesota, United States of America, 4 National Heart, Lung, and Blood Institute, National Institutes of Health, Washington, District of Columbia, United States of America, 5 Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America, 6 Heart and Vascular Institute, Advocate Christ Medical Center, Oak Lawn, Illinois, United States of America, 7 Division of Cardiology/Cardiovascular Institute, University of Colorado School of Medicine, Aurora, Colorado, United States of America, 8 Division of Cardiology, University of Florida Health Sciences Center, Jacksonville, Florida, United States of America, 9 Research Center, Montreal Heart Institute, Montreal, Quebec, Canada, 10 ARCA biopharma, Broomfield, Colorado, United States of America, 11 Department of Psychiatry and Behavioral United States of America, Sciences and of Pediatrics, Stanford University, Stanford, California, United States of America, 12 Ohio State University, Columbus, Ohio, United States of America, 13 Center for Personalized Medicine and Genomics, University of South Florida, Morsani College of Medicine, Tampa, Florida, United States of America

Competing interests: Drs Bristow, Carr, Murphy, and Port and Mr Davis are employees of and own stock or stock options in ARCA biopharma, Inc., which owns the rights to bucindolol. Drs Fiuzat, Liggett, Lindenfeld, and Robertson are consultants of ARCA biopharma. Also, Drs Fiuzat and Liggett own stock or stock options in ARCA biopharma. Drs O’Connor, Carson, Anand, Plehn, Gottlieb, Silver, Miller, White, Lazzeroni, and Abraham and Mr Walsh, Ms Nelson, and Mr Medway have no conflicts to report. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.* E-mail: christophe.oconnor@duke.edu

Background

Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β₁ adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α_2C AR Ins [wild-type (Wt)] 322–325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology.

Methodology

In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β₁389 and α_2C322–325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β₁389 AR variants was measured in human explanted left ventricles.

Principal Findings

The combination of β₁389 Arg+α_2C322–325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in β₁389 Arg homozygotes+α_2C322–325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in β₁389 Arg vs. Gly ARs, which converts α_2CDel minor allele-associated NE lowering from a therapeutic liability to a benefit.

Conclusions

On combination, the two sets of AR polymorphisms

1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and

2) identified subpopulations with enhanced (β₁389 Arg homozygotes), intermediate (β₁389 Gly carriers+α_2C322–325 Wt homozygotes), and no (β₁389 Gly carriers+α_2C322–325 Del carriers) efficacy.

Figure 1:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0044324

Limitations

There are some limitations to this study. First, although the substudy was prospectively designed and hypothesis-driven, the pharmacogenetic data were generated and analyzed after the trial’s main results were analyzed and published [5]. However, the investigators generating the pharmacogenetic data remained blinded to the treatment code and to clinical outcomes throughout. Second, approximately two-thirds of the patients were enrolled into the DNA substudy after being randomized into the parent trial. This “late entry” phenomenon has been extensively analyzed, by both L-truncation [12] and, most recently, propensity score statistical methods (unpublished observations). The effect of late entry into the DNA substudy is only to lower event rates for all clinical endpoints, without affecting genotype-specific treatment effects.

Conclusions

The combinatorial interaction of two sets of AR polymorphisms that influence bucindolol’s drug action resulted in unanticipated effects on HF clinical responses, non-additivity in efficacy enhancement for the major allele homozygotes, and additive effects for minor allele carrier-associated efficacy loss. An explanation for these disparate results was provided by the effects of the α_2C322–325 minor (Del) allele on facilitating bucindolol’s NE-lowering properties, where excessive NE lowering abolished efficacy when the β₁389 Gly minor allele and low NE affinity AR were present but did not alter or even enhance efficacy in the presence of the major allele homozygous β₁389 Arg genotype, which encodes ARs with a NE affinity of ~100-fold more than 389 Gly ARs.

Combinatorial genotyping led to improvement in pharmacogenetic differentiation of drug response compared with monotype genotyping. The use of β₁389 Arg/Gly and α_2C322–325 Wt/Del genotype combinations accomplishes the goal of pharmacogenetics to identify response outliers from both ends of the therapeutic spectrum. Compared with the use of β₁389 Arg/Gly or α_2C322–325 Wt/Del monotypes, the differential efficacy gained by the use of genotype combinations was increased by respective amounts of 54% and 94%. The new identification of a completely unresponsive genotype, supported by biologic plausibility and bolstered by data consistency across multiple clinical endpoints, is especially important inasmuch as a major goal of pharmacogenetics is to identify patients with no likelihood of benefit who can then be spared drug side effects [21]. Other β-blockers that have been used to treat HF do not have these pharmacogenetic interactions [22], [23], but rather exhibit response heterogeneity through other, unknown mechanisms[8]. Thus, the ability to predict drug response through pre-treatment pharmacogenetic testing should improve therapeutic response to this drug class but will need to be confirmed by prospective studies.

Finally, the unexpected results of this study, (i.e., the additive loss of efficacy by minor allele combinations in the absence of additive gain of efficacy by major allele homozygotes) emphasizes that combinations of response-altering polymorphisms may behave in unpredictable ways and in-silico predictions of combinatorial genetic effects will need to be supported by empirical data.

References

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[No authors listed] (1999) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353: 2001–2007.FIND THIS ARTICLE ONLINE
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Domanski MJ, Krause-Steinrauf H, Massie BM, Deedwania P, Follmann D, et al. (2003) A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS. J Card Fail 9: 354–363. FIND THIS ARTICLE ONLINE
O’Connor CM, Fiuzat M, Caron MF, Deedwania P, Follmann D, et al. (2011) Influence of global region on outcomes in large heart failure β-blocker trials. J Am Coll Cardiol 58: 915–922. FIND THIS ARTICLE ONLINE
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Bristow MR, Murphy GA, Krause-Steinrauf H, Anderson JL, Carlquist JF, et al. (2010) An α_2C-adrenergic receptor polymorphism alters the norepinephrine lowering effects and therapeutic response of the beta blocker bucindolol in chronic heart failure. Circ Heart Fail 3: 21–28. FIND THIS ARTICLE ONLINE
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Source:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0044324

BROOMFIELD, Colo. (TheStreet) — Wacky, inexplicable things sometimes happen to biotech stocks. Like Friday, when ARCA Biopharma (ABIO) shares more than tripled after the small drug company was granted a new U.S. patent for its experimental heart failure drug.

Arca shares rose an astonishing $5.57, or 210%, to close Friday at $8.22. Calculated another way, one U.S. patent for Arca added $40 million in market value.

Not bad, especially considering Friday’s announcement wasn’t particularly new. Arca issued a press release in January announcing the U.S. Patent and Trademark Office had informed the company that the patent was coming. Friday’s press release simply confirmed that the patent had been issued.

In case you’re wondering, Arca shares rose just 17 cents as a result of the January press release.

So, what’s made Arca rocket Friday when it barely budged in January on the same patent news?

Like I said, some things in biotech defy logic. Fundamentals had nothing to do it, clearly. Instead, Friday’s move was more likely a function of momentum traders finding an easy plaything in Arca, which sports a tiny float of just 4.4 million shares.

More than 49 million Arca shares traded hands Friday, or seven times the number of shares outstanding.

It was little noticed Friday, but Arca actually disclosed some bad news regarding the development of its heart failure drug bucindolol. Arca and the U.S. Food and Drug Administration have still not come to agreement on a Special Protocol Assessment for a proposed phase III study of bucindolol. Arca said Friday it had to submit revisions to the design of the study, which will now enroll 3,200 heart failure patients, up from 3,000 patients previously.

Arca needs FDA sign off on the bucindolol trial design, after which the company needs to raise money to conduct the trial. Arca says it can likely start the pivotal bucindolol study one year after both those things happen. The company expects the study to take two years to complete once fully enrolled.

As of December 31, Arca had $7.8 million in its coffers.

http://www.thestreet.com/story/10712682/1/arca-biopharma-patent-deja-vu-biobuzz.html

In a study sponsored by ARCA Biopharma ($ABIO) and carried out by a number of U.S. universities, a pharmacogenetic test predicted which patients would respond to the company’s beta blocker and vasodilator bucindolol (Gencaro), in development for the treatment of chronic heart failure. The level of clinical activity of this oral drug depends on two changes in two genes.

The researchers screened more than a thousand of the patients with congestive heart failure who took part in the Beta-Blocker Evaluation of Survival Trial (BEST) and were given either bucindolol or dummy pills. Based on the patients’ clinical results and genetic profile, the team created a “genetic scorecard.” The results were published in PLoS ONE.

A biomarker for bucindolol will not only speed it through development but could also be used to point out those patients who will (and won’t) respond to which drug, sparing those patients who won’t respond the risk of potential side effects.

According to Stephen B. Liggett of the University of South Florida and founder of ARCA Biopharma, the researchers were able to use the two-gene test to “identify individuals with heart failure who will not respond to bucindolol and those who have an especially favorable treatment response. We also identified those who will have an intermediate level of response. The results showed that the choice of the best drug for a given patient, made the first time without a trial-and-error period, can be accomplished using this two-gene test.”

Bucindolol has been designated as a fast track development program for the reduction of cardiovascular mortality and cardiovascular hospitalizations in a genotype-defined heart failure population.

http://www.fiercebiomarkers.com/press-releases/two-gene-test-predicts-which-patients-heart-failure-respond-best-beta-block?utm_medium=nl&utm_source=internal

October 17, 2012

Two-gene test predicts which patients with heart failure respond best to beta-blocker drug, study finds
Personalized medicine research at University of South Florida strikes early for heart genes

Tampa, FL – A landmark paper identifying genetic signatures that predict which patients will respond to a life-saving drug for treating congestive heart failure has been published by a research team co-led by Stephen B. Liggett, MD, of the University of South Florida.

The study, drawing upon a randomized placebo-controlled trial for the beta blocker bucindolol, appears this month in the international online journal PLoS ONE. In addition to Dr. Liggett, whose laboratory discovered and characterized the two genetic variations, Christopher O’Connor, MD, of Duke University Medical Center, and Michael Bristow, MD, PhD, of ARCA biopharma and the University of Colorado Anschutz Medical Campus, were leading members of the research team.
The analysis led to a “genetic scorecard” for patients with congestive heart failure, a serious condition in which the heart can’t pump enough blood to meet the body’s needs, said Dr. Liggett, the study’s co-principal investigator and the new vice dean for research and vice dean for personalized medicine and genomics at the USF Morsani College of Medicine.
“We have been studying the molecular basis of heart failure in the laboratory with a goal of finding genetic variations in a patient’s DNA that alter how drugs work,” Dr. Liggett said. “We took this knowledge from the lab to patients and found that we can indeed, using a two-gene test, identify individuals with heart failure who will not respond to bucindolol and those who have an especially favorable treatment response. We also identified those who will have an intermediate level of response.” The research has implications for clinical practice, because the genetic test could theoretically be used to target the beta blocker to patients the drug is likely to help. Equally important, its use could be avoided in patients with no likelihood of benefit, who could then be spared potential drug side effects. Prospective studies are needed to confirm that bucindolol would be a better treatment than other classes of beta blockers for a subset of patients with health failure.

Dr. Liggett collaborated with medical centers across the United States, including the NASDAq-listed biotech company ARCA biopharma, which he co-founded in Denver, CO. This genetic sub-study involved 1,040 patients who participated in the Beta-Blocker Evaluation of Survival Trial (BEST). The researchers analyzed mortality, hospital admissions for heart failure exacerbations and other clinical outcome indicators of drug performance.

“The results showed that the choice of the best drug for a given patient, made the first time without a trial-and-error period, can be accomplished using this two-gene test,” Dr. Liggett said.

The genetic test discovered by the Liggett team requires less than 1/100th of a teaspoon of blood drawn from a patient, from which DNA is isolated. DNA is highly stable when frozen, so a single blood draw will suffice for many decades, Dr. Liggett said. And since a patient’s DNA does not change over their lifetime, as new discoveries are made and other tests need to be run, it would not be necessary to give another blood sample, he added.

This is part of the strategy for the USF Center for Personalized Medicine and Genomics. The discovery of genetic variations in diseases can be targeted to predict three new types of information: who will get a disease, how the disease will progress, and the best drug to use for treatment.

“In the not too distant future, such tests will become routine, and patient outcomes, and the efficiency and cost of medical care will be impacted in positive ways. We also will move toward an era where we embrace the fact that one drug does not fit all,” Dr. Liggett said. “If we can identify by straightforward tests which drug is best for which patient, drugs that work with certain smaller populations can be brought to the market, filling a somewhat empty pipeline of new drugs.”

This approach is applicable to most diseases, Dr. Liggett said, but the USF Center has initially concentrated on heart disease, because it is a leading cause of deaths, hospitalizations and lost productivity in the Tampa Bay region and Florida. Dr. Liggett is a recent recruit to the USF Health Morsani College of Medicine, coming from the University of Maryland School of Medicine. His work at USF has been supported by several National Institutes of Health grants and $2 million in funding from Hillsborough County.

Heart failure is characterized by an inability of the heart muscle to pump blood, resulting in dysfunction of multiple organs caused by poor blood and oxygen flow throughout the body. An estimated 6 million Americans are living with heart failure, and more than half a million new cases are diagnosed each year. About 50 percent of patients diagnosed with heart failure die within five years. The economic burden of heart failure in the United States is estimated at $40 billion a year.

Article citation:
Christopher M. O’Connor, Mona Fiuzat, Peter E. Carson, Inder S. Anand, Jonathan F. Plehn, Stephen S. Gottlieb, Marc A. Silver, JoAnn Lindenfeld, Alan B. Miller, Michel White, Ryan Walsh, Penny Nelson, Allen Medway, Gordon Davis, Alastair D. Robertson, J. David Port, James Carr, Guinevere A. Murphy, Laura C. Lazzeroni, William T. Abraham, Stephen B. Liggett and Michael Bristow, “Combinatorial Pharmacogenetic Interactions of Bucindolol and β1, α2C Adrenergic Receptor Polymorphisms,” PLoS ONE 7(10): e44324. doi:10.1371/journal.pone.0044324

-USF Health-

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities.

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Anne DeLotto Baier, USF Health Communications
(813) 974-3303 or abaier@health.usf.edu

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Crucial role of Nitric Oxide in Cancer

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Metabolomics, Nitric Oxide in Health and Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged Akt, angiogenesis, anti-apoptotic, Apoptosis, Bcl-2, C-Src, Cancer - General, cancer risk, carcinogenesis, cell cycle, cell proliferation, Cisplatin, conformational, cytotoxicity, DNA damage, DNA repair, Endothelium, eNOS, genotoxicity, HIF-1, HIF-1a, inflammation, inflammatory, iNOS, intracellular localization, macrophages, MMP, nitric oxide, Nitric oxide synthase, nNOS, NO, NO donors, NOS, p53, PI3K, post translational modifications, pro-apoptotic, proteasomal, PTEN, RAW264.7, S-nitrosylation, transcription, tumorigenesis, Ubiquitin on October 16, 2012| 21 Comments »

Author and Curator: Ritu Saxena, Ph.D.

Word Cloud By Danielle Smolyar

Introduction

Nitric oxide (NO) is a lipophilic, highly diffusible and short-lived molecule that acts as a physiological messenger and has been known to regulate a variety of important physiological responses including vasodilation, respiration, cell migration, immune response and apoptosis. Jordi Muntané et al

NO is synthesized by the Nitric Oxide synthase (NOS) enzyme and the enzyme is encoded in three different forms in mammals: neuronal NOS (nNOS or NOS-1), inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3). The three isoforms, although similar in structure and catalytic function, differ in the way their activity and synthesis in controlled inside a cell. NOS-2, for example is induced in response to inflammatory stimuli, while NOS-1 and NOS-3 are constitutively expressed.

Regulation by Nitric oxide

NO is a versatile signaling molecule and the net effect of NO on gene regulation is variable and ranges from activation to inhibition of transcription.

The intracellular localization is relevant for the activity of NOS. Infact, NOSs are subject to specific targeting to subcellular compartments (plasma membrane, Golgi, cytosol, nucleus and mitochondria) and that this trafficking is crucial for NO production and specific post-translational modifications of target proteins.

Role of Nitric oxide in Cancer

One in four cases of cancer worldwide are a result of chronic inflammation. An inflammatory response causes high levels of activated macrophages. Macrophage activation, in turn, leads to the induction of iNOS gene that results in the generation of large amount of NO. The expression of iNOS induced by inflammatory stimuli coupled with the constitutive expression of nNOS and eNOS may contribute to increased cancer risk. NO can have varied roles in the tumor environment influencing DNA repair, cell cycle, and apoptosis. It can result in antagonistic actions including DNA damage and protection from cytotoxicity, inhibiting and stimulation cell proliferation, and being both anti-apoptotic and pro-apoptotic. Genotoxicity due to high levels of NO could be through direct modification of DNA (nitrosative deamination of nucleic acid bases, transition and/or transversion of nucleic acids, alkylation and DNA strand breakage) and inhibition of DNA repair enzymes (such as alkyltransferase and DNA ligase) through direct or indirect mechanisms. The Multiple actions of NO are probably the result of its chemical (post-translational modifications) and biological heterogeneity (cellular production, consumption and responses). Post-translational modifications of proteins by nitration, nitrosation, phosphorylation, acetylation or polyADP-ribosylation could lead to an increase in the cancer risk. This process can drive carcinogenesis by altering targets and pathways that are crucial for cancer progression much faster than would otherwise occur in healthy tissue.

NO can have several effects even within the tumor microenvironment where it could originate from several cell types including cancer cells, host cells, tumor endothelial cells. Tumor-derived NO could have several functional roles. It can affect cancer progression by augmenting cancer cell proliferation and invasiveness. Infact, it has been proposed that NO promotes tumor growth by regulating blood flow and maintaining the vasodilated tumor microenvironment. NO can stimulate angiogenesis and can also promote metastasis by increasing vascular permeability and upregulating matrix metalloproteinases (MMPs). MMPs have been associated with several functions including cell proliferation, migration, adhesion, differentiation, angiogenesis and so on. Recently, it was reported that metastatic tumor-released NO might impair the immune system, which enables them to escape the immunosurveillance mechanism of cells. Molecular regulation of tumour angiogenesis by nitric oxide.

S-nitrosylation and Cancer

The most prominent and recognized NO reaction with thiols groups of cysteine residues is called S-nitrosylation or S-nitrosation, which leads to the formation of more stable nitrosothiols. High concentrations of intracellular NO can result in high concentrations of S-nitrosylated proteins and dysregulated S-nitrosylation has been implicated in cancer. Oxidative and nitrosative stress is sensed and closely associated with transcriptional regulation of multiple target genes.

Following are a few proteins that are modified via NO and modification of these proteins, in turn, has been known to play direct or indirect roles in cancer.

NO mediated aberrant proteins in Cancer

Bcl2

Bcl-2 is an important anti-apoptotic protein. It works by inhibiting mitochondrial Cytochrome C that is released in response to apoptotic stimuli. In a variety of tumors, Bcl-2 has been shown to be upregulated, and it has additionally been implicated with cancer chemo-resistance through dysregulation of apoptosis. NO exposure causes S-nitrosylation at the two cysteine residues – Cys158 and Cys229 that prevents ubiquitin-proteasomal pathway mediated degradation of the protein. Once prevented from degradation, the protein attenuates its anti-apoptotic effects in cancer progression. The S-nitrosylation based modification of Bcl-2 has been observed to be relevant in drug treatment studies (for eg. Cisplatin). Thus, the impairment of S-nitrosylated Bcl-2 proteins might serve as an effective therapeutic target to decrease cancer-drug resistance.

p53

p53 has been well documented as a tumor suppressor protein and acts as a major player in response to DNA damage and other genomic alterations within the cell. The activation of p53 can lead to cell cycle arrest and DNA repair, however, in case of irrepairable DNA damage, p53 can lead to apoptosis. Nuclear p53 accumulation has been related to NO-mediated anti-tumoral properties. High concentration of NO has been found to cause conformational changes in p53 resulting in biological dysfunction.. In RAW264.7, a murine macrophage cell line, NO donors induce p53 accumulation and apoptosis through JNK-1/2.

HIF-1a

Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor that is predominantly active under hypoxic conditions because the HIF-1a subunit is rapidly degraded in normoxic conditions by proteasomal degradation. It regulates the transciption of several genes including those involved in angiogenesis, cell cycle, cell metabolism, and apoptosis. Hypoxic conditions within the tumor can lead to overexpression of HIF-1a. Similar to hypoxia-mediated stress, nitrosative stress can stabilize HIF-1a. NO derivatives have also been shown to participate in hypoxia signaling. Resistance to radiotherapy has been traced back to NO-mediated HIF-1a in solid tumors in some cases.

PTEN

Phosphatase and tensin homolog deleted on chromosome ten (PTEN), is again a tumor suppressor protein. It is a phosphatase and has been implicated in many human cancers. PTEN is a crucial negative regulator of PI3K/Akt signaling pathway. Over-activation of PI3K/Akt mediated signaling pathway is known to play a major role in tumorigenesis and angiogenesis. S-nitrosylation of PTEN, that could be a result of NO stress, inhibits PTEN. Inhibition of PTEN phosphatase activity, in turn, leads to promotion of angiogenesis.

C-Src

C-src belongs to the Src family of protein tyrosine kinases and has been implicated in the promotion of cancer cell invasion and metastasis. It was demonstrated that S-nitrosylation of c-Src at cysteine 498 enhanced its kinase activity, thus, resulting in the enhancement of cancer cell invasion and metastasis.

Reference:

Muntané J and la Mata MD. Nitric oxide and cancer. World J Hepatol. 2010 Sep 27;2(9):337-44. http://www.ncbi.nlm.nih.gov/pubmed/21161018

Wang Z. Protein S-nitrosylation and cancer. Cancer Lett. 2012 Jul 28;320(2):123-9. http://www.ncbi.nlm.nih.gov/pubmed/22425962

Ziche M and Morbidelli L. Molecular regulation of tumour angiogenesis by nitric oxide. Eur Cytokine Netw. 2009 Dec;20(4):164-70.http://www.ncbi.nlm.nih.gov/pubmed/20167555

Jaiswal M, et al. Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G626-34. http://www.ncbi.nlm.nih.gov/pubmed/11518674

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Chemo Regimens Selected by MDs: SNP Test to Predict Side Effects

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Medical and Population Genetics, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Technology Transfer: Biotech and Pharmaceutical, tagged chemo regimens, Pathwork Diagnostics, SNP Test on October 16, 2012| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Inform Genomics Developing SNP Test to Predict Side Effects, Help MDs Choose among Chemo Regimens

October 10, 2012

By Molika Ashford

Inform Genomics, a Boston-based diagnostics company, said its “Oncology Preferences and Risk of Toxicity,” or OnPART, test showed greater than 90 percent accuracy in predicting which cancer patients are at risk of experiencing serious side effects to various chemotherapy regimens in an early-stage study.

The company is developing the test to predict a patient’s risk for six common adverse events to combination chemotherapy regimens for colorectal, breast, lung, or ovarian cancer.

Inform Genomics’ president and CEO, Ed Rubenstein, told PGx Reporter that the company is narrowing down a set of SNP signatures that can predict six common moderate to serious side effects linked to different, but equally effective chemotherapy regimens, including dose-dense doxorubicin, cyclophosphamide and paclitaxel for breast cancer; oxaliplatin-based regimens for colorectal cancer; and carboplatin plus paclitaxel-based regimens for lung and ovarian cancer.

Rubenstein said that results from the discovery study, performed at the West Clinic in Memphis, Tenn., showed the signatures for all six side effects — nausea and vomiting, mouth sores, diarrhea, fatigue, cognitive dysfunction, and peripheral neuropathy — had greater than 90 percent predictive accuracy.

“What’s unique about [OnPART],” he said, “is that [it analyzes] not only genomic risk of six common side effects of combination chemotherapy regimens the way they are actually used in clinical practice, but it also includes a way to quantify patients’ concerns for how they view these side effects,” through a copyrighted patient questionnaire the company calls “Preference Assessment Inventory.”

He explained that Inform Genomics intends the test to display for oncologists the risk of these six side effects across different chemotherapy regimens that are considered “relatively equivalent” from an efficacy standpoint “but have wide variation in their toxicity profile.”

The company hopes this will allow patients to discuss with doctors, before beginning therapy, what their real risks are “as opposed to theoretical risks from population-based studies,” Rubenstein said.

He cited the example of a cancer patient who is a professional musician with a high genetic risk for neuropathy, according to OnPART. This patient’s quality of life would be greatly impacted if the chemotherapy regimen he or she was on caused debilitating nerve damage. “When they fill out their concerns and say neuropathy is a concern for them, that allows the doctor to help them understand their risk, and switch their chemotherapy regimen to another that is equally effective but does not put the patient at risk for neuropathy,” Rubenstein explained.

In the company’s discovery study, researchers tested saliva from 384 patients at the West Clinic who had been followed for a minimum of two cycles of chemotherapy and who had reported symptoms of the six side effects using a validated questionnaire.

Using Illumina microarrays, the group profiled 2.5 million potential SNPs to find those that correlated with particular side effects and regimens. Then the team used Inform Genomics’ proprietary Bayesian analysis algorithms to look at interactions between these SNPs.

“We have list of SNPs, and then from that we look at location on genes or outside genes and look at functional pathways and biology to make sure that what we are looking at makes sense,” Rubenstein explained.

Though the exact number of SNPs to be used for each side effect-predictor in OnPART has not yet been determined, Rubenstein said the marketed panel would likely include about 400 SNPs.

“[Our] commercial product is likely to be a custom chip because we don’t need 2.5 million once we’ve narrowed down the predictive SNPs,” he said. “So, let’s say we have six symptoms and each have 80 to 100 SNPs; maybe the chip would be 400 SNPs.”

The company plans to release a more detailed picture of the study and its results at future oncology meetings.

Rubenstein said the next step will be to raise additional capital and then design prospective validation studies for both OnPART and another test the company is developing to predict oral and gastrointestinal mucositis: side effects of high-dose chemotherapy administered before autologous stem cell transplant for multiple myeloma, Hodgkin’s disease, and non-Hodgkin’s lymphoma.

He said Inform Genomics is currently “in dialogue” with large practices and oncology networks who may be part of these future validation efforts.

“Our current plan is that we would launch the [OnPART] product by the third quarter of 2014,” he said. According to the company’s website, the transplant test would follow in 2015.

Molika Ashford is a GenomeWeb contributing editor and covers personalized medicine and molecular diagnostics. E-mail her here.

Personalized Pancreatic Cancer Treatment Option

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Human Immune System in Health and in Disease, Imaging-based Cancer Patient Management, Liver & Digestive Diseases Research, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Technology Transfer: Biotech and Pharmaceutical, tagged Cancer - General, Chemotherapy, Clinical trial, Gemcitabine, gene expression, Pancreatic cancer, tumor on October 16, 2012| 6 Comments »

Personalized Pancreatic Cancer Treatment Option

Reporter: Aviva Lev-Ari, PhD, RN

Clovis on Track to Unveil Data on New Personalized Pancreatic Cancer Treatment Option by Year End

October 10, 2012

By Turna Ray

Drug developer Clovis Oncology is planning to report data from a clinical trial later this year that may yield a new treatment option for pancreatic cancer patients who are poor responders to gemcitabine.

Clovis is conducting a study, called LEAP, of 360 chemotherapy-naïve metastatic pancreatic cancer patients who are randomized to receive the current standard of care gemcitabine, or the investigational CO-101, a gemcitabine-lipid conjugate. The study investigators are hypothesizing that unlike gemcitabine, CO-101 won’t depend on the expression levels of the protein cellular transporter hENT1 to enter and destroy tumor cells.

Gemcitabine, currently the first-line standard chemotherapy treatment for metastatic pancreatic cancer patients, requires a transport mechanism to help it enter tumor cells. Previously published data suggest that patients with high hENT1 expression respond well to gemcitabine, while those with low expression — about two-thirds of pancreatic cancer patients — respond poorly to the chemotherapeutic.

LEAP researchers have prospectively collected biopsy samples and have enrolled both high- and low-hENT1 expressers. Study investigators will be blind to the hENT1 expression status of patients until the end of the trial. Clovis is working with Roche subsidiary Ventana Medical Systems to simultaneously develop and validate a companion diagnostic that can gauge low and high hENT1 expression. The primary outcome that study investigators are measuring in LEAP is overall survival in the hENT1-low population.

“The question really is whether the lipid, which facilitates entry into the cell through passive diffusion, is going to be able to deliver gemcitabine as efficiently as when a nucleoside transporter is present,” Clovis CEO Patrick Mahaffy told PGx Reporter. “The answer is we don’t know, but we’ll find out in the study.”

The study may reveal that since CO-101 doesn’t depend on hENT1 to enter tumor cells, all metastatic pancreatic cancer patients, regardless of low or high expression of this protein, derive a level of benefit from the new treatment. Still, Clovis is using a companion test to stratify patients after factoring in reimbursement and cost-effectiveness considerations, which currently are perhaps the biggest barriers to the adoption of personalized treatments.

“Nothing we know suggests that we would be better than gemcitabine … in the hENT1 high population. Given the evolving reimbursement environment and the fact that gemcitabine is generic and is priced as such, pending a successful outcome we anticipate that [CO-101] would be used primarily, if not solely, in the hENT1 low population where we anticipate poor outcomes for gemcitabine,” Mahaffy said. “We anticipate that gemcitabine would continue to be the favored product on price alone even if we were to show equivalence to CO-101 in the hENT1 high population.”

Clovis Oncology will commercialize CO-101 globally. The company is currently setting up commercialization infrastructure in the US for the drug, anticipating a launch as early as next year. Clovis won’t necessarily co-promote CO-101 and the companion test with Ventana. The test developer will be in charge of commercializing the test, and Clovis will market the drug with its sales representatives, who will also be educating oncologists about the need for a companion test.

Ventana will submit its premarket approval application for the hENT1 expression test at the same time that Clovis submits its new drug application for CO-101. The test will be marketed as not just a companion diagnostic to assess whether pancreatic cancer patients have low levels of hENT1 and would therefore respond to CO-101, but Ventana will also be able to market the diagnostic as a tool to determine which high-hENT1 expressing patients should be given gemcitabine.

“The [LEAP] trial will clinically validate the diagnostic both for determining response to both gemcitabine and CO-101,” Mahaffy said.

There are around 120,000 cases of pancreatic cancer each year in the US, EU, and Japan, and around 24 percent of patients survive for one year. Around 80 percent of pancreatic cancer patients receive gemcitabine as monotherapy or in combination with other cytotoxic agents. Based on the low incidence of metastatic pancreatic cancer, Clovis has garnered Orphan Drug status for CO-101 from US and European regulatory authorities.

Although a number of retrospective trials have demonstrated that hENT1 expression levels impact outcomes in pancreatic cancer patients in the metastatic and adjuvant setting, LEAP will be the first prospective validation of this observation. “That’s why this trial is so important to the pancreatic cancer community,” Mahaffy said. “Because not only are we going to learn about CO-101, but we’re going to learn prospectively about the role hENT1 plays in determining the outcome for patients’ treatment with gemcitabine alone.”

Testing for hENT1 expression status is not widely conducted by doctors in the care of pancreatic patients. “In fact, it’s not even widely known in the broader community setting,” noted Mahaffy, adding that academic oncologists are increasingly aware of the association between hENT1 expression and gemcitabine efficacy. After LEAP concludes and if the trial is successful, Clovis plans to initiate discussions with treatment guideline-setting bodies.

In addition to looking at CO-101 as a first-line metastatic pancreatic cancer treatment in hENT1-low patients, Clovis is also studying the drug-conjugate as a second-line treatment in metastatic pancreatic cancer (Phase II), as well as in non-small cell lung cancer (Phase I).

Personalized NSCLC Drug

In addition to CO-101, Clovis has a number of investigational agents in its pipeline that it is developing in molecularly defined patient subsets. For example, CO-1686 is a selective covalent inhibitor of EGFR mutations that the firm is exploring in patients with NSCLC. Currently Clovis is conducting a dose-finding Phase I/II trial involving CO-1686 in NSCLC patients with T790M mutations. Patients with these “gatekeeper” mutations become resistant to treatment to widely prescribed EGFR-inhibiting NSCLC drugs, Roche/Genentech’s Tarceva and AstraZeneca’s Iressa.

CO-1686 “is a very potent inhibitor of T790M … [mutations in] which occur in 50 percent of lung cancer patients, after treatment with Tarceva,” Mahaffy said. After the dose-finding portion of the Phase I/II trial, Clovis plans to initiate an expansion cohort looking at T790M mutation-positive patients who are resistant to Tarceva. “If we see the kind of results we hope to in that expansion cohort, we would initiate a registration study beginning in 2014 in Tarceva-failed patients with T790M mutations,” he said.

While CO-1686 is an inhibitor of T790M mutations and other activating mutations of EGFR, the drug doesn’t inhibit wild-type EGFR like Tarceva and Iressa do, which can make NSCLC patients prone to serious side effects. “What is interesting about [CO-1686] is it is a very potent inhibitor of activating mutations of EGFR, the same targets that Tarceva or Iressa address, but unlike those drugs, [CO-1686] does not inhibit wild-type EGFR,” Mahaffy said. With CO-1686, “we should see very limited rash and diarrhea side effects associated with Tarceva and Iressa.”

First, Clovis will study CO-1686 as a second-line treatment in NSCLC patients with T790M mutations. Eventually, Clovis plans to study the drug head-to-head against Tarceva in the first-line setting. “Given the activity of our drug in animal models so far, we think we may have the ability to demonstrate superiority in terms of efficacy and from the side effects of Tarceva,” Mahaffy said. “We would hope to demonstrate in addition to a cleaner safety profile, a longer duration of benefit, because we would prevent that primary resistance mechanism in T790M from emerging.”

Roche Molecular Systems has partnered with Clovis to develop a companion diagnostic for CO-1686.

Meanwhile, last year, the European Commission approved the use of Roche/Genentech’s Tarceva as a first-line treatment for NSCLC in patients with EGFR mutations (PGx Reporter 9/7/2012). Last month, UK’s National Institute for Health and Clinical Excellence issued a draft guidance recommending that the country’s National Health Service pay for Tarceva as an option for this patient population. The company is in discussions with the US Food and Drug Administration about launching Tarceva in this population (PGx Reporter 06/08/2011).

Additionally, Boehringer Ingelheim is developing afatinib, a drug intended for advanced NSCLC patients with EGFR mutation-positive tumors (PGx Reporter 6/6/2012). Boehringer is working with Qiagen to advance a companion test for its drug.

An NGS-Based Companion Dx?

Another drug in Clovis’ pipeline is an inhibitor of PARP 1 and PARP 2, called rucaparib, which the company licensed from Pfizer. Rucaparib is currently undergoing Phase I/II trials in breast and ovarian cancer. The company is investigating the efficacy and safety of the drug in patients who lack the ability to repair damaged DNA that cancer cells need to thrive.

Mahaffy highlighted that Clovis is currently continuing a dose-finding Phase I study initiated by Pfizer combining rucaparib with carboplatin, and is conducting a Phase I trial investigating the drug as a monotherapy. This latter study will include an extension cohort of ovarian cancer patients with germline BRCA mutations.

Clovis is among a handful of drug developers, including Abbott and AstraZeneca, that are advancing PARP inhibitors with a personalized medicine strategy, betting that patients with BRCA 1/2 mutations will respond better to this class of drugs than those without these mutations. Previous studies have demonstrated that the PARP 1 enzyme and the BRCA gene work in concert to repair DNA damage, enabling survival of cancer tumors. Patients with BRCA mutations can’t repair DNA damage in this way, so then PARP inhibitors can be more effective in stopping cancer growth.

Abbott and AstraZeneca are using a companion test developed by Myriad Genetics to study their PARP inhibitors in BRCA-mutated patients with these diseases. Myriad markets BRACAnalysis, a test that gauges germline BRCA mutations associated with hereditary breast and ovarian cancer. However, gene alternations other than germline BRCA 1/2 mutations are linked to faulty DNA repair and PARP inhibitor response. For example, Clovis estimates that around 15 percent of women with ovarian cancer harbor germline BRCA 1/2 mutations, but another 8 percent of patients have somatic mutations in BRCA. Meanwhile, germline BRCA 1/2 mutations comprise only 5 percent of breast cancers.

When Pfizer was developing rucaparib, it was working with MDxHealth to explore methylation-specific markers associated with DNA damage repair and response to PARP inhibiters (PGx Reporter 2/2/2011). According to MDxHealth both methylation and mutation testing can characterize BRCA gene activity. The company previously estimated that BRCA methylation appears in about 40 percent to 50 percent of triple-negative breast cancer patients, and in about 10 percent to 30 percent in sporadic breast cancers.

Clovis has an open contract with MDxHealth looking at methylation profiles in breast and ovarian cancer, and will continue to explore this approach, specifically for methylated BRCA in triple-negative breast cancer. Additionally, Clovis is “considering the opportunity to look at both germline and somatic mutations of BRCA, based on a tissue-based assay,” Mahaffy said.

Beyond this, in August, Clovis and Foundation Medicine announced they are working together to investigate other genetic defects related to DNA repair deficiency.

“We went with Foundation Medicine … because it will allow us to reach a broader population,” Mahaffy said. For example, in ovarian cancer, Foundation Medicine’s next-generation sequencing platform could identify other mechanisms of DNA repair deficiencies that could potentially increase the intent-to-treat population for rucaparib from 15 percent of ovarian cancer patients with germline BRCA mutations to as much as 50 percent of the population that has somatic mutations in 28 additional genes that have been described as conferring “BRCA-ness” or as having a BRCA-like effect on DNA repair.

Clovis plans to develop a companion test for rucaparib on Foundation Medicine’s Foundation One targeted NGS platform. However, one challenge for Clovis is that the FDA hasn’t yet elucidated how it plans to regulate NGS-based tests. “Clearly, there is a seismic shift underway, and we may be one of the first to have plans to go forward on a premarket approval path with next-gen sequencing,” Mahaffy said. “But clearly the FDA and everyone else knows this tidal wave is coming.”

Clovis hopes to initiate a registration trial in the second half of next year looking at rucaparib as a maintenance therapy in ovarian cancer patients sensitive to platinum-based chemotherapy who have alterations in BRCA and deficiencies in other DNA repair genes. Foundation Medicine and Clovis have separately initiated discussions with the FDA about getting taking NGS-based tests through regulatory approval, Mahaffy said.

Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail her here or follow her GenomeWeb Twitter account at @PGxReporter.

Country’s Genetic Diversity can predict the success of its Economy: On Economics and Genetics

Posted in Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, tagged Genetic diversity, Harvard Medical School, Harvard University, Stephen Jay Gould, Tufts University on October 16, 2012| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Economics and genetics meet in uneasy union

Use of population-genetic data to predict economic success sparks war of words.

Ewen Callaway

10 October 2012 Corrected:

12 October 2012

The United States has the right amount of genetic diversity to buoy its economy, claim economists.

picture: D. ACKER/BLOOMBERG VIA GETTY

“The invalid assumption that correlation implies cause is probably among the two or three most serious and common errors of human reasoning.” Evolutionary biologist Stephen Jay Gould was referring to purported links between genetics and an individual’s intelligence when he made this familiar complaint in his 1981 book The Mismeasure of Man.

Fast-forward three decades, and leading geneticists and anthropologists are levelling a similar charge at economics researchers who claim that a country’s genetic diversity can predict the success of its economy. To critics, the economists’ paper seems to suggest that a country’s poverty could be the result of its citizens’ genetic make-up, and the paper is attracting charges of genetic determinism, and even racism. But the economists say that they have been misunderstood, and are merely using genetics as a proxy for other factors that can drive an economy, such as history and culture. The debate holds cautionary lessons for a nascent field that blends genetics with economics, sometimes called genoeconomics. The work could have real-world pay-offs, such as helping policy-makers to “reduce barriers to the flows of ideas and innovations across populations”, says Enrico Spolaore, an economist at Tufts University near Boston, Massachusetts, who has also used global genetic-diversity data in his research.

But the economists at the forefront of this field clearly need to be prepared for harsh scrutiny of their techniques and conclusions. At the centre of the storm is a 107-page paper by Oded Galor of Brown University in Providence, Rhode Island, and Quamrul Ashraf of Williams College in Williamstown, Massachusetts¹. It has been peer-reviewed by economists and biologists, and will soon appear in American Economic Review, one of the most prestigious economics journals.

Corrected:

In the original text, we wrongly attributed to Enrico Spolaore the opinion that using genetic data in economics could help policy-makers to set immigration levels. He actually suggested that the work could reduce barriers to the flows of ideas and innovations across populations. The text has been amended to reflect that.

References

Ashraf, Q. & Galor, O. Am. Econ. Rev. (in the press).
Show context
Spolaore, E. & Wacziarg, W. Q. J. Econ. 124, 469–529 (2009).
Show context
Benjamin, D. J. et al. Annu. Rev. Econ. 4, 627–662 (2012).

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Mediterranean Diet is BEST for patients with established Heart Disorders

Posted in Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Chemical Biology and its relations to Metabolic Disease, Metabolomics, Nutrigenomics, Nutrition, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Nutrition and Phytochemistry, tagged Beth Israel Deaconess Medical Center, Mediterranean, Mediterranean Diet, Monounsaturated fat, Murray Mittleman, Seven Countries Study on October 15, 2012| 1 Comment »

Reporter: Aviva Lev-Ari, PhD, RN

What’s Up with the Mediterranean Diet?

Why Heart Doctors Love It

Most of us have heard about the Mediterranean diet, which has generated interest from both the media and the medical community as the gold standard in healthy eating. But what’s all the fuss about – is this diet really worth all the attention?

The answer is yes, according toMurray Mittleman, MD, DrPH, a physician in the CardioVascular Institute at Beth Israel Deaconess Medical Center, Director of the Master’s in Public Health program at Harvard Medical School, and Director of cardiovascular epidemiological research at BIDMC.

“The Mediterranean diet is a very healthy eating style that has been shown to improve cardiovascular risk factors – even for patients with established heart disorders,” Mittleman says.

What is the Mediterranean Diet?

While most healthy diets include produce, whole grains, and fish, the Mediterranean diet and lifestyle offer subtle differences that may reduce the risk for heart disease, while making it easier to stick to healthy eating habits.

According to the American Heart Association, traditional Mediterranean diets have the following characteristics in common:

High consumption of fruits, vegetables, beans, nuts and grains
Use of olive oil rather than saturated fats like butter, lard, and cottonseed, palm and coconut oils
Low to moderate consumption of dairy, eggs, fish and poultry
Very little red meat
Wine in low-to-moderate amounts

The Diet’s “Discovery”

Originating from the culture and traditional foods found in the area bordering the Mediterranean Sea, this diet first drew the attention of the American scientist Ancel Keys, who was stationed in Italy during World War II. Keys became convinced that middle-aged American men were experiencing heart attacks due to their diets and lifestyles. After conducting studies in the U.S., he began to work with researchers overseas in the first cross-cultural comparison of males and heart attack risk in what is known as the Seven Countries Study.

Starting in 1958, the Seven Countries Study followed 11,579 men, 40 to 59 years of age, in four regions of the world (United States, Northern Europe, Southern Europe and Japan). This study found that men in Southern Europe were far less likely to experience coronary deaths than those in the U.S. and Northern Europe. The study also began to identify the eating pattern known as the Mediterranean diet and its protective benefits.

Since then, “additional research has continued to show the beneficial effects of the diet,” says Mittleman. “The Lyon Diet Heart Study, conducted in the 1990s in France, showed that those who followed the Mediterranean Diet for three years had significantly fewer additional heart attacks and a 76 percent reduction in cardiovascular deaths compared to the control group.”

How Does it Work?

Murray A. Mittleman, MD, DrPH

The Mediterranean diet is a combination of many healthy choices that work together to promote good health, according to Mittleman.

“There is a low intake of refined carbs and very little processed food, which is an important distinction that also lowers fat and salt content,” he explains. “There is more variety in fruit and vegetable consumption, and portions are smaller than those commonly found in the U.S.”

Understanding how and why the Mediterranean diet works involves looking at each of the components that make up this particular style of eating.

Healthy Fats

The Mediterranean diet does not focus on limiting total fat consumption, but it does avoid the use of saturated fats and hydrogenated oils (trans fats), which both contribute to heart disease.

Most of the fat calories in a Mediterranean diet come from “good” or monounsaturated fats, mainly from olive oil and also from nuts.

“These plant-based fats don’t raise blood cholesterol levels the way saturated fat does,” says Mittleman. “In fact, monounsaturated fats actually help reduce LDL cholesterol levels when used in place of saturated or trans fats.”

Monounsaturated fats such as olive, canola, sesame, sunflower and corn oils contain alpha-linolenic acid, a type of omega-3 fatty acid from plant sources. Omega-3 fatty acids lower triglycerides, moderate blood pressure, decrease blood clotting and improve the health of your blood vessels.

Light Protein Sources

Fish is frequently on the menu of the Mediterranean diet, and red meat is rarely served. Light in calories, fish is a beneficial substitute for meat-heavy Western cuisine, which is higher in unhealthy saturated fat. In addition, fish such as mackerel, lake trout, herring, sardines, albacore tuna and salmon are rich sources of omega-3 fatty acids.

Other plant-based protein sources, such as beans and nuts, also predominate in this style of eating. These vegetable protein sources are also light on saturated fat, helping to keep cholesterol and blood pressure in check.

Plenty of Produce

A wide variety of fruits and vegetables play an important role in the Mediterranean diet, and include fresh salads, greens sautéed in garlic and olive oil, soups, and vegetarian pasta dishes.

Fruits, such as melon, often serve as dessert, rather than the sweetened, high-fat concoctions that Western-style dining offers. Baked sweets are generally reserved for holidays or special occasions. Fresh produce provides phytonutrients that prevent and repair damage to cells and protect blood vessels. In addition, the added fiber in the diet slows the release of glucose in the blood stream, which is an important way to help prevent or control diabetes.

A Little Wine

Kenneth J. Mukamal, MD, MPH

The Mediterranean diet typically includes a small amount of wine. While red wine has antioxidant properties, the amount, frequency and style of enjoying wine is what makes this an important part of Mediterranean dining, according toDr. Kenneth J. Mukamal, an internist and cardiovascular researcher at BIDMC.

Mukamel served as lead researcher in a BIDMC study that linked the heart benefits of alcohol to the frequency of drinking. The study, which investigated 38,000 men over a 12-year period, was published in the New England Journal of Medicine in January 2003.

“The study confirmed that people who have one drink a day have the lowest rate of heart disease compared with non-drinkers or heavy drinkers,” says Mukamal. “It doesn’t seem to be the type of alcohol that matters; it’s the frequency. Individuals who drink a little bit three to-seven days a week are at lowest risk. There’s also evidence that alcohol consumed with meals — which is typical in the Mediterranean diet — is safest, providing a more gradual increase in blood alcohol levels.”

How much alcohol is appropriate? The American Heart Association recommends up to one drink a day for women and one to two drinks a day for men. Examples of one drink include 4 ounces of wine, 12 ounces of beer, or 1.5 ounces of distilled spirits (80 proof).

Mukamal cautions that for some people, such as those who have or are at risk for breast cancer or hepatitis C, regular consumption of alcohol may not be advisable.

“It’s a complex mixture of potential risks and benefits, so it’s always worth a discussion with your doctor to be sure that drinking small amounts of alcohol is right for your situation,” he says.

Taking the Mediterranean Route

The incidence of heart disease and deaths in Mediterranean countries is lower than in the United States, but such statistics may not be entirely dependent upon diet. The Mediterranean diet is part of a lifestyle in which exercise, such as walking, is frequent. Families and friends gather to enjoy meals and each other’s company. And the pace of living seems less frenetic than elsewhere.

But you don’t have to go to Rome to live as the Romans do. With some planning and attention to diet and lifestyle, you can bring the flavor and health benefits of the Mediterranean into your own life.

The changes aren’t as severe as you might think. Here are some steps that can get you moving in the right direction:

Take a half-hour walk each day.
Use olive oil instead of butter or margarine.
Increase servings of fresh veggies and fruits – aim for at least seven per day.
Eat fish and poultry and minimize or eliminate red meat.
Aim for several meatless meals each week, incorporating legumes as a protein source when possible.
Use fresh herbs and spices to flavor food instead of salt.
Avoid foods that are processed, high in fat, or contain trans or saturated fat.
Have a small glass of wine with dinner, if your doctor agrees.
Invite your family and friends to join you!

“The Mediterranean diet is very sustainable and livable,” says Mittleman. “There’s a lot of variety for your palate and it’s easy to maintain. The heart-health benefits will pay you back for a lifetime.”

Above content provided by the CardioVascular Institute at Beth Israel Deaconess Medical Center. For advice about your medical care, consult your doctor.

Posted October 2012

http://bidmc.org/CentersandDepartments/Departments/CardiovascularInstitute/CVINewsletter/MediterraneanDiet.aspx

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Genes involved in Male Fertility and Sperm-egg Binding

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Biology & Bio Instrumentation, tagged DEFB126 protein, fertility, gene, genetics, In vitro fertilisation, infertility, male fertility, mutation, sperm, sperm-egg binding on October 8, 2012| 3 Comments »

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

An estimated 10 to 15% of couples suffer from infertility, and many treatment decisions rely on trial and error. A team of international scientists has found a common genetic variant which may explain why some men with normal sperm counts and good quality sperm are affected by infertility.

The study findings suggested that men with a variation in a gene which codes for a sperm-coating protein called beta defensin 126 (DEFB126) have a reduction in the protein coat on the outside of the sperm which makes it difficult for the sperm to ‘swim’ to the egg.

Dr Edward Hollox of the University of Leicester and co-author of the study said: ‘If you’ve got this gene variant you should allow that little bit longer if your partner’s planning to get pregnant’. The researchers, including scientists from the University of California and the Anhui Medical University in China, carried out the study on over 500 newly-wed Chinese couples who were trying for a baby.

They found that when men’s sperm lacked a coat of the DEFB126 protein, their wives were significantly less likely than expected to become pregnant.

Previous studies have shown that two copies of the genetic variant may be found in up to one quarter of men around the world, with about half of all men having one copy. The DEFB126 protein coat helps sperm to swim through cervical mucus and evade the woman’s immune system, as well as enabling it to attach to the walls of fallopian tubes.

The study showed, however, that men with two copies of the variant produced sperm that were less able to swim through a substitute to cervical mucus, hyaluronic acid gel. In macaques, it has already been shown that this protein is important in evading the immune system and the researchers believe the protein coat plays the same role in humans. Commenting on the study, Dr Allan Pacey, senior lecturer in Andrology at the University of Sheffield, said: ‘We actually understand very little about the subtle molecular events which occur in sperm as they make their journey through the woman’s body to fertilise an egg’. The research was published in the journal Science Translational Medicine. If replicated in future studies, these findings promise to guide choices about the timing and type of assisted reproduction interventions—and further hint at the possibility of treating sperm from del/del homozygotes to promote fertility.

A gene which helps sperm bind to an egg has been identified by scientists. Sperm-to-egg binding is an essential process during fertilization and although the preliminary studies were performed on mice, the gene may represent a new target for infertility treatments. Sperm from mice that had the gene switched off were only able to fertilise eggs from female mice three percent of the time compared to 80 percent fertilisation success in normal mice.

The gene codes for a protein called PDILT which helps another gene product to form and assemble correctly and then to reach the surface of a sperm. Once this happens the sperm is able to navigate the uterus and oviduct and penetrate the sticky outer layers of an egg. The study, which is published in PNAS (Proceedings of the National Academy of Sciences), also demonstrates the importance of cumulus cells, a cluster of cells that surround and protect the egg, as their presence allows sperm to bind to their target. Sperm from mice that had their PDILT gene switched off would not bind to a bare egg, but would bind to an egg surrounded by cumulus cells.

Co-author Dr Adam Benham from Durham University in the UK said that the PDILT protein is ‘an essential part of the navigation system of sperm. Like any navigation system, you have to programme where it is that you want to go and this protein plays an essential role in getting sperm to the right destination, in good shape, and in good time’. A question now for the scientists is whether the PDILT gene has as much importance in human fertility as it does in mice. ‘Mutations in the gene may be responsible for unexplained male fertility problems and further research may aid more effective IVF treatment‘, said Dr Benham.

Source References:

http://stm.sciencemag.org/content/3/92/92ps31.abstract

http://www.bionews.org.uk/page_142955.asp

http://www.itv.com/news/update/2012-05-01/scientists-discover-new-gene-key-to-fertility/

http://www.bionews.org.uk/page_102705.asp

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Calcium Dependent NOS Induction by Sex Hormones: Estrogen

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Nitric Oxide in Health and Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Reproductive Biology & Bio Instrumentation, Technology Transfer: Biotech and Pharmaceutical, tagged Calcium, Endothelium, Estradiol, Estrogen, Isozyme, Messenger RNA, nitric oxide, Nitric oxide synthase, NO, sex hormones on October 3, 2012| 5 Comments »

Calcium Dependent NOS Induction by Sex Hormones: Estrogen

Reporter and Curator: Sudipta Saha, Ph.D.

Nitric oxide (NO) synthases (NOSs) constitute a family of isozymes that catalyze the oxidation of L-arginine to NO and citrulline. First identified in the vascular endothelium, NO synthesis has subsequently been shown to play important roles in:

the regulation of vascular and gastrointestinal tone,
in cell-mediated cytotoxicity against bacteria and tumors, and
in a variety of central and peripheral nervous system activities.

NOSs can be divided into three functional classes based on their sensitivity to calcium.

The cytokine- or bacterial product-inducible isoenzyme iNOS binds calmodulin tightly at resting intracellular calcium concentrations.
The constitutive forms, isozymes eNOS (originally described in endothelial cells) and
nNOS (originally described in neuronal tissue), bind calmodulin in a reversible and calcium-dependent fashion.

The mechanisms by which their synthesis is controlled are unknown. The cDNA species encoding the rat, mouse, and human nNOS, the human and bovine eNOS, and iNOS from several species and cell types have been cloned and sequenced. The three human isozymes characterized to date are distinct, with their deduced protein sequences showing only 50-60%o amino acid identity. nNOS, which in rats and humans localizes to neurons in the central and peripheral nervous system and colocalizes with NADPHdiaphorase activity, has also been shown to be widely distributed in several non-neuronal tissues including human skeletal muscle.

It had been thought that both nNOS and eNOS were purely constitutive enzymes, although studies suggest eNOS may be induced by shear stress. Studies demonstrate that these NOSs can be induced in several tissues during pregnancy and in nonpregnant female and male animals by estradiol and that in skeletal muscle it is accompanied by an increase in NOS-specific mRNA.

Evidences emerging from various laboratories showed that there is an increase in the release of NO from the vasculature during pregnancy. Furthermore, treatment of pregnant animals at the end of gestation with tamoxifen reduced NOS activity in the cerebellum, an organ where tamoxifen acts as a pure estrogen-receptor antagonist. Thus, the increase in calcium-dependent NOS activity during pregnancy is mediated by estrogen. This conclusion is supported by the fact that treatment of nonpregnant females and male animals with estradiol also increased calcium-dependent NOS activity in all tissues studied.

Interestingly, testosterone treatment also increased cerebellar NOS activity without affecting other tissues. However, testosterone may increase brain NOS by directly binding estrogen receptors as has been reported. Furthermore, the cerebellum was the only tissue in the male to respond to a 5-day course of estradiol, suggesting that it may have a larger number and/or a greater availability of estrogen receptors than other tissues. In addition, the brain is rich in aromatase, which converts testosterone into estradiol. This, together with the observation that progesterone does not induce NOS, indicates that the induction of both nNOS and eNOS is specific for estrogen and not a characteristic of all sex steroids. These experiments do not exclude the possibility that the addition of progesterone might modify the estradiol effect.

The increases in NOS activity are the result of augmented enzyme synthesis (enzyme induction) since they are accompanied by increases in the specific mRNAs for both eNOS and nNOS. It is not, however, possible to tell whether the increases in mRNA are caused by an upregulation of mRNA synthesis (transcriptional induction) or decreased mRNA breakdown.

Although calcium-dependent NOS activity was increased by estradiol in tissues obtained from both female and male guinea pigs, a longer duration of treatment was necessary in the male. The most likely explanation for this observation is that the number or availability of estrogen receptors is initially too low in most tissues of the male and requires a period of estrogen priming. Although other factors may play a role, the duration of exposure may well explain the observation that the effect of pregnancy on NOS-specific mRNA is greater than estradiol alone.

The observation that estradiol induces calcium-dependent NOSs has several important implications:

An increase in release of NO from the endothelium would decrease vascular tone and contractility, events that are characteristic in pregnancy.
Heterogeneity among tissue endothelium regarding the effects of estrogen on basal NO release could explain the selective redistribution of maternal cardiac output to organs important for a successful pregnancy.
Consistent with this possibility is the observation that the effect of pregnancy on endothelium-derived NO is greatest in the uterine artery, followed by the mesenteric artery and then renal arteries.
An alternative hypothesis to explain the adaptation of smooth muscle to pregnancy is that it is caused by prostacyclin. Prostacyclin is increased during pregnancy and contributes to the observed reduced contractility of the ovine uterine artery to angiotensin II.

However, estradiol does not increase the synthesis of prostacyclin by the endothelium, nor does inhibition of prostacyclin synthesis prevent the effects of pregnancy on smooth muscle. In addition, both the incidence of esophageal reflux and the gastrointestinal transit time are increased during pregnancy. Although this phenomenon has previously been attributed to a direct effect of progesterone, NO is a powerful dilator of the gastrointestinal smooth muscle. If the increase in NOS activity observed in the esophagus applies to the bowel, enhanced NO might be the mechanism underlying both increased esophageal reflux and transit time.

The biological signifcance of an estradiol-dependent increase in the NOS in the central nervous system is of great interest and deserves further investigation. Furthermore, an estradiol-mediated increase in NOS in the vasculature could be the mechanism whereby premenopausal women are protected from coronary artery disease since increased NOS may slow the development of atherosclerosis and reduce the contractile response to acute thrombosis. Finally, the induction of calcium-dependent NOS enzymes by estradiol suggests that the present classification of this family of enzymes into constitutive and inducible types needs to be revised, since eNOS and nNOS enzymes at least are both constitutive and inducible.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed?term=Calcium%20dependent%20NOS%20induction%20by%20sex%20hormones

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Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppressor phosphatase and tensin homologue (PTEN)

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Liver & Digestive Diseases Research, Medical and Population Genetics, Metabolomics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Technology Transfer: Biotech and Pharmaceutical, tagged Cancer and PTEN, Churchill Hospital, Gloyn, Insulin Sensitivity, John Radcliffe Hospital, Obesity, Oxford Centre, Oxford University, PTEN, Wellcome Trust on October 1, 2012| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

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Word Cloud By Danielle Smolyar

PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity

Aparna Pal, M.R.C.P., Thomas M. Barber, D.Phil., M.R.C.P., Martijn Van de Bunt, M.D., Simon A. Rudge, Ph.D., Qifeng Zhang, Ph.D., Katherine L. Lachlan, M.R.C.P.C.H., Nicola S. Cooper, M.R.C.P., Helen Linden, M.R.C.P., Jonathan C. Levy, M.D., F.R.C.P., Michael J.O. Wakelam, Ph.D., Lisa Walker, D.Phil., M.R.C.P.C.H., Fredrik Karpe, Ph.D., F.R.C.P., and Anna L. Gloyn, D.Phil.

N Engl J Med 2012; 367:1002-1011 September 13, 2012DOI: 10.1056/NEJMoa1113966

BACKGROUND

Epidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer-predisposition syndrome, providing an opportunity to study the effect of PTENhaploinsufficiency in humans.

METHODS

We measured insulin sensitivity and beta-cell function in 15 PTENmutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adipose-tissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness.

RESULTS

Measures of insulin resistance were lower in the patients with aPTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P=0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P=0.009). The patients’ insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.

CONCLUSIONS

PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity. (Funded by the Wellcome Trust and others.)

Supported by grants from the Wellcome Trust (095101/Z/10Z, to Dr. Gloyn), the Medical Research Council (G0700222, to Dr. Gloyn; and G0800467, to Drs. Pal and Gloyn), the National Institute for Health Research Oxford Biomedical Research Centre (to Drs. Pal, Karpe, and Gloyn), the Biotechnology and Biological Sciences Research Council (to Drs. Rudge, Zhang, and Wakelam), and the European Union Seventh Framework Program LipodomicNet (202272, for adipocyte signaling work, to Drs. Wakelam and Karpe).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the clinicians Trevor R.P. Cole, Louise Izatt, Carole McKeown, Eamonn R. Maher, and Mary Porteous for referring patients for this study; the research nurses Beryl Barrow and Jane Cheeseman for assistance with collecting clinical data; Amy Barrett for analysis of PTEN expression; Sandy Humphries for analysis of apolipoprotein B; Tim James and colleagues at the John Radcliffe Hospital, Oxford, for analysis of glucose and insulin; the NIHR Cambridge Biomedical Research Centre Core Biochemical Assay Laboratory for analysis of leptin and adiponectin; Leanne Hodson and Barbara Fielding for access to control dual-emission x-ray absorptiometry scans and phenotypic data on postmenopausal controls; and Jonathan Clark and Izabella Niewczas for providing lipid standards for the mass-spectrometry analysis.

SOURCE INFORMATION

From the Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford (A.P., T.M.B., M.V.B., J.C.L., F.K., A.L.G.); the Oxford National Institute for Health Research Biomedical Research Centre (A.P., J.C.L., F.K., A.L.G.) and the Oxford Regional Genetics Centre (H.L., L.W.), Churchill Hospital, Oxford; the Inositide Laboratory, the Babraham Institute, Babraham, Cambridge (S.A.R., Q.Z., M.J.O.W.); Wessex Clinical Genetics Service, University Hospital Southampton, Southampton (K.L.L.); the Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton (K.L.L.); and West Midlands Regional Clinical Genetics Service, Birmingham Women’s Hospital, Birmingham (N.S.C.) — all in the United Kingdom.

Address reprint requests to Dr. Gloyn at the Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LE, United Kingdom, or atanna.gloyn@drl.ox.ac.uk.

Source:

http://www.nejm.org/doi/full/10.1056/NEJMoa1113966?query=genetics

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What’s Up with the Mediterranean Diet?

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What is the Mediterranean Diet?

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Healthy Fats

Light Protein Sources

Plenty of Produce

A Little Wine

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Calcium Dependent NOS Induction by Sex Hormones: Estrogen

Other research published on Nitric Oxide on this Scientific Web Site include the following:

PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity

BACKGROUND

METHODS

RESULTS

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