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Archive for October, 2012

Memory Insights

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Genome Biology, Innovations in Neurophysiology & Neuropsychology, tagged California sea hare, Long-term memory, Mitogen-activated protein kinase, New York University, Proceedings of the National Academy of Sciences of the United States of America, Protein kinase A, Thomas Carew, University of California Irvine on October 20, 2012| Leave a Comment »

Larry H. Bernstein, MD, Reporter

This is another very interesting contribution.  I submit without change.

Neuroscientists find the molecular “when”, “where” of memory formation

Fri, 10/19/2012 – 11:30am

 

Neuroscientists from New York University and the University of California, Irvine have isolated the “when” and “where” of molecular activity that occurs in the formation of short-, intermediate-, and long-term memories. Their findings, which appear the Proceedings of the National Academy of Sciences, offer new insights into the molecular architecture of memory formation and, with it, a better roadmap for developing therapeutic interventions for related afflictions.

“Our findings provide a deeper understanding of how memories are created,” explains the research team leader Thomas Carew, a professor in NYU’s Center for Neural Science and dean of NYU’s Faculty of Arts and Science. “Memory formation is not simply a matter of turning molecules on and off; rather, it results from a complex temporal and spatial relationship of molecular interaction and movement.”

Neuroscientists have previously uncovered different aspects of molecular signaling relevant to the formation of memories. But less understood is the spatial relationship between molecules and when they are active during this process.

To address this question, the researchers studied the neurons inAplysia californica, the California sea slug. Aplysia is a model organism that is quite powerful for this type of research because its neurons are 10 to 50 times larger than those of higher organisms, such as vertebrates, and it possesses a relatively small network of neurons—characteristics that readily allow for the examination of molecular signaling during memory formation. Moreover, its coding mechanism for memories is highly conserved in evolution, and thus is similar to that of mammals, making it an appropriate model for understanding how this process works in humans.

The scientists focused their study on two molecules, MAPK and PKA, which earlier research has shown to be involved in many forms of memory and synaptic plasticity—that is, changes in the brain that occur after neuronal interaction. But less understood was how and where these molecules interacted.

English: Figure 1: A possible mechanism of cAMP/PKA inhibition of ERK activation (MAPK pathway). cAMP activation of PKA activates Rap1 via Src. Rap1 then phosphorylates Ras and inhibits signaling to Raf-1. (Photo credit: Wikipedia)

To explore this, the researchers subjected the sea slugs to sensitization training, which induces increased behavioral reflex responsiveness following mild tail shock, or in this study, mild activation of the nerve form the tail. They then examined the subsequent molecular activity of both MAPK and PKA. Both molecules have been shown to be involved in the formation of memory for sensitization, but the nature of their interaction is less clear.

What they found was MAPK and PKA coordinate their activity both spatially and temporally in the formation of memories. Specifically, in the formation of intermediate-term (for example, hours) and long-term (for example, days) memories, both MAPK and PKA activity occur, with MAPK spurring PKA action. By contrast, for short-term memories (for example, less than 30 min), only PKA is active, with no involvement of MAPK.

Source: New York University

 

 

Related articles

• Neuroscientists find the molecular “when”, “where” of memory formation (rdmag.com)

 

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Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Posted in Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Origins of Cardiovascular Disease, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Angiotensin, Aviva Lev-Ari, Battistini, Clinical trial, Endothelin, Endothelin ETA/ETB, Endothelin Receptors on October 19, 2012| 22 Comments »

Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 8/17/2018

Ambrisentan (U.S. trade name Letairis; E.U. trade name Volibris; India trade name Pulmonext by MSN labs) is a drug indicated for use in the treatment of pulmonary hypertension.

The peptide endothelin constricts muscles in blood vessels, increasing blood pressure. Ambrisentan, which relaxes those muscles, is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ET_A).^[1] Ambrisentan significantly improved exercise capacity (6-minute walk distance) compared with placebo in two double-blind, multicenter trials (ARIES-1 and ARIES-2).^[2]

Ambrisentan was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency, and designated an orphan drug, for the treatment of pulmonary hypertension.^{[3][4][5][6][7]}

Ambrisentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Ambrisentan has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury.

Ambrisentan was first approved by the U.S. Food and Drug Administration (FDA) on Jun 15, 2007, then approved by the European Medicines Agency (EMA) on Apr 21, 2008 and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jul 23, 2010. In 2000, Abbott, originator of ambrisentan, granted Myogen (acquired by Gilead in 2006) a license to the compound for the treatment of PAH. In 2006, GlaxoSmithKline obtained worldwide rights to market the compound for PAH worldwide, with the exception of the U.S. It is marketed as Letairis^® by Gilead in US.

Ambrisentan is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA). It is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).

Letairis^® is available as film-coated tablet for oral use, containing 5 or 10 mg of free Ambrisentan. The recommended starting dose is 5 mg once daily with or without food, and increase the dose to 10 mg once daily if 5 mg is tolerated.

SOURCE

https://newdrugapprovals.org/

Introduction to Endothelin

Endothelin (ET) derived from vascular endothelial cells (ECs), which consists of a 21 amino acid peptide, has a strong and persistent vasoconstrictive action (1). ET has three family peptides (ET-1, ET-2, and ET-3). As the distribution and properties of these peptides are different, each peptide is believed to play specific physiological roles. ET has two types of receptor: the ETA receptor with a high affinity for ET-1 and ET-2 is mainly located on muscle cells, whereas the ETB receptor with an affinity for all three peptides lies on endothelial, epithelial, endocrine, and nerve cells. Of the three ET isoforms,

ET-1 plays a much more important role in the regulation of vascular tone than the others and has a powerful effect on the cardiovascular system. Thus, the role of ET-1 and its receptors as the etiology or precipitating factors in various cardiovascular diseases (CVD) has been investigated (2, 3). In addition, numerous studies have reported effective treatment targeted at ET-1 in pulmonary hypertension, salt-sensitive hypertension, diabetes, and acute and chronic kidney diseases using ETconverting enzyme (ECE) inhibitors and ET-receptor antagonists (2, 4). Several animal models genetically lacking ET-1 and ET receptors have also been used as a tool for determining the physiological and pathophysiological roles of ET-1 and ET receptors in CVD (5 – 10).

Fig. 1.

Schematic illustration of ET-1 production and ET receptor–mediated actions on vascular endothelial cells and smooth muscle cells. G: G protein, ROS: reactive oxygen species, CaM: calmodulin, AA: arachidonic acid, PGI2: prostaglandin I2, AC: adenylate cyclase, sGC: soluble guanylate cyclase.

Figure Source: Journal of Pharmacological Sciences, 119, 302 – 313 (2012)

Introduction to the ET system

Endothelial Cells (ECs) are known as the main physiological source of vascular ET-1. Vascular smooth muscle cells (VSMCs), macrophages, leukocytes, cardiomyocytes, and fibroblasts are also capable of ET-1 production (11 – 13).

Several studies have indicated that various physical and chemical factors such as thrombin, angiotensin II, cytokines, hypoxia, and shear stress stimulate ET-1 gene expression in ECs by DNA binding of transcription factors including activator protein-1, GATA-2, Smad, nuclear factor-kappa B (NF-κB), and hypoxia inducible factor-1 (14 – 18). On the other hand, ET-1 is synthesized as an inactive 203-amino-acid precursor, preproET-1, which is proteolytically cleaved to yield a second inactive 39 (or 38)-amino-acid segment called ‘big’ ET-1.

The last part of the proteolytic process is mainly carried out by ECE (ECE-1 and ECE-2) and leads to the production of the bioactive form of 21-amino-acid peptide ET-1. As ET-1 release from ECs is constitutive, ET-1 biosynthesis and release appear to be mainly controlled via regulation of gene transcription and/or ECE activity.

On the other hand, although another ETB-receptor subtype (ETB2) located on VSMCs exerts vasoconstriction, it has become clear that ETB2 receptor–induced vasoconstriction is negligible under normal conditions but becomes more important in some kinds of diseases such as atherosclerosis and essential hypertension (24 – 26).

Has the considerable promise of ET-1 manipulation as a therapeutic option been realized? Its release, perhaps from a dysfunctional endothelium, could have a major role in the pathogenesis of a variety of cardiovascular diseases (reviewed by Haynes and Webb, 1992 andRubanyi and Polokoff, 1994). The discovery of endothelin-1 (ET-1) almost 20 years ago (Yanagisawa et al., 1988) was rapidly followed by prospects that pharmacological manipulation of the ET-1 system might provide powerful new treatments for many clinically significant cardiovascular conditions.

Fig. 2.

Proposed explanation for the interaction between the ET-1 system and norepinephrine (NE) release from cardiac sympathetic nerve endings in protracted myocardial ischemia. ATP is depleted and axoplasmic pH is reduced under ischemic conditions.This diminishes vesicular storage of NE, leading to a large increase in free axoplasmic NE. Compensatory activation of the neuronal Na+/H+ exchanger (NHE) by axoplasmic acidification causes influx of Na+ in exchange for H+. The resulting Na+ accumulation triggers a massive release of free axoplasmic NE via a reversal of the NE transporter (NET). Released NE acts on postsynaptic adrenoceptors on myocytes. Stimulation of the ETA receptor existing in sympathetic nerve endings by endogenously generated or exogenously applied ET-1 enhances neuronal NHE activity and results in increases in NE release. In contrast, exogenously applied big ET-1 is converted to ET-1 by ECE-1 expressed on the cell surface, and this ET-1 preferentially binds to the ETB receptor located on NOS-containing cells. As a result, increments in NO production cause inhibition of NE release. NCX: Na+/Ca2+ exchanger, VMAT: vesicular monoamine transporter.

Figure Source: Journal of Pharmacological Sciences, 119, 302 – 313 (2012)

Over 200 references in this paper trace the trail of experiments and clinical trials conducted by induction of therapeutic potential compounds that target the ET system. The role of ET-1 in cardiovascular disease and development of pharmacological tools that manipulate its activity, include agents that

• inhibit generation of ET-1 (Jeng et al., 2002) and
• block the action of ET-1 (Battistini et al., 2006)

The rapid identification of such compounds led remarkably quickly to the development of orally active antagonists (Clozel et al., 1994) and their administration to patients (Kiowski et al., 1995). Additional insight into ET physiology has been gained from studies with

• selective antagonists in man (Haynes and Webb, 1994) and from
• knockout and transgenic animals

most dramatically revealing the crucial role of ET-1 in development (Kurihara et al., 1994) and regulation of salt excretion (Ahn et al., 2004; Bagnall et al., 2006; Ge et al., 2006).

The recent licensing of

• bosentan
• sitaxsentan and
• ambrisentan

for treatment of PAH is the most obvious demonstration of the clinical benefit derived from therapeutic manipulation of the ET-1 system in cardiovascular disease. This development of one of the first effective treatments for a condition with poor prognosis has obvious clinical significance and is likely to be extended to include PAH associated with connective tissue disorders.

Thus, ET antagonists are already realizing their potential in treatment of cardiovascular diseases, while early clinical data suggest these compounds may prove beneficial in other conditions, such as resistant hypertension, chronic kidney disease and SAH. In contrast, a potential role in conditions associated with vascular remodelling (restenosis, chronic obstructive pulmonary disease and transplant graft rejection) remains speculative and requires further investigation. It should also be noted that the clinical experience with ET antagonists in patients with cardiovascular disease remains relatively limited and the design of new trials could be improved using knowledge gained from previous studies, particularly with regard to drug dose and selectivity. These successes must obviously be balanced against the failure of ET antagonists to realize their potential in the treatment of heart failure, and the fact that teratogenic effects have restricted their possible use to treatment of conditions where childbearing potential is unlikely to be an issue.

Several reasons have been proposed to account for the disappointing outcomes in clinical trials as compared to investigations using animal models of disease, including

• inadequate models or a bias in publication towards positive outcomes;
• incorrect dose/timing of administration;
• the need to show additional benefit over existing treatments; and
• ET activation being a consequence rather than a cause of the condition.

Whatever the reason, this experience urges caution in extrapolating data obtained in vitro and in animals to humans. It is hoped that additional information will emerge from unpublished clinical trials that will shed light on previous failures (Kelland and Webb, 2006), and that the combination of powerful pharmacological and molecular approaches will help us to better understand the role of ET_A and ET_B receptors in health and disease so as to fully realize the clinical potential created by the identification of the powerful vasoconstrictor peptide, ET-1.

Further studies have addressed the role of ET receptor antagonism in erectile dysfunction and aneurysmal SAH, with mixed results. A double-blind pilot study of 53 patients with mild-to-moderate erectile dysfunction demonstrated no benefit of the ET_A-selective antagonist BMS-193884 (100mg by mouth) over placebo (Kim et al., 2002).

The ET_A-selective antagonist clazosentan was specifically designed for intravenous use in conditions characterized by cerebral vasoconstriction. Its potential in treating severe aneurysmal SAH has recently been addressed in a phase IIa pilot study for the Clazosentan to Overcome Neurological iSChaemia and Infarction OccUrring after Sub-arachnoid haemorrhage (CONSCIOUS-1) trial (Vajkoczy et al., 2005). This ‘pre-CONSCIOUS-1′ study documented a reduction in the frequency and severity of cerebral vasospasm following SAH.

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET_A receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH).

In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including

• resistant hypertension,
• chronic kidney disease,
• connective tissue disease and
• sub-arachnoid haemorrhage

are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies.

(more…)

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A Prion Like-Protein, Protein Kinase Mzeta and Memory Maintenance

Posted in Alzheimer's Disease, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Innovations in Neurophysiology & Neuropsychology, Proteomics, tagged behavioral performance, Ebonyi StateUniversity, learning, memory, memory encoding, neuronal astrocyte, neuronal plasticity, Prion, protein kinase, synaptic function on October 19, 2012| Leave a Comment »

English: diagram based on Squire and Zola (1996) about decalarative and non-declarative memory (Photo credit: Wikipedia)

Larry H Bernstein, MD, FCAP, Reporter

An interesting paper recently published.

I only show abstract and part of introduction.

Available online http://www.interesjournals.org/JMMS

Copyright © 2012 International Research Journals
Review

Martin Ezeani, Maxwell Omabe, J.C. Onyeanusi, I.N. Nnatuanya, Elom S.O.
*1Department of Neurosciences, University of Sussex UK
*2Molecular Pathology Division, Department of Medical Laboratory Sciences, Faculty of Health Sciences, Ebonyi State
University.
*3Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Ebonyi State University.

ABSTRACT
Molecular studies of both declarative and non-declarative memory in Aplysia californica, lymaea stagnalis and hippocampal slices implicate experience-dependent changes of synaptic structure and strength as the fundamental basis of memory storage and maintenance. The essential outcome of these changes in synaptic structure and strength is our ability to remember what we are thought.
Remembrance is of critical importance. In disease conditions like Alzheimer’s there is lack of the ability to recreate the past. From this perspective, memory literally is the glue that binds our mental life, the scaffolding that holds our personal history and that makes it possible to change throughout life. What causes memory persistence after labile phase of memory is not yet fully known.

Elegant discoveries have explained why labile memory phase could persist over time into long term memory phase. Synaptic connections are not fixed but become modified by learning. These modifications in synaptic structure and strength persist and become the fundamental component of memory storage
after learning. Learning-induced changes in behavioural performance are the result of a fundamental physiological phenomenon.

The fundamental physiological phenomenon is neuronal plasticity. In the
process of neuronal plasticity, we review only the emerging aspect of the roles of prion like-protein, neuronal astrocyte and protein kinase Mzeta (PKMζ) in memory maintenance.
Keywords: Memory Maintenance, NMDARs and AMPARs, CPEB, Neuronal Lacate and Protein Kinase Mzeta.

INTRODUCTION
Memory defines the ability to retain, store and recall events. Memory maintenance is the process of keeping optimally these events. For instance, the beautiful nature of Sussex genomic center and its Medical School are
examples of explicit or declarative memory. Memories such as these are stored very well in the brain for recall of details later in life. Apart from these explicit or
declarative memories another type of memory is implicit or non-declarative memory. In this latter type of memory, motor skills and other type of tasks are done through performance with no conscious recall of past experience.
For instance riding a bicycle and driving a car.

Studies suggest that experience-dependent changes of synaptic strength, growth, structure and fundamental mechanism are ways of which these memories are encoded, processed and stored within the brain (Hawkins et al.,
2006; Bailey et al., 2004; and Beckinschtein et al., 2010). In these processes of initial memory formation and consolidation, memory basically exists in forms. These forms may include; short term memory (STM), intermediate memory (IM) and Long term memory (LTM) (Beckinschtein et al., 2010). There is also early and late LTM. Memories are maintained because, if all these memories are formed by similar molecular process, then what accounts for these types of basic memory?

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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

1. Hermioni Zouridis¹,*,†,
2. Niantao Deng¹,²,*,
3. Tatiana Ivanova¹,
4. Yansong Zhu¹,
5. Bernice Wong³,
6. Dan Huang⁴,
7. Yong Hui Wu¹,⁵,
8. Yingting Wu⁶,⁷,
9. Iain Beehuat Tan²,⁸,
10. Natalia Liem⁹,
11. Veena Gopalakrishnan¹,
12. Qin Luo¹,
13. Jeanie Wu⁵,
14. Minghui Lee⁵,
15. Wei Peng Yong⁹,¹⁰,
16. Liang Kee Goh¹,
17. Bin Tean Teh¹,³,⁴,
18. Steve Rozen⁶,¹¹ and
19. Patrick Tan¹,⁵,⁹,¹²,‡

+Author Affiliations

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

1. ↵‡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.

Related Stories

• Age-Related Gene Expression Differences in Autism Detected in Post-Mortem Brain Samples
  March 23, 2012 / GenomeWeb Daily News
• Teams Explore Epigenetic Consequences of Mutating Cancer-Associated Enzyme
  February 15, 2012 / GenomeWeb Daily News
• Study Suggests Widespread Loss of Epigenetic Regulation in Cancer Genomes
  June 27, 2011 / GenomeWeb Daily News
• Gene Expression Study Points to Common Transcription Shifts in Autistic Brains
  May 25, 2011 / GenomeWeb Daily News
• Methylation Market Heats up as Illumina, RainDance Debut New Offerings
  January 4, 2011 / BioArray News
  Source:
  http://www.genomeweb.com//node/1141161?hq_e=el&hq_m=1378037&hq_l=2&hq_v=e1df6f3681

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  • Article SELECTION from Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com for Training Small Language Models (SLMs) in Domain-aware Content of Medical, Pharmaceutical, Life Sciences and Healthcare by 15 Subjects Matter January 10, 2026

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