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Archive for June, 2012
Investigational Devices: Edwards Sapien Transcatheter Aortic Heart Valve Replacement Transfemoral Deployment
Posted in Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D and Inventions, Valves & Tools, tagged Aortic valve, Aortic valve stenosis, Cardiac surgery, Edwards SAPIEN, Heart valve, Valve replacement on June 10, 2012| 7 Comments »
Target ‘alpha-SYN’
Posted in Uncategorized on June 8, 2012| Leave a Comment »
Foundation Medicine, Novartis Ink New Deal for Clinical Oncology Programs
Posted in Uncategorized, tagged clinical trail, Foundation Medicine, molecular information, novartis, oncology on June 7, 2012| Leave a Comment »
Foundation Medicine and Novartis have reached a 3 year agreement to use Foundation’s clinical grade, next-generation sequencing to support the drug firm’s clinical oncology programs. The agreement builds on a 2011 deal between the firms and calls for the use of Foundation Medicine’s molecular information platform across many of Novartis’ Phase 1 and Phase 2 oncology clinical programs. The initial collaboration generated “very interesting” data, and this type of tumor genomic profiling has become an important part of Novartis’ clinical trials, Foundation Medicine said.
Foundation Medicine added that it may develop additional diagnostic products from the partnership.
“The comprehensive molecular assessment of Novartis’ Oncology clinical trial samples is expected to help to bring potentially lifesaving therapies to the right patients more quickly, and we expect that the wealth of molecular information will help fundamentally improve the way cancer is understood and treated,” Michael Pellini, president and CEO of Foundation Medicine, said in a statement.
Source:
Reported by: Dr. V.S.Karra, Ph.D.
LabCorp Acquires Medtox
Posted in Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, tagged diagnostic testing, genomic testing, LabCorp, MEDTOX on June 7, 2012| 1 Comment »
Reporter: Ritu Saxena, Ph.D.
LabCorp or the laboratory Corporation of America on June 4th announced in the company’s press release that they would acquire MEDTOX for approximately $241 million,
“We are extremely pleased that MEDTOX, a premier forensic and clinical laboratory with a reputation for exceptional quality, dependability and customer service is joining our family,” said David P. King, Chairman and CEO of LabCorp. “This transaction highlights the fundamental value of the MEDTOX brand, the talent and expertise of our team and the quality of our products and testing services,” said Dick Braun, Chairman and CEO of MEDTOX. “As part of LabCorp with its substantial resources and infrastructure, we expect to accelerate MEDTOX’s profitable growth and provide a stable and sustainable environment for our employees and clients.”
About LabCorp:
Laboratory Corporation of America specializes in diagnostic testing including genome testing. The company is actively engaged in developing new laboratory diagnostics, evaluating existing diagnostic tests, defining indications for laboratory diagnostics, enhancing interpretation of laboratory test results, setting standards for the performance of laboratory diagnostics and analyzing LabCorp’s disease specific data for clinical trends and patterns.
About MEDTOX:
MEDTOX Scientific, Inc., is a provider of specialized laboratory testing services and on-site/point-of-collection testing (POCT) devices. The Company also supports customers with complete logistics, data and program management services. MEDTOX is a leader in providing esoteric laboratory testing services to hospitals and laboratories nationwide. This includes both central laboratory and bio-analytical testing for pharmaceutical clinical trials.
Source:
LabCorp Press release http://phx.corporate-ir.net/phoenix.zhtml?c=84636&p=irol-newsArticle&ID=1702041&highlight=
Genome web: http://www.genomeweb.com//node/1084141?hq_e=el&hq_m=1288261&hq_l=12&hq_v=e618131fd2
How to deal with the most common form of inherited amyloidoses?
Posted in Alzheimer's Disease, Biological Networks, Gene Regulation and Evolution, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Etiology, Genome Biology, International Global Work in Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, Uncategorized, tagged Alzheimers Disease, Amyloidosis, familial amyloidosis, retinol binding protein, Scripps Research Institute, Tafamidis, Transthyretin, TTR on June 5, 2012| 9 Comments »
In our recent article on “Amyloidosis” we discussed about its causes and forms. One such form is familial amyloidosis (ATTR) a most common form of inherited amyloidoses.
Transthyretin protein structure (Photo credit: Wikipedia)
ATTR is caused by a mutation in the transthyretin (TTR) gene that produces abnormal transthyretin protein which deposits as amyloid fibrils.
Symptoms of disease are usually:
Neuropathy (numbness and tingling in the arms and legs, dizziness upon standing, and alternating constipation and diarrhea), and
Cardiomyopathy and occur in mid to late life.
The standard treatment is liver transplantation since the transthyretin protein which causes familial amyloidosis is made in the liver, replacing this organ removes the source of mutant protein production. A new liver will make only normal transthyretin.
It is known that the transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by above mentioned progressive neuropathy and/or cardiomyopathy. The early onset TTR amyloidoses are caused by inherited TTR mutations that weaken the tetramers’ ability to stick together, producing monomers which are more likely to aggregate into amyloids and other aggregate structures.
Transthyretin (TTR) is a tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation.
Scientists from The Scripps Research Institute and Pfizer Inc. have published a new study showing how this type of amyloidosis can be inhibited. A new drug called tafamidis (Vyndaqel®)) has been developed to treat this deadly nerve disease caused by transthyretin (TTR) amyloid fibril formation, or the accumulation of abnormal assemblies of the TTR protein. Researchers have designed tafamidis to grab either of those thyroxine-binding sites, in a way that bridges the seam and helps keep the tetramer from coming apart.
Tafamidis binds to the natural, functional TTR structure (mutant and wild type), in a way that prevents it from deviating from this natural, functional form into the amyloid state. TTR’s natural, functional form is a “tetramer”made from four copies of the protein. Amyloidosis occurs when these tetramers come apart and the individual TTR proteins (“monomers”) undergo shape changes enabling them to misassemble into dysfunctional amyloid aggregates. Included in the TTR aggregate distribution are amyloid fibrils—protein stacks made from millions of TTR monomers—although researchers suspect that smaller, shorter-lived pre-amyloid aggregates do more direct damage to nerve cells and nerve fibers.
Tafamidis treats ATTR by reducing the rate of amyloid formation, and clinical trials have shown that it delays the typical progression of nerve destruction in polyneuropathy patients.
This drug is approved for use in Europe and currently under review by the US Food and Drug Administration (FDA), and it is the first medication approved by a major regulatory agency to treat an amyloid disease, a class of conditions that include Alzheimer’s.
Source:
http://www.scripps.edu/newsandviews/e_20120604/tafamidis.html
http://www.pnas.org/content/suppl/2012/05/29/1121005109.DCSupplemental/sapp.pdf
Curated by: Dr. Venkat S. Karra, Ph.D.
HBV and HCV-associated Liver Cancer: Important Insights from the Genome
Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Genome Biology, Personalized and Precision Medicine & Genomic Research, tagged breakpoints, genome, HBV, HCC, HCV, hepatitis B, hepatitis C, Hepatocellular carcinoma, integration, liver cancer, mutations, sequencing on June 4, 2012| 6 Comments »
HBV and HCV-associated Liver Cancer: Important Insights from the Genome
Author: Ritu Saxena, PhD
UPDATED on 7/21/2022
HBV drug shifts to next-gen approaches
“While we respect Assembly’s decision to discontinue clinical development of VBR, we believe that it is premature to make any conclusions about any results in this triple combination clinical trial,” Arbutus CEO William Collier said in a separate release, referring to the study that involved his company’s drug. “We intend, in collaboration with Assembly, to continue the clinical trial in order to fully and accurately assess the results.”
So as Assembly shuts the door to future trials and wraps
Study 203 — a Phase II study testing VBR plus NrtI (nucleoside analogue reverse transcriptase inhibitor) plus interferon —
Study 204 will go on, with primary endpoints being safety and tolerability.
Patients are given either
- VBR, NrtI and Arbutus’ AB-729,
- VBR plus NrtI, or
- NrtI plus AB-729.
The RNAi drug is designed to reduce all HBV viral proteins and antigens.
For Assembly Bio, the focus now shifts to two next-generation core inhibitors that it hopes could prove potent treatments for HBV. At the same time, it’s also working on earlier-stage research programs, including
- a hepatitis D virus entry inhibitor,
- a liver-focused interferon-α receptor agonist and
- new antivirals to be introduced later.
With CMO Luisa Stamm and CFO Michael Samar set to leave in the next few weeks, McHutchison — a former Gilead CSO — will now lead a remaining team of 70.
Meanwhile, Michele Anderson, SVP of development operations, is being promoted to chief development officer; and COO Jason Okazaki will add president to his title and finance to his slate of duties. The company now expects to have a cash runway into the first half of 2024.
SOURCE
Updated on July 5, 2013
(research article published in New England Journal of Medicine regarding the role of SALL4 gene in aggressive hepatocellular carcinoma)
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The incidence of HCC varies considerably with the geographic area because of differences in the major causative factors. Chronic hepatitis B and C, mostly in the cirrhotic stage, are responsible for the great majority of cases of HCC worldwide.
Hepatitis B and C viruses (HBV/HCV) can be implicated in the development of HCC in an indirect way, through induction of chronic inflammation, or directly by means of viral proteins or, in the case of HBV, by creation of mutations by integration into the genome of the hepatocyte.http://www.wjso.com/content/3/1/27
With the advent of genome sequencing methodologies, it was about time that the scientists look clues within the genome of HCC tumor cells that would provide clues for disease progression via virus integration into the liver cells.
Two studies published in the recent issue of Nature Genetics (May 2012) explored the genome of HCC cells for genetic mutations that might be related to HBV and HCV highlighting the types of genetic mutations that underlie the liver cancer hepatocellular carcinoma, including forms of the disease related to hepatitis B and hepatitis C virus infection.
In the first study, Sung et al performed an extensive whole genome analysis using a large sample size of 88 Chinese individuals with HCC http://www.ncbi.nlm.nih.gov/pubmed?term=Genome-wide%20survey%20of%20recurrent%20HBV This was in the fact first unbiased, genome-wide, HBV-integration map in HCC leading to new recurrent integration sites and molecular mechanisms.
Although integration of viral DNA sequence within HCC genome has been reported in several studies, however, fewer cases of recurring mutations within genes during these integrations have been studied. The reason might be limited sample size in these studies. Tumor and non-tumor adjacent liver cells were surveyed in 81 HBV positive and 7 HBV negative HCC tumor samples. After the survey of whole genome of the 88 patients, several viral integration sites were discovered referred to as breakpoints. The breakpoints were found to be much more common in tumor than normal samples. Although the observed breakpoints were randomly distributed across the genome, a handful or frequently occurring sites referred to as ‘hotspots’ were discovered. The frequency of integration revealed that there were five genes with recurring integrations in HBV tumors- TERT, MLL4, CCNE5, SENP1, and ROCK1.
Apart from genome analysis, expression levels of the 5 genes implicated in the study were determined. In other words, the levels of proteins formed from the genes were compared and it was observed that samples with HBV integration had significantly higher level of protein expression of TERT, MLL4 and CCNE5 than the samples harboring no HBV integration sites. Although not statistically significant, overexpression of SENP1 and ROCK1 genes was also observed in HBV integration samples. This lead to an important conclusion from the study that the five genes that harbor recurrent HBV integrations might be implicated in HCC tumor development and that overexpression of these proteins is a probable molecular mechanism of tumorigenesis.
Interestingly, analysis of the HBV analysis revealed that almost 40% of the HBV genomes were cleaved at approximately 1,800 bp and then integrated into the human genome. The cleaved HBV sites had the necessary machinery (enhancers and ORF replication sites) for protein formation.
The study also confirmed the popular belief that HBV integrations might worsen the prognosis of HCC patients revealing a significant correlation between the number of HBV integrations and the survival of patients.An interesting observation from the study that had not been reported before was that HBV integration was associated with the occurrence of HCC at a younger age.
The study presented convincing evidence that chromosomal instability of HCC genome may originate from HBV integration.
A parallel study published in the same issue of Nature Genetics explored the genome of HCC tumors to gain insights into HBV and HCV-related genomic alterations. The research team sequenced whole-exon (protein forming genomic regions) of 27 liver tumors from 25 patients and compared with the corresponding genome sequences from matched white blood cell samples.
The study involved both HBV-related and HCV-related tumors along with two samples of tumors from individuals without HBV or HCV infection. The genome wide sequencing of HCC tumor cells revealed several mutations that included deletions and mutations of genes with predicted functional consequences. “Considering the high complexity and heterogeneity of [hepatocellular carcinomas] of both etiological and genetic aspects,” they concluded, “further molecular classification is required for appropriate diagnosis and therapy in personalized medicine.” Additionally, recurrent alterations were observed in the four genes – ARID1A, RPS6KA3, NFE2L2 and IRF2 that had not been previously described in HCC. The comprehensive mutation pattern observed in the study might be indicative of specific mutagenesis mechanisms occurring in tumor cells.
Authors said “Although no common somatic mutations were identified in the multicentric tumor pairs,” further stating “their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns.”The researchers suggested a major role of chromatin remodeling complexes and involvement of both interferon and oxidative stress pathways in hepatocellular malignant proliferation and transformation based on the genes showing recurrent mutations in the observed genes.
http://www.ncbi.nlm.nih.gov/pubmed?term=Genome-wide%20survey%20of%20recurrent%20HBV
Thus, in both the studies new genes recurrently altered in HCC were identified along with uncovering some important clues relating to the molecular mechanism of virus-associated HCC.
Role of SALL4 in HCC
The oncofetal gene SALL4 is a marker of a subtype of HCC with progenitor-like features and is associated with a poor prognosis. Investigators at Cancer Science Institute of Singapore, National University of Singapore studied the role of oncofetal gene, SALL4 in HCC and the results were published were in a recent issue of New England Journal of Medicine ((Yong KJ, et al, Oncofetal Gene SALL4 in Aggressive Hepatocellular Carcinoma. http://www.ncbi.nlm.nih.gov/pubmed/23758232). Yong and colleagues (2013) screened specimens from patients with primary HCC for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. Furthermore, in vitro functional and in vivo xenograft assays were performed to assess the therapeutic effects of a peptide that targets SALL4.
According to the results, SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have HCC and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive HCC. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. The peptide targeting SALL4 blocked SALL4-corepressor interactions that released suppression of PTEN and inhibited tumor formation in xenograft assays in vivo. In conclusion, the results from the study indicate that SALL4 is a marker for a progenitor subclass of HCC with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in HCC.
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