**BIOTECH AND PHARMA NEWS**

[Preciouslife1]

Genome Update Defines Landscape Of Breast And Colon Cancers

http://www.sciencedaily.com/releases/2007/10/071011142616.htm

One year after completing the first large-scale report sequencing breast and colon cancer genes, Johns Hopkins Kimmel Cancer Center scientists have studied the vast majority of protein-coding genes which now suggest a landscape dominated by genes that each are mutated in relatively few cancers.

Their report, published online in the October 11 issue of Science Express, indicates that while little is known about these less-commonly mutated genes, they can be grouped into clusters according to their pathways.

"There are gene 'mountains' represented by those that are frequently altered and have been the focus of cancer research for years, in part because they were the only genes known to contribute to cancer," says Bert Vogelstein, M.D., an investigator at the Howard Hughes Medical Institute and co-director of the Ludwig Center at Johns Hopkins. "Now, we can see the whole picture, and it is clear that lower peaks or gene 'hills' are the predominant feature."

In a systematic search of 18,191 genes representing more than 90 percent of the protein-coding genes in the human genome -- about 5,000 more than in the first screen -- the Johns Hopkins scientists found that most cancer-causing gene mutations are quite diverse and can vary from person to person. They found that an average 77 genes are mutated in an individual colon cancer and 81 in breast cancer. Of these, about 15 are likely to contribute to a cancer's key characteristics, and most of these genes may be different for each patient.

"Fifteen years ago, we said the p53 gene was the most commonly mutated gene in cancer. It's amazing that this is still true," says Kenneth W. Kinzler, Ph.D., professor of oncology at Hopkins' Kimmel Cancer Center.

With no more higher-frequency mutations on the horizon, the investigators say that "personalized medicines" may now focus on the more complicated pathways that link these less-commonly mutated genes.

As an example, the Hopkins team charted the path of nine genes less frequently mutated in breast or colon cancers. Each of the genes' protein products interacted with an average of 25 other proteins, encoded by separate genes also found to be mutated in the cancers. It suggests that these genes converge in similar pathways. "The hard part used to be finding these mutant genes, now the challenge will be to link them to specific pathways and understand their function," says Victor Velculescu, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

The scientists say that directing therapies at common pathways that are linked by both prevalent and rare gene mutations is a better approach than aiming treatments at specific genes. They also note that personalized cancer genomics paves the way for tailored therapies and diagnostics focusing on the alterations identified in a particular patient's cancer. Many of the mutations identified by scientists could be important in developing individualized cancer vaccines and monitoring patients for early recurrence of their disease.

For the study, the scientists screened the same set of tissue samples that were used for their first genome draft - 11 each of breast and colorectal cancers, removed from patients after surgery. Then, they evaluated all mutated genes in a second group of 24 samples from each cancer, and a subset of the most promising mutations were studied in a further 96 colorectal cancers. They compared the genetic sequence of these tumors with that of normal tissue samples from the same patients using computer software that matches up gene codes in cancer and normal cells.

Within each cell, chemicals called nucleotides pair up to form the rungs of a DNA ladder that carry genetic instructions guiding everything from cell-to-cell contact to eye color. Changes in the nucleotide arrangement can create errors in the proteins made from the DNA. Buildup of damaged proteins can turn a normal cell into a cancerous one.

Laura Wood, a postdoctoral fellow at Hopkins' Kimmel Cancer Center says that these results can help to direct the global race to map additional cancer genomes. For other cancers, she says scientists should expect to find a similar genetic landscape - "few mountains surrounded by many hills."

Funding for this study was provided by The Virginia and D.K. Ludwig Fund for Cancer Research, the Department of Defense, Pew Charitable Trusts, The Palmetto Health Foundation, The Maryland Cigarette Restitution Fund, the State of Ohio Biomedical Research and Technology Transfer Commission, the Clayton Fund, the Blaustein Foundation, the National Colorectal Cancer Research Alliance, the Strang Cancer Prevention Center, the Division of Cancer Prevention of the National Cancer Institute, the Avon Foundation, the Flight Attendant Medical Research Institute, the V Foundation for Cancer Research, and the Summer Running Fund.

Additional research participants include D. William Parsons, Sian Jones, Jimmy Lin, Tobias Sjoblom, Rebecca Leary, Dong Shen, Simina M. Boca, Thomas Barber, Janine Ptak, Natalie Silliman, Steve Szabo, Saraswati Sukumar, Ben Ho Park, Nickolas Papadopoulos, and Giovanni Parmigiani from Johns Hopkins; Zoltan Dezso, Vadim Ustyanksky, Tatiana Nikolskaha, and Yuri Nicolsky from GeneGo Inc. and the Vavilov Institute of General Genetics, Moscow, Russia; Rachel Karchin and Paul Wilson from the Department of Biomedical Engineering at The Johns Hopkins University; Joshua S. Kaminker and Zemin Zhang from Genentech; Randal Croshaw and Phillip Buckhaults from the University of South Carolina; Joseph Willis and Dawn Dawson and Sanford Markowitz from Case Western Reserve University; Michail Shipitsin and Kornelia Polyak from the Dana Farber Cancer Institute, James K.V. Willson from the University of Texas Southwestern Medical Center; Charit L. Pathiyagoda, P.V. Krishna Pant, and Dennis G. Ballinger from Perlegen Sciences; Andrew B. Sparks from Complete Genomics Inc.; James Hartigan, Douglas R. Smith, and Erick Suh from Agencourt Bioscience Corporation.

[Preciouslife1]

FDA Approves ISENTRESSTM (raltegravir) Tablets, First-in-Class Oral HIV-1 Integrase Inhibitor

http://money.aol.com/news/articles/_a/merck-wins-approval-for-new-aids-drug/20071012164309990001?nci...


WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)
Merck & Co., Inc., announced today that the U.S. Food and Drug Administration (FDA) granted ISENTRESSTM (raltegravir) tablets accelerated approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of ISENTRESS [pronounced i-sen-tris]. These studies were conducted in clinically advanced, three-class antiretroviral [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] treatment-experienced adults. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response. The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients. There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection. Longer term data will be required before the FDA can consider traditional approval for ISENTRESS.

ISENTRESS is the first medicine to be approved in a new class of antiretroviral drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit two other enzymes critical to the HIV replication process – protease and reverse transcriptase – but ISENTRESS is the only drug approved that inhibits the integrase enzyme.

The FDA’s decision was based on a 24-week analysis of clinical trials in which ISENTRESS in combination with optimized background therapy (OBT) in treatment-experienced patients, provided significant reductions in HIV RNA viral load and increases in CD4 cell counts.

“The development of ISENTRESS is a significant milestone in the history of HIV/AIDS therapy because we now have a drug that's potent against another key enzyme essential for viral replication,” said Joseph J. Eron Jr., M.D., professor of medicine, Division of Infectious Diseases, UNC Chapel Hill School of Medicine. "It's important for physicians to know that ISENTRESS should always be used in combination with other active agents."

Data from two ongoing Phase III multi-center, double-blind, randomized, placebo-controlled studies (BENCHMRK-1 and BENCHMRK-2) in 699 treatment-experienced adult patients with documented resistance to at least one drug in each of three classes (NRTIs, NNRTIs and PIs) of antiretroviral therapies showed that ISENTRESS 400 mg dosed twice daily in combination with OBT was significantly more effective at both reducing levels of HIV viral RNA and increasing CD4 cell counts in these patients living with HIV, when compared to a regimen of placebo plus OBT.

Pooled analyses from the two Phase III studies showed that after 24 weeks of therapy, 75.5 percent of patients (216 out of 286) receiving ISENTRESS in combination with OBT achieved HIV viral RNA load reduction to below 400 copies/mL compared to 39.3 percent of patients (59 out of 150) receiving placebo plus OBT. In addition, after 24 weeks of therapy, 62.6 percent of patients (179 out of 286) receiving ISENTRESS plus OBT achieved viral load reduction to below 50 copies/mL compared to 33.3 percent of patients (50 out of 150) receiving placebo plus OBT. After 24 weeks of therapy, increases in CD4 cell counts from baseline were 89 and 35 cells/mm3 for patients receiving ISENTRESS plus OBT and for those receiving placebo plus OBT, respectively.

“ISENTRESS is the first drug in a new class of antiretroviral therapies that when used in combination with other effective antiretroviral agents, offers a new opportunity for individuals whose HIV infection is no longer adequately controlled and whose virus is resistant to multiple agents," said Peter S. Kim, Ph.D., president, Merck Research Laboratories. "This approval builds on our long standing commitment to research in HIV/AIDS, with the goal of making truly differentiated therapies available to patients in need."

Important safety information about ISENTRESS

ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, which may necessitate further evaluation and treatment.

The most commonly reported adverse experiences of any severity (mild, moderate or severe) regardless of drug relationship were diarrhea (16.6 percent vs. 19.5 percent), nausea (9.9 percent vs. 14.2 percent), headache (9.7 percent vs. 11.7 percent) and fever (4.9 percent vs. 10.3 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.

Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.

Safety and tolerability profile of ISENTRESS

Results from pooled safety analyses from three separate studies in treatment-experienced patients taking 400 mg of ISENTRESS dosed twice daily plus OBT or placebo plus OBT showed that after 24 weeks of therapy the rates of discontinuation of therapy due to adverse experiences were 2.0 percent in patients receiving ISENTRESS plus OBT and 1.4 percent in patients receiving placebo plus OBT. In addition, drug-related clinical adverse events of moderate to severe intensity occurring in greater than or equal to 2.0 percent of patients were diarrhea (3.7 percent vs. 4.6 percent), nausea (2.2 percent vs. 3.2 percent) and headache (2.4 percent vs. 1.4 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.

Drug interactions

Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other antiretroviral agents. Also, preclinical studies show that ISENTRESS is not ********************bolized by cytochrome P450 enzymes. Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of ISENTRESS.

About ISENTRESS

ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS does not require boosting with ritonavir.

Merck has worked closely with the HIV community regarding the price of ISENTRESS. The wholesale acquisition cost (WAC) of ISENTRESS will be $27 per day, comparable to the price of several available ritonavir-boosted protease inhibitors.

"ISENTRESS is the first drug in a new class of medications and the Fair Pricing Coalition is pleased to report that Merck has acted responsibly in its pricing of the drug. While we still believe that lower prices are always possible, Merck has avoided the temptation to set ever higher prices for each new HIV drug,” said Martin Delaney of the Fair Pricing Coalition (FPC) and Project Inform. The FPC is a nationwide network of activists and organizations concerned with drug pricing that works with pharmaceutical companies to set responsible prices.

To help patients in the United States who cannot afford treatment with ISENTRESS, the SUPPORT™ program is available. The SUPPORT program is a patient assistance program to help patients who have been prescribed ISENTRESS by providing personalized support and patient advocacy regarding individual reimbursement issues. In addition, Merck also participates in the Partnership for Prescription Assistance program, a single point of access to more than 475 public and private patient assistance programs. ISENTRESS will be available in pharmacies in approximately two weeks. For more information on ISENTRESS, visit www.isentress.com.

Expanded access program

ISENTRESS is currently available worldwide to qualified patients through an expanded access clinical research program, EARMRK. This global program provides early access to ISENTRESS for patients failing current therapy whose HIV is resistant to drugs in three existing classes (NRTIs, NNRTIs, PIs) of antiretroviral medications. Information about the program can be found at www.benchmrk.com.

Merck HIV research

Merck is committed to developing innovative therapies that offer advances in the treatment of infectious diseases – including HIV. Merck's efforts to develop investigational treatments for HIV/AIDS have been under way for more than 20 years and continue today. Merck began its HIV integrase inhibitor research in 1993 and was the first to demonstrate inhibition of HIV integrase in vitro and in vivo.

[Preciouslife1]

Biogen Idec on the block

TheDeal.com - Oct. 15, 2007 Biogen Idec Inc. of Cambridge, Mass., said after market close Friday, Oct. 12, it is willing to listen to buyout offers.
The company's board has authorized a review, led by bankers Goldman, Sachs & Co. and Merrill Lynch & Co., to see if any buyers would be interested in Biogen Idec's portfolio of cancer and auto-immune disease treatments.
The interest of big pharmaceutical companies in particular will be weighed.
The company said in its statement it has already received "expressions of interest, including one from investor Carl Icahn."
Icahn caused a stir in August when he disclosed a 1% investment in the business, with regulatory clearance to buy more.
Biogen Idec had a market cap just under $20 billion at the end of the day Friday. Its stock closed at $69.43 but shot up more than 20% to $84 in the first hour of after-market trading.
The company should attract interest from large pharmaceutical companies that face productivity problems and are looking to the biotech sector to help fill future pipelines. Sales of one key type of biotech drug, monoclonal antibodies, are expected to grow 14% a year until 2012, according to research firm Datamonitor.
But at least one analyst isn't convinced Biogen Idec will make hay out of big pharma's desperation.
"We do not believe an acquisition of Biogen would command a material premium from current levels," UBS analyst Maged Shenouda wrote in a research note last month when the stock was near $65.
The biotech drug maker itself is the product of a megamerger, the 2003 combination of Biogen Inc. and Idec Pharmaceuticals.
The $6 billion linkup, however, has not produced the expected results, thanks in large part to the scare over the company's next-generation multiple sclerosis drug Tysabri. Highly anticipated for its therapeutic advantage and its billion-dollar sales potential, Tysabri was pulled from the market three months after its launch when it was linked to a rare, deadly brain infection in a few patients.
The setback in early 2005 cut Biogen Idec stock in half, to about $35. But the past two years it has recovered all that it lost, and at least for now gone well beyond.
Tysabri returned to the market last year but with limited scope. Biogen Idec CEO Jim Mullen recently said he expects 100,000 Tysabri patients by end of 2010, a highly ambitious goal.
The company also owns the best-selling multiple sclerosis drug Avonex and shares rights with Genentech Inc. to the blockbuster cancer and auto-immune drug Rituxan.
UBS analyst Shenouda cited concerns over more competition in the multiple sclerosis market, lower returns from blockbuster drug Rituxan, and continued worry that Tysabri safety problems could crop up again.
http://www.TheDeal.com

[Preciouslife1]

Key To Blood Vessel Growth And Possible Drug Target Identified

Researchers have identified a molecular pathway that plays a critical role in the growth of blood vessels. The finding not only offers an important insight into the development of the vascular system during embryonic development but suggests a potential target for inhibiting the blood vessels that fuel cancers, diabetic eye complications and atherosclerosis, the researchers say.

The study, published online on Oct. 14 in "Nature Genetics." was conducted in the zebrafish, the tiny, blue-and-silver striped denizen of India's Ganges River and many an aquarium.
"We expect this finding will offer important insights into blood vessel formation in humans," says lead author Massimo Santoro, PhD, UCSF visiting postdoctoral fellow in the lab of senior author Didier Stainier, PhD, UCSF professor of biochemistry and biophysics. "The zebrafish has proven to be an important model for discovering molecules relevant to human disease."
Angiogenesis, or the growth of blood vessels, is active not only during embryonic development but throughout the life of the body, providing a source of oxygenated blood to tissues damaged by wounds.
However, it is also active in a number of disease processes, including cancer. Without a blood supply, tumors cannot grow beyond the size of a small pea. Cancerous tumors release chemical signals into their environment that stimulate healthy blood vessels to sprout new vessels that then extend into the tumors. During the last decade, scientists have identified several molecules that promote angiogenesis. A drug that inhibits these molecules is now commercially available and others are being studied in clinical trials.
Scientists are also exploring strategies for stimulating the growth of new blood vessels in patients whose clogged arteries prevent a sufficient blood supply to the heart muscle.
In the current study, the UCSF team determined that two well known signaling molecules, birc2 and TNF, are crucial to the survival of endothelial cells -- which line the blood vessels and maintain the integrity of the blood vessel wall during vascular development -- in zebrafish embryos.
"The pathway these molecules make up during vascular development has not been looked at before," says Stainier. "It offers a new target for therapeutic strategies."
The birc2 gene belongs to a family of proteins that control the balance between cell survival and cell death (apoptosis). A cell induces apoptosis when it detects that it is irreparably damaged. The integrity of the blood vessel wall is determined by a dynamic balance between endothelial cell survival and apoptosis.
The scientists started the investigation by examining zebrafish with unusual physical characteristics and working to identify the mutated genes that were responsible for the traits.
"We began with a genetic mutant that displayed vascular hemorrhage associated with vascular defects, and soon proved that the mutant had a defective birc2 gene," says Santoro. "Without the birc2 gene, hemorrhage and blood pooling occurred, resulting in vascular regression and cell death."
Next, through a series of genomic analyses and biochemical studies, the team discovered the critical role of birc2 and TNF in blood vessel health in the zebrafish embryo. They showed that birc2 is needed for the formation of the tumor necrosis factor receptor complex 1, a group of proteins and peptides that activate cell survival by initiating signals. Tumor necrosis factor promotes activation of NF-kB, a protein complex transcription factor involved in the transfer of genetic information. Further tests proved the existence of a genetic link between the birc2/NF-kB pathway, and that it is critical for vascular health and endothelial cell survival.
"Studies on vascular development are important so that we can better understand the molecular basis of how endothelial cell-related pathologies such as cancer, diabetic eye complications, known as retinopathies, atherosclerosis and system lupus develop," Santoro said. "It can also help us design new therapeutic strategies for these diseases."
The team hopes that future researchers will investigate other avenues and alternative pathways. "Because vascular health impacts many different diseases, understanding how to genetically control endothelial cell survival and apoptosis is critical to future work in these areas," Stainier said.
Stainier is a member of the UCSF Institute for Regeneration Medicine, the programs in Genetics and Human Genetics, and the Cardiovascular Research Institute.
Co-authors of the study were Tracy Mitchell, of the UCSF Department of Biophysics and Biochemistry, Programs in Developmental Biology, Genetics and Human Genetics, and Cardiovascular Research Institute; Temesgen Samuel, of the Burnham Institute for Medical Research and John C. Reed of the Burnham Institute.
The study was funded by the National Institutes of Health, American Heart Association, Packard Foundation and Human Frontier Science Program Fellowship.

[Preciouslife1]

New Method Of Selecting DNA For Resequencing Accelerates Discovery Of Subtle DNA Variations

A new technology developed by scientists at Emory University will allow researchers to more easily discover subtle and overlooked genetic variations that may have serious consequences for health and disease. Called Microarray-based Genomic Selection (MGS), the research protocol allows scientists to extract and enrich specific large-sized DNA regions, then compare genetic variation among individuals using DNA resequencing methods.

The technology reported will be published online on Oct. 14 and will appear in the November print issue of the journal Nature Methods. Lead author is David Okou, PhD, postdoctoral fellow in the laboratory of Michael Zwick, PhD, assistant professor of human genetics at Emory University School of Medicine.
The goal of most human genetics researchers is to find variations in the genome that contribute to disease. Despite the success of the human genome project and the availability of a number of next-generation DNA sequencing platforms, however, the lack of a simple, inexpensive method of selecting specific regions to resequence has been a serious barrier to detecting subtle genetic variability among individuals. The Emory scientists believe that goal will be much more obtainable thanks to MGS.
MGS uses DNA oligonucleotides (probes) arrayed on a chip at high density (microarray) to directly capture and extract the target region(s) from the genome. The probes are chosen from the reference human genome and are complementary to the target(s) to capture. Once the target is selected, resequencing arrays or other sequencing technologies can be used to identify variations. The Emory scientists believe MGS will allow them to easily compare genetic variation among a number of individuals and relate that variation to health and disease.
"The human genome project focused on sequencing just one human genome--an amazing technological feat that required a very large industrial infrastructure, hundreds of people and a great deal of money," says Dr. Zwick. "The question since then has been, can we replicate the ability to resequence parts of the genome, or ultimately the entire genome, in a laboratory with a single investigator and a small staff" The answer is now 'yes.'"
Geneticists have found many different types of obvious gene mutations that are deleterious to health, explains Dr. Zwick, but more subtle variations, or variations located in parts of the genome where scientists rarely look, may also have negative consequences but are not so easily discovered.
Other methods for isolating and studying a particular region of the genome, such as PCR and BAC cloning (bacterial artificial chromosomes) are comparatively labor intensive, difficult for single laboratories to scale to large sections of the genome, and relatively expensive, says Dr. Zwick.
Whereas typical microarray technology measures gene expression, MGS is a novel use of microarrays for capturing specific genomic sequences. For the published study, a third type of microarray--a resequencing array--was used to determine the DNA sequence in the patient samples.
"The logic behind the resequencing chip is that you design the chip to have the identity of the base at every single site in a reference sequence," says Dr. Zwick. "You use the human genome reference sequence as a shell and you search for variation on the theme. This alternative new technology allows a regular-sized laboratory and single investigator to generate a great deal of data at a cost significantly less than what a sequencing center would charge," Dr. Zwick says.
The MGS chips were manufactured by NimbleGen Systems, Inc., in Madison, Wisconsin, while the resequencing arrays were manufactured by Affymetrix, Inc. Other authors of the paper include David J. Cutler, Emory Department of Human Genetics; Karyn Meltz Steinberg, Emory Department of Human Genetics and Emory Program in Population Biology, Ecology and Evolution; and Thomas J. Albert and Christina Middle, NimbleGen Systems, Inc.
The research was funded by the National Institute of Mental Health of the National Institutes of Health and by the NIH Gift Fund.

[Preciouslife1]

Stem Cell Nuclei Are Soft 'Hard Drives,' Study Finds


Biophysicists at the University of Pennsylvania have discovered that the nuclei of human stem cells are particularly soft and flexible, rather than hard, making it easier for stem cells to migrate through the body and to adopt different shapes, but ultimately to put human genes in the correct nuclear "sector" for proper access and expression.

Researchers pulled cell nuclei into microscopic glass tubes under controlled pressures and visualized the shear of the DNA and associated proteins by fluorescence microscopy. The study showed that nuclei in human embryonic stem cells were the most deformable, followed by hematopoietic stem cells, HSCs, that generate a wide range of blood and tissue cells.
Both types of stem cells lack lamins A and C, two filamentous proteins that interact to stabilize the inner lining of the nucleus of most tissue cells. Lamins A and C stiffen cell nuclei and are expressed in cells only after gastrulation, when most stem cells generate the specific tissues of complex organisms.

The fluid-like character of the nucleus is shown to be set largely by the DNA and the DNA-attached proteins that form chromatin. The extent of deformation of the nucleus is further modulated by the lamina.

"Understanding the sensitivity of stem cells and their nuclei to external stresses has very practical implications in handling these cells as well as in technologies such as cloning in which nuclei are manipulated," said Dennis Discher, a professor in Penn's School of Engineering and Applied Science and the Penn School of Medicine¡¯s Cell and Molecular Biology Graduate Group.

The study, published in the Oct. 2 issue of the Proceedings of the National Academy of Sciences, supports the theory that lamin proteins are responsible for much of the genomic "lock-down" within differentiated cells. Differentiated cells, typified by muscle cells, fat cells and bone cells, all arise from stem cells that have committed to these specialized cell types by locking the DNA into a set pattern of gene expression.

To verify that lamin proteins were responsible for nuclear stiffness, the authors created a line of epithelial cells in which lamin filaments had been almost eliminated. Once as stiff as any other differentiated tissue cell derived from stem cells, the cell became as pliable as HSCs.

"Controlling structural proteins within the nucleus might lead to new means for controlling genomic regulatory factors and for generating stem cells from adult tissue cells," J. David Pajerowski, lead author and a graduate student in Penn's School of Engineering and Applied Science, said.

Researchers also found that over time nuclear deformations in stem cells and hematopoietic cells became resistant to returning to their original shape, which provides evidence of plastic flow similar to that of wet clay in the hands of a sculptor. Continued application of force eventually pulled nuclei into irreversible forms in which genes were re-arranged and massaged into new nuclear locations. Researchers literally visualized the flow of chromatin, the structure that carries DNA, and found irreversible distortions occurring on a timescale of minutes, a long time compared to many other cell processes but short compared to the lifetimes of nuclei in our tissue cells.

The research was performed by Pajerowski, Franklin L. Zhong and Discher of the Molecular and Cell Biophysics Laboratory at Penn, Kris Noel Dahl of Carnegie Mellon University and Paul J. Sammak of the University of Pittsburgh.

The research was funded by the National Institutes of Health, the National Science Foundation, an Ashton Fellowship and the Muscular Dystrophy Association.

[Preciouslife1]

Matching Pathogens To Their Antibodies: Could Lead To HIV Vaccine

The search for a vaccination against HIV has been in progress since 1984, with very little success. Traditional methods used for identifying potential cellular targets can be very costly and time-consuming.

The key to creating a vaccination lies in knowing which parts of the pathogen to target with which antibodies. A new study by David Heckerman and colleagues from Massachusetts General Hospital, publishing in PLoS Computational Biology, has come up with a way to match pathogens to their antibodies.
At the core of the human immune response is the train-to-kill mechanism in which specialized immune cells are sensitized to recognize small peptides from foreign pathogens (e.g., HIV). Following this sensitization, these cells are then activated to kill cells that display this same peptide. However, for sensitization and killing to occur, the pathogen peptide must be "paired up" with one of the infected person's other specialized immune molecules--an HLA (human leukocyte antigen) molecule. The way in which pathogen peptides interact with these HLA molecules defines if and how an immune response will be generated.
Heckerman's model uses ELISpot assays to identify HLA-restricted epitopes, and which HLA alleles are responsible for which reactions towards which pathogens. The data generated about the immune response to pathogens fills in missing information from previous studies, and can be used to solve a variety of similar problems.
The model was applied to data from donors with HIV, and made 12 correct predictions out of 16. This study, says David Heckerman, has "significant implications for the understanding of...vaccine development." The statistical approach is unusual in the study of HLA molecules, and could lead the way to developing an HIV vaccine.
Citation: Listgarten J, Frahm N, Kadie C, Brander C, Heckerman D (2007) A statistical framework for modeling HLA-dependent T cell response data. PLoS Comput Biol 3(10): e188. doi:10.1371/journal.pcbi.0030188

[Preciouslife1]

New Initiative To Create Seamless Network Of Genetic Information Launched


A new international consortium aimed at linking together the world's databases of mouse genetics -- the field of research which saw the Nobel Prize for Medicine awarded to Mario R. Capecchi, Martin J. Evans and Oliver Smithies -- has bee launched.

The Cambridge University scientist leading the initiative says the project will ultimately support new medical advances and potentially reduce the number of animals used in research.

Because they are so genetically similar to humans, the mouse has become the animal of choice for studying human disease. Research on genetic mutations in laboratory mice has led to new models for diseases such as Type 2 diabetes, currently a growing epidemic in the developed world, rheumatoid arthritis and otitis media, an acutely painful condition which affects thousands of children and which can lead to permanent deafness.

The success of research programmes in the field, particularly following advances in genome sequencing and other high-throughput technologies means that the volume of data available has become enormous. The new consortium, funded by the Commission of the European Union, is essential if we are to make the best use of the data, both for discovery and for experimental design.

Dr Paul Schofield, Senior Lecturer at the University of Cambridge, said the existing information system was "currently a virtual Babel" and that unifying the global data systems would produce "a well-ordered network in which all databases will be able to speak to each other fluently in the same language."

Maximising the availability and ease of use of the information "will allow discoveries to be made from existing data, and potentially reducing the use of animals in research", he added.

The Commission has awarded ?1.3 million over three years for the new Coordination Action, CASIMIR, co-led by the University of Cambridge and the Medical Research Council's Mammalian Genetics Unit (MRC Harwell), that will make recommendations on the integration and funding of databases across the European Union that hold information on the biology and genetics of the laboratory mouse.

The interdisciplinary team is drawn from ten European countries and includes:

In the UK -- the Medical Research Council's Harwell and Edinburgh Units, the European Bioinformatics Institute, Hinxton, the Biotech company Geneservice, Cambridge, with the University of Cambridge acting as Co-ordinator.

In Germany -- the Helmholtz Centre for Infection Research, Braunschweig, and the GSF National Research Center for Environment and Health, Munich.

In Italy -- the European Molecular Biology Laboratory EMBL- Monterotondo Outstation, and the Cell Biology Institute of the Italian National Research Council.

In Greece -- the Alexander Fleming Biomedical Sciences Research Center, Athens

In France-- the Institut Clinique de la souris, Strasbourg

In Sweden -- the Karolinska Institute, Stockholm

The consortium is joined in its discussions by the Wellcome Trust Sanger Institute, the Jackson Laboratory, USA, the Riken Genome Science Centre, Japan, and the United States National Institutes of Health, amongst many other major players, to establish a way forward to a global scientific information network.

[Preciouslife1]

Cancer genetics: Networks uncover new cancer susceptibility suspect
http://www.nature.com/nrg/journal/v8/n11/full/nrg2229.html
Patrick Goymer

Cancer susceptibility genes such as breast cancer 1 (BRCA1) do not function in isolation — they are parts of networks, and deciphering how these networks operate is an important step in understanding cancer progression. A new study has constructed a network for breast cancer susceptibility using various 'omic' data sets, and identified the hyaluronan-mediated motility receptor gene (HMMR) as a new susceptibility locus for the disease.

The authors sought to construct a network around four genes that are known to be associated with breast cancer: BRCA1, BRCA2, ataxia telangiectasia mutated (ATM) and checkpoint homologue (CHEK2). They used published expression data from normal cells to identify 164 other genes, the expression of which correlated with all four of their reference genes. The relevance of these genes for the BRCA-related network was confirmed by the fact that their expression was in many cases upregulated in tumours from carriers of BRCA1 mutations compared with sporadic tumours.

This list was integrated with published functional genomic data about interactions between the genes on the list. The resultant network consisted of 118 genes and proteins, with 321 direct and 545 indirect interactions. One of the most highly connected nodes in the network, and the one with the closest coexpression with BRCA1, was HMMR, which probably has a role in centrosome function.

The authors further explored the role of HMMR using a yeast two-hybrid assay, and found that HMMR interacts with several components of BRCA1 complexes. Using co-immunoprecipitation assays, the association of BRCA1 and HMMR was seen specifically as cells entered mitosis, and the authors also showed that HMMR was ubiquitylated by the BRCA1 complex and was localized to the centrosome. Knocking down either HMMR or BRCA1 caused abnormal increases in centrosome number, but this effect was abolished if the expression of both genes was inhibited simultaneously.

In the light of this functional information, the authors looked for associations between SNPs in HMMR and breast cancer susceptibility. Typing for five SNPs in several independent populations showed that two haplotypes significantly increased susceptibility to breast cancer, and that this effect was independent of BRCA1 or BRCA2 status. Interestingly, expression analysis showed that one of these haplotypes was associated with an increase in HMMR expression whereas the other was associated with a decrease. This implies that any perturbation from a precise level is detrimental.

This study comprised several components — the construction of a network model from published data, the functional molecular characterization of a candidate component of this network, and a candidate-gene population association study to demonstrate its link with cancer susceptibility. It shows the power of network modelling to generate hypotheses for both molecular and population genetics.

References and links
ORIGINAL RESEARCH PAPER
Pujana, M. A. et al. Network modeling links breast cancer susceptibility and centrosome dysfunction. Nature Genet. 7 October 2007 (doi: 10.1038/ng.2007.2)

Article FURTHER READING
Jensen, L. J., Saric, J. & Bork, P. Literature mining for the biologist: from information retrieval to biological discovery. Nature Rev. Genet. 7, 119–129 (2006)

ArticleBadano, J. L., Teslovich, T. M. & Katsanis, N. The centrosome in human genetic disease. Nature Rev. Genet. 6, 194–205 (2005)

[Preciouslife1]

Genomics: HapMap Phase II unveiled
http://www.nature.com/nrg/journal/v8/n11/full/nrg2235.html
Magdalena Skipper

Phase II of the International HapMap Project has just been published, adding substantial amounts of human genetic variation data to the Phase I release and providing important insights for the design of gene association studies.

Phase II involved genotyping 3.1 million SNPs from the same populations as Phase I. The increased SNP density — to about one SNP per kilobase — provides higher-resolution fine-scale genetic maps, and facilitates detection and localization of recombination hotspots. Because the newly identified SNPs have lower minor allele frequencies than those from Phase I, rare variation is better represented. Importantly for genome-wide association studies, 25–35% of all common SNPs are thought to have been genotyped, correlating with up to 95% of all common SNPs. Although currently available arrays capture 68–88% of this variation, analytical approaches that use the HapMap data can further increase the value of these arrays.

The new data provide two important insights into the structure of linkage disequilibrium. First, the apparent long-range similarity among haplotypes reveals recent common ancestry and inbreeding within populations. The high-quality haplotype data is a further asset for genome-wide association studies, as haplotype-sharing approaches can complement standard SNP association tests and should be especially useful to identify potential rare variants that are associated with complex diseases. Second, despite high SNP density, no tag could be identified for up to 1% of all high-frequency SNPs (a tag is a SNP that provides information on other variants nearby).
Most of these untaggable SNPs lie in recombination hotspots, suggesting that regions of interest that contain hotspots might require additional sequencing to identify variants.

Another new insight is that hotspots account for 60% of recombination in the human genome and for 6% of its sequence. Recombination is lower in transcribed genic regions and peaks 5' of transcription start sites, although most hotspots do not lie in promoters. Average recombination rates vary among gene classes, with defense and immunity genes having the highest and chaperone-encoding genes having the lowest rates. The authors propose that recombination might be favoured in regions that are exposed to recurrent selection (for example, from the environment or by pathogens).

Now that the fleshed out HapMap is available, what is the future of the HapMap project? Additional samples and populations will need to be sequenced and genotyped to provide information on rarer variants. Other important goals will involve generating molecular phenotypes for the HapMap samples and integrating SNP information with structural variation.

Links
WEB SITE
International HapMap Project dbSNP
References and links

ORIGINAL RESEARCH PAPER
The International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007)

[Preciouslife1]

Gene regulation: The many paths to coexpression
http://www.nature.com/nrg/journal/v8/n11/full/nrg2228.html
Louisa Flintoft

For gene products to function together, they often need to be expressed together. A new study that explores coexpression in Ciona urochordates reveals that the sequence elements involved are remarkably flexible in their architecture.

Brown and colleagues explored the basis of coexpression for 19 genes that function in muscle differentiation in two Ciona species. Cis-regulatory elements in all of these genes contain three classes of motif that bind different transcription factors and are responsible for directing muscle-specific expression. Within these motif classes there is variation — motifs of each type vary in sequence and, potentially, function.

The authors generated reporter constructs for regulatory elements involved in the expression of the 19 genes, and carried out extensive mutagenesis on them. After generating transgenic embryos expressing the mutagenized constructs, a quantitative whole-embryo gene expression assay was used to explore regulatory element function. This allowed the authors to define the elements that explain the expression of each gene. They then disrupted each of the putative transcription factor binding motifs in each element, either individually or in different combinations, allowing the relationship between the composition and function of the regulatory elements to be explored.

To analyse their results, the authors first needed to be able to determine the contribution of each motif to the expression that was driven by each element. A key question here was whether interactions between motifs are important for element function. This proved not to be the case — an additive model provided a good fit for the data, showing that motif interactions generally affect expression very little and providing a basis for further analysis.

Brown and colleagues then set about exploring how the architecture of different elements contributes to their function. Surprisingly, despite their shared expression pattern, there is a high level of flexibility among the elements that were investigated. First, these elements are diverse in terms of the number and types of motifs that they contain. Also, no rules related to motif spacing, order or orientation seem to explain their regulatory function. So, many different combinations and arrangements of motifs can be used to give rise to the same expression pattern.

Far less flexibility in the architecture of cis-regulatory elements is permitted over evolutionary time. When the authors compared orthologues of the coexpressed genes between the two Ciona species, they found a high degree of sequence constraint within the regulatory elements. Furthermore, measuring motif function in both species independently revealed that the functional contribution of each motif to the total regulatory activity is extraordinarily well conserved, despite the fact that the two species are diverged enough to have accumulated significant change at these motifs. This constraint seems to be relaxed when genes are duplicated: paralogous genes showed much more flexibility in terms of element use and composition.

As the authors point out, these findings have implications for understanding how genetic variation influences phenotype through polymorphisms in regulatory elements: the effect of alterations on both cis- and trans-acting factors is expected to vary widely between elements as a result of their diverse architectures.

Links
WEB SITE
The Sidow laboratory

References and links
ORIGINAL RESEARCH PAPER
Brown, C. D., Johnson, D. S. & Sidow, A. Functional architecture and evolution of transcriptional elements that drive gene coexpression. Science 317, 1557–1560 (2007)

[Preciouslife1]

Aspirin -- Just For Men?

http://www.sciencedaily.com/releases/2007/10/071017194549.htm

(Oct. 18, 2007) — First it was an apple, now it is an aspirin a day that may keep the doctor away. Aspirin has become standard for heart attack prevention, but research published in the online open access journal BMC Medicine suggests that this may really be a man's drug.

Scientists have long puzzled over why the protective effects of aspirin vary so widely between clinical trials. Some trials show no difference between aspirin and placebo, whilst others report that aspirin reduces the risk of a heart attack by more than 50%.

This latest study, from The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, highlights the influence of gender on aspirin's protective powers. Investigators examined the results of 23 previously published clinical trials for the effect for aspirin in heart attack prevention, involving more than 113,000 patients. The authors then analysed how much the ratio of men to women in these trials affected the trials' outcomes.

"Trials that recruited predominantly men demonstrated the largest risk reduction in non-fatal heart attacks," says Dr Don Sin, one of the study's authors. "The trials that contained predominately women failed to demonstrate a significant risk reduction in these non-fatal events. We found that a lot of the variability in these trials seems to be due to the gender ratios, supporting the theory that women may be less responsive to aspirin than men for heart protection."

The mechanisms of this resistance are not yet understood, although recent studies have shown that men and women have major differences in the structure and physiology of the heart's blood vessels.

"From our findings we would caution clinicians on the prescribing aspirin to women, especially for primary prevention of heart attacks," says Dr Sin. "Whether or not other pharmaceutical products would be more effective for women is unclear; more sex-specific studies should now be conducted."

Article: T Yerman, W Q Gan, D D Sin , The Influence of Gender on the Effects of Aspirin In Preventing Myocardial Infarction , BMC Medicine

[Preciouslife1]

Genetic Journey Of HIV From Birth To Death

http://www.sciencedaily.com/releases/2007/10/071016151541.htm

(Oct. 18, 2007) — University of Florida scientists have discovered how HIV evolves over the course of a person's lifetime into a more deadly form that heralds the onset of full-blown AIDS. The findings could pave the way for new therapeutic agents that target the virus earlier in the disease process, before it takes a lethal turn, researchers say.

"We were very interested in understanding how the virus mutates from the beginning of the infection until the end," said Marco Salemi, an assistant professor of pathology, immunology and laboratory medicine in the UF College of Medicine and lead author on the study, which appeared in an online issue of the journal PLoS ONE in September. "Previously, the only thing known was that somehow the HIV population mutates. And as soon as that happens, patients start developing AIDS. But no one knew how and where the population evolved over time."

To find out, UF researchers began tracking four children born with HIV, studying blood samples taken at birth, throughout life and just after death, when tissues samples were also taken. Using a high-resolution computational technique, they monitored mutations in a protein that helps HIV attach to human cells and then categorized the virus into two groups, R5 and X4. The R5 population is usually present in high numbers during the early stages of infection. But the X4 population enters the scene later, just before HIV gives way to full-blown AIDS. The researchers tracked the viruses in each patient to find out when and where the telltale X4 population first appeared.

"The general dogma has always been that the X4 viruses are more pathogenic than the R5 viruses. And that really isn't true. People die from the R5 viruses," said Maureen Goodenow, senior author of the paper and the Stephany W. Holloway university chair for AIDS research in the UF College of Medicine.
"But certainly evolution of these X4 viruses is not a good prognostic indicator. So if we could understand the selective pressures that push viruses to develop like that, and the steps involved in the conversion of viruses, then we might be able to set up new targets for drug development."

Previous studies have relied on cell culture or animal models to follow the virus' mutations over time. The UF researchers are among the first groups to study the progression of HIV in human patients.

As the study revealed new information about the evolution of HIV, UF scientists learned that most viral changes take place in the thymus, a small organ located behind the breastbone that is responsible for immune cell development.

"We found that the late-stage viruses, the X4 viruses, were localized predominantly in the thymus," Goodenow said. "It says that the thymus is the place where these viruses develop, or at least where they're localized and replicate."

The origin of the X4 viruses has puzzled scientists for years. The UF research reveals that the X4 viruses are not present in the body all along, as some scientists had speculated, but rather, that they evolve directly from the R5 population just before the onset of AIDS. The researchers also found that HIV followed a similar path in each child, regardless of variations in the patients' medical histories.

"We're starting to see what looks like a program of virus development over time. And it doesn't matter who the person is. And it doesn't matter what the time scale is," Goodenow said. "It's raising the possibility that, in fact, the evolutionary track of the virus is not totally random. There could be a real developmental program that the virus goes through."

Eight years ago, when the National Institutes of Health-funded study began, pregnant women infected with HIV had few therapeutic options. But recent advances in prenatal drug therapies have substantially decreased the rates of mother-to-child transmission. The Centers for Disease Control and Prevention estimates that less than 2 percent of American mothers currently infected with HIV/AIDS will transmit the viruses to their babies during birth. Without the drugs, about 40 percent of infected mothers would give birth to babies with HIV.

Those therapies may help future children, but they came too late for the subjects enrolled in the study. The children received minimal medication and all developed full-blown AIDS by their first birthdays.

"Their whole virus infection was what we call the natural history," Goodenow said. "This tells you what happens in the absence of combination antiretroviral therapy."

The next step, Goodenow said, will be to track the evolution of HIV in adults before and after treatment. The researchers hope their findings will pave the way for new drugs that interfere with the virus' ability to evolve in the thymus.

"This is an excellent study that reveals fine-scale patterns in the evolution and adaptation of HIV during infection," said Oliver Pybus, a research fellow in the department of zoology at Oxford University. Pybus was part of a team that, three years ago in Science, published descriptions of the high-resolution technique UF researchers used in their study. "For the first time, it shows how the movement of immune cells with the body is linked to the evolutionary behavior of the virus, which in turn determines the clinical outcome of infection."

[Preciouslife1]

ARIUS announces cancer stem cell antibody program successfully completes first toxicology study

PR Newswire Europe (inc. UK Disclose) - Oct. 23, 2007


TORONTO, Oct. 23 /PRNewswire-FirstCall/ -- ARIUS Research Inc., (TSX: ARI), a biotechnology company discovering and developing the next wave of antibody therapeutics, today announced that the lead drug candidate from its CD44 Cancer Stem Cell program has successfully completed its first toxicology study and has shown good efficacy in animal models. ARIUS' program targets a novel epitope of CD44 that has been found in a number of cancer indications including breast, colon, and prostate cancers. Two humanized versions of the CD44 targeting antibody have been generated in preparation for the initiation of human clinical trials in 2008.

"To be effective against cancer, a treatment must eliminate the cancer stems cells that at the heart of the disease that are driving tumor growth and seeding new tumors," said Dr. David Young, President and CEO. "Our CD44 targeting antibody is one of the most advanced drug candidates to target cancer stem cells. CD44 is considered an especially attractive target for anti-tumor drug discovery and development because it has been identified as a cancer stem cell marker in breast, prostate and colon cancers. Having now successfully completed our initial CD44 toxicology study, we look forward to moving our CD44 antibody toward human clinical trials in 2008."

Toxicology Presentation

ARIUS has demonstrated that its antibody targets a novel epitope of CD44 that is present on the majority of human tumors. A dose-ranging pilot toxicology study in non-human primate models demonstrated no dose-limiting toxic effects at doses up to 95 mg/kg. Effects observed in healthy animals were minor and transient.

Additional information can be found at AACR-NCI-EORTC 2007 International Conference on Molecular Targets and Cancer Therapeutics in San Francisco at the following location and times: Abstract B41: "Toxicology and pharmacokinetics of chimeric ARH460-16-2, a therapeutic monoclonal antibody targeting CD44." Session B, Wednesday, October 24, 2007, between 12:30-2:30 p.m. and 5:30-7:30 p.m.

Efficacy Presentation

ARIUS' CD44 targeting antibody has demonstrated significant tumor growth inhibitory activity in in vivo animal models of breast, prostate, liver, and AML cancers. In breast cancer models, the antibody demonstrated tumor regression with increased survival at all doses. Two humanized versions of the antibody have been generated and their affinity is comparable to that of the chimeric and murine antibodies. The results of this study have also demonstrated the potential for the antibody to target the cancer stem cell antigen in breast cancer. The potency of the two humanized antibodies on tumor growth inhibition has been demonstrated in established tumor models in preparation for human clinical trials in 2008.

Additional information can be found at AACR-NCI-EORTC 2007 International Conference on Molecular Targets and Cancer Therapeutics in San Francisco at the following location and times: Abstract A74: "Chimeric and humanized versions of the anti-CD44 monoclonal antibody ARH460-16-2 have potent anti-tumor efficacy in established models of human breast and ********************static liver cancer." Session A, Tuesday, October 23, 2007, between 12:30-2:30 p.m. and 5:30-7:30 p.m.

About ARIUS

ARIUS is a biotechnology company discovering and developing the next wave of antibody therapeutics. Established in 1999, ARIUS has built a proprietary technology platform, FunctionFIRST(TM), that rapidly identifies and selects antibodies based on their functional ability to affect disease. This antibody generation engine has enabled ARIUS to assemble a portfolio of more than 400 antibody candidates. In addition to the antibodies it is developing in-house, ARIUS has ongoing partnerships with key biotechnology and drug development companies. ARIUS is listed on the TSX under the symbol "ARI". For further information, visit http://www.ariusresearch.com/

[Preciouslife1]

Jury Rules Roche Infringes Amgen's EPO Patents
Tuesday October 23, 12:16 pm ET

THOUSAND OAKS, Calif.--(BUSINESS WIRE)
Amgen (NASDAQ:AMGN - News) announced today that a jury in the U.S. Federal District Court in Boston ruled that Roche’s pegylated-erythropoietin (peg-EPO) product MIRCERA infringes 11 Amgen EPO patent claims.

Amgen is pleased with the jury’s verdict and will now seek an injunction to prevent Roche from commercializing its peg-EPO product in the United States in violation of Amgen’s affirmed patent rights. The injunction hearing is scheduled for Nov. 15, 2007.

In addition to infringing its EPO patents, Amgen firmly believes Roche’s peg-EPO product provides no clinical or patient benefit over Amgen’s innovative therapies, EPOGEN® (Epoetin alfa) and Aranesp® (darbepoetin alfa).

Amgen remains committed to investing in innovative research and to delivering medicines that treat grievous illness and meet unmet medical needs.

About Amgen

Amgen discovers, develops and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science’s promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people’s lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.

Contact:
Amgen, Thousand Oaks
David Polk, 805-447-4613 (media)
Dan Whelan, 805-447-5995 (media)
Arvind Sood, 805-447-1060 (investors)