Each year, millions of patients are put on warfarin, an anti-coagulant drug that is notoriously hard to administer. If the warfarin dose is too high, patients are at risk of hemorrhage, and if it is too low, they risk blood clots that can lead to stroke, heart attack or even death, says Dr. Brian Gage, Associate Professor of medicine at the Washington University School of Medicine (WUSM) and Director of the outpatient Anti-coagulation Service at Barnes-Jewish Hospital, the United States.

Now a study from the International Warfarin Pharmacogenetics Consortium (IWPC), which includes WUSM researchers, confirms that using a patients genetic information can make it easier to get the warfarin dose right. At WUSM, Dr. Gage, Dr. Charles Eby, Associate Professor of pathology and immunology, and colleagues recently developed improved dosing formulas for warfarin. They calculated the warfarin dose by taking into account the effect of two genes involved in warfarin sensitivity and metabolism. Their research showed that gene-based dosing could more quickly and accurately estimate the appropriate warfarin dose.

The new study gave gene-based dosing a rigorous test in an international collaboration that included more than 5,000 patients who had achieved a stable effective dose of warfarin. The researchers calculated a warfarin dose for each of the patients with the gene-based dosing algorithm and with a formula based only on clinical data. Both formulas incorporate data such as age, body size, medications and race to estimate appropriate warfarin dose, but only the gene-based formula includes genetic information. Using both formulas, the IWPC researchers checked how closely the calculated dose matched the dose actually used for each patient. In 60 per cent of the patients, the gene-based formula got closer to the actual dose than did the clinical formula.

The researchers showed that the gene-based formula was better than the clinical formula at identifying the patients at the low and high ends of the dosing spectrum. It also lays important groundwork for a new clinical trial, the Clarification of Optimal Anticoagulation through Genetics trial. The trial will compare gene-based warfarin dosing to the traditional dosing approach in a prospective, randomized trial involving 1,200 participants of diverse backgrounds and ethnicities at 12 clinical sites in the United States.

Source: www.eurekaalert.com

Researchers believe that they have found a way to regenerate nerves by stimulating a gene and said their work in worms might some day help people with spinal cord injuries. The gene is part of a network, or pathway, of four genes that appear to be essential for nerve repair, they wrote in the journal Science. We found a pathway that not only regenerates nerves in the worm, but also exists in humans, and we think it serves the same purpose, said Dr. Michael Bastiani of the University of Utah, the United States. The gene could serve as a target for a future drug that could vastly improve the ability of a neuron to regenerate after injury, he added.

In humans, nerve fibres in the arms and legs can regenerate, but not in the brain and spinal cord. Many teams are working to understand why. Dr. Bastianis team looked to nematode worms for clues. Using RNA interference, the team systematically blocked the action of 5,000 worm genes to isolate those important for nerve repair. They found that a gene called dlk-1 was essential to the process at every stage of the worms life. When they blocked this gene network, the worms were unable to repair nerve damage. But when they stimulated the gene, worms with damaged nerves recovered much more quickly.

Curiously, this network of genes is not used by the nervous system during normal development in the embryo, but it is essential for nerve repair after birth. Most of us believed that virtually everything we found in regeneration also would be involved in development, Dr. Bastiani said. His team noted that to be effective, the dlk-1 gene must be stimulated soon after injury to make a protein that activates repair, suggesting that there might be a time window for activating this pathway.


Source: www.newsdaily.com

A gene that affects how the kidneys process salt may help determine a persons risk of high blood pressure, a discovery that could lead to better ways to treat the condition, said researchers from University of Maryland School of Medicine, the United States. They identified the role of the gene a common variant of the gene STK39 in high blood pressure susceptibility by analysing the genes of 542 people in the insular Old Order Amish community in Lancaster County, Pennsylvania. The researchers confirmed the findings by looking at the genes of another group of Amish people, as well as four other groups of white people in the United States and Europe.

About 20 per cent of the people studied had either one or two copies of this particular variant, the researchers said. The gene produces a protein involved in regulating the way the kidneys process salt in the body a key factor in determining blood pressure, the researchers said. Dr. Yen-Pei Christy Chang, who led the study, said the findings could lead to the development of new high blood pressure drugs targeting the activity of STK39.

While STK39 may play a pivotal role in some people, Dr. Chang said numerous other genes also may be involved. Many factors such as being overweight, lack of exercise, smoking and too much salt in the diet are involved in hypertension. She said the researchers want to find out how people with different versions of this gene respond to the various drugs diuretics, beta blockers, ACE inhibitors and calcium channel blockers used in treating hypertension and to lifestyle interventions such as cutting the amount of salt in the diet.

Source: www.reuters.com

In the United States, scientists at the Johns Hopkins Kimmel Cancer Centre and Duke University Medical Centre have associated mutations in two genes, IDH1 and IDH2, to nearly three-quarters of several of the most common types of brain cancers known as gliomas. Reporting in the New England Journal of Medicine, the scientists say they looked for IDH1 and IDH2 gene alterations in material obtained from 500 brain tumours and 500 non-central nervous system cancers. They located changes in the IDH1 gene in more than 70 per cent of three common types of gliomas: low-grade astrocytomas, oligodendrogliomas and secondary glioblastomas. The changes occurred within a single spot along a string of thousands of genetic coding letters. Some of the brain cancers that did not have IDH1 alterations had equivalent mutations in IDH2, another closely related gene.

Further analysis of their data showed that glioblastoma and anaplastic astrocytoma patients carrying the mutations survived longer than those who did not. The median survival was 31 months for the glioblastoma patients with mutations versus 15 months for those who lacked mutations. Anaplastic astrocytoma patients with mutations were found to have a median survival of 65 months as compared with 20 months for those who did not. The mutations appear to occur very early in the progression of these cancers, perhaps at the stem cell level, observes Prof. Bert Vogelstein, Co-Director of the Ludwig Centre at Johns Hopkins.

Source: www.medicalnewstoday.com

In the United States, scientists led by Dr. Yoshihiro Kawaoka, professor of pathobiological sciences in the University of Wisconsin-Madison School of Veterinary Medicine, have identified a set of three genes that enhanced the virulence of the 1918 Spanish flu virus. While conventional flu viruses replicate only in the upper respiratory tract, these genes gave the virus the capacity to reproduce in lung tissue as well.

To find the gene or genes that enabled the virus to invade the lungs, the scientists blended genetic elements from the 1918 flu virus with those of a currently circulating avian influenza virus and tested the variants on ferrets. Substituting single genes from the 1918 virus onto the template of a much more benign contemporary virus called K173 yielded, for the most part, agents that could only replicate in the upper respiratory tract. One exception, however, included a complex of three genes that, acting in concert with another key gene, allowed the virus to efficiently colonize lung cells and make RNA polymerase. Without the protein, the virus is unable to make new virus particles and spread infection to nearby cells.

Using relic genes recovered earlier from the 1918 virus, Dr. Kawaokas group was able to generate viruses that carry different combinations of the 1918 virus and modern seasonal influenza virus. When tested, most of the hybrid viruses only infected the nasal passages of ferrets and didnt cause pneumonia. But one did infect the lungs and it carried the RNA polymerase genes from the 1918 virus that allowed the virus to synthesize its proteins.

In 2004, Dr. Kawaoka and his team identified another key gene from the 1918 virus that enhanced the pathogens virulence in mice. That gene makes hemagglutinin, a protein found on the surface of the virus that confers on viral particles the ability to attach to host cells. This could be another mechanism, Dr. Kawaoka says. The RNA polymerase is used to make copies of the virus once it has entered a host cell. The role of hemagglutinin is to help the virus gain access to cells.

                     
Source: www.genengnews.com

Researchers from Virginia Commonwealth University (VCU), the United States, have identified a new anti-tumour gene called SARI that can interact with and suppress a key protein that is over-expressed in 90 per cent of human cancers. According to Dr. Paul Fisher, Professor and Chair of the Department of Human & Molecular Genetics and Director of the VCU Institute of Molecular Medicine, and lead investigator of the study, this novel gene highlights a previously unrecognized molecular pathway underlying the anti-tumour action of a potent immune system modulator called interferon (IFN).

In the study, published in the Proceedings of the National Academy of Sciences, the researchers report the discovery of a new gene named SARI, which was uncovered by subtraction hybridization, a powerful technique pioneered in the laboratory of Dr. Fisher. SARI, which is induced by IFN, was found to suppress growth and survival of tumour cells by interfering with the action of cancer cell molecules that drive cell division and promote survival.

The researchers delivered SARI to cancer cells using a virus and the infected cancer cells subsequently stopped dividing and died. Since 90 per cent of all cancer types rely on a similar mechanism to proliferate and evade destruction, Dr. Fisher noted that SARI could be an effective anti-cancer treatment for many tumours. Additionally, IFNs are powerful immune modulating agents that contribute to the immune response to cancer and they are effective inhibitors of new blood vessel formation, the process of angiogenesis, which is obligatory for the growth of both primary and metastatic cancers, he said.

IFNs are relevant in the clinical treatment of a number of solid tumours and hematological malignancies, either as a monotherapy or as an adjuvant to chemotherapy of radiotherapy. The SARI gene may provide novel and selective gene therapy applications for cancer. It could also prove amenable for inhibiting proliferative disorders that depend on AP-1 activity, Dr. Fisher said. AP-1 plays a key role in regulating cancer cell proliferation and transformation.

Source: www.medicalnewstoday.com

Scientists at the Carnegie Institution for Science, the United States, have identified a fruit fly gene, named scrawny, that appears to be a key factor in keeping a variety of stem cells in their undifferentiated state. While the scrawny gene has so far only been identified in fruit flies, very similar genes that may carry out the same function are known to be present in all multi-cellular organisms including humans, say the researchers.

The scientists found that scrawny modifies a chromosomal protein histone H2B that is used by cells to package DNA into chromosomes. By controlling the proteins that package the genes, scrawny can silence genes that would otherwise cause a generalized cell to differentiate into a specific type of cell. The scientists report that they observed the effects of scrawny on every major type of stem cell found in fruit flies. In the experiments, mutant flies without functional copies of the scrawny prematurely lost their stem cells in reproductive tissue, skin and intestinal tissue.

Source: www.genengnews.com