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Tag Archives: Warfarin

Friday Science Review: December 11, 2009

WOW!  A busy week in the bioscience world…

Pull Down Your ‘SOCS’ and Grow Some Nerves: A long standing question is how to get mature neurons, which stop growing at around the age of two, to start growing again after sustaining nerve damage.  The answer may lie in a protein called SOCS3 (suppressor of cytokine signaling 3).  SOCS3 controls neuronal growth in adults but when it is absent (in a knockout mouse model), axons can regenerate after nerve injury.  This process may be enhanced by supplying a cocktail of neurotrophic growth factors that the researchers also identified in their study.  This is a very important discovery that will push regenerative medicine to new therapeutic strategies.  Dr. Patrice Smith started the research as a postdoctoral fellow at Harvard University and now runs her own lab at Carleton University.  The study is published in the latest edition of Neuron.  There is also an inspirational story about Dr. Smith in the Globe and Mail.

Protecting your Brain after a Stroke: Following a stroke, neurons are at risk of permanent damage caused by overactivation of NMDARs (N-methyl-D-aspartate glutamate receptors).  A key molecular step leading to this excitotoxic neuronal death was discovered in this recent study.  The trauma causes degradation of Insig-1 (insulin-induced gene-1), which triggers the activation of the transcription factor SREBP-1 (sterol regulatory element binding protein-1).  However, when they blocked the activation of SREBP-1 they were successful in reducing the neuronal damage.  This is a promising target for generating therapeutic drugs aimed at minimizing the detrimental effects of strokes and brain trauma.  The research team was guided by Dr. Yu Tian Wang at the University of British Columbia and the study is reported in the latest Nature Medicine.

Breakthrough in Children’s Brain Cancer Research: A rare pediatric brain tumour called Central Nervous System-Primitive Neuroectodermal Tumours (CNS-PNET) offers a very poor prognosis for young patients.  In this gene expression study, a cluster of microRNAs called C19MC was found to be amplified in the diseased tissue in about 25% of the patients. This cluster acts as an oncogene that enhances cell growth and affects differentiation of neural stem cells.   The new discovery will advance opportunities to study this rare pediatric cancer and possibly use C19MC as a diagnostic marker and/or therapeutic target.  The international study was led by Dr. Annie Huang at SickKids Hospital and is reported in the current issue of Cancer Cell.

Genomics Study on Pathogenic Factors: In a large scale study of bacterial genomes, it was proven broadly across microbial species that many of the bacterial virulence factors are contained within genomic islands or clusters of genes.  The virulence factors are proteins that have more “offensive” functions such as toxins that help the bacteria invade the host.  Another significant outcome of this research is the discovery of potentially new pathogen-associated genes that are present pre-dominantly in pathogenic bacteria but less frequently in the non-pathogenic bacteria.  These factors require a closer look as they may represent novel targets for anti-microbial drug development, a critical area of research to combat the increasing prevalence of drug resistant bacteria.   Dr. Fiona Brinkman’s team at Simon Fraser University conducted the research and is detailed in PLoS One.

Dabigatran vs. Warfarin (round 2): Following up on a study that I mentioned here earlier this year, new research further supports the use of Dabigatran over Warfarin.  Patients with a common clotting disorder called venous thromboembolism (VTE) can benefit from Dabigatran as an equally effective and safe blood thinning treatment but without the complications associated with using Warfarin, which requires frequent visits to the clinic for blood monitoring and dosage adjustments.  The study was conducted by Dr. Sam Schulman at McMaster University and appears in this week’s The New England Journal of Medicine.

Research on Congenital Myopathy in Mice:  University of Toronto scientists have generated a mouse model to study a specific type of skeletal muscle disorder.  The mice express a mutant form of the RyR1 protein (type 1 ryanodine receptor/Ca2+ release channel), which causes a severe form of central core disease (CCD). Symptoms in mice that mimic the human condition include progressive congenital myopathy, respiratory stress, skeletal muscle weakness and impaired mobility.  Their study offers insight and future potential to unravel the mechanism behind the disorder.  Dr. David MacLennan’s research is published in The Proceedings of the National Academy of Sciences.

Here is a list of many more important research reports this week from across the country:

Cofactor-activated phosphorylation is required for inhibition of cortical neuron differentiation by Groucho/TLE1. (Dr. Stefano Stifani, McGill University)

Dlx5 Is a cell autonomous regulator of chondrocyte hypertrophy in mice and functionally substitutes for Dlx6 during endochondral ossification. (Dr. Andrew Bendall, University of Guelph)

Pluripotent transcription factors possess distinct roles in normal versus transformed human stem cells. (Dr. Mickie Bhatia, McMaster University)

Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. (Dr. Tak Mak, The Campbell Family Institute for Breast Cancer Research and University of Toronto).

A novel enediynyl peptide inhibitor of furin that blocks processing of proPDGF-A, B and proVEGF-C. (Dr. Amik Basak, University of Ottawa)

The specificity of the FOXL2 c.402C>G Somatic mutation: a survey of solid tumors. (Dr. David Huntsman, University of British Columbia)

Nuclear function of Smad7 promotes myogenesis. (Dr. John McDermott, York University)

Asf1-like structure of the conserved Yaf9 YEATS domain and role in H2A.Z deposition and acetylation. (Dr. Michael Kobor, University of British Columbia)

Friday Science Review: September 4, 2009

Potential future therapeutic options…

Dabigatran versus Warfarin: Dabigatran (PRADAX®, Boehringer-Ingelheim) was compared with warfarin (a commonly used anti-coagulant) in a large scale study for the treatment of patients with atrial fibrillations.  The trial demonstrated that the group of patients taking the higher dose of Dabigatran had significantly reduced risk of stroke compared to patients on warfarin but with similar risk of hemorrhaging.  With a lower dose of Dabigatran, they achieved protection from strokes that was similar to that afforded patients using warfarin but with a significantly reduced risk of major bleeding.  Dabigatran is the first alternative therapy option to warfarin treatment showing efficacy and improved safety to patients.  The global study was headquartered out of Hamilton at McMaster University and Hamilton Health Science Centre and appears in this week’s The New England Journal of Medicine.

Drug combo for Bell Palsy: Combinatorial therapy may be a better treatment method to improve the facial paralysis symptom of Bell Palsy patients. In the study lead by Dr. John de Almeida at Sunnybrook Health Science Centre, they compared the standard treatment with corticosteroids alone versus corticosteroids supplemented with antiviral drugs.  It is thought that a herpes infection is likely the cause of the disorder.  As the patients appeared to have experienced a slight incremental benefit from the combo therapy, the researchers will continue their study to provide a definitive answer.  The report was published in the current issue of the Journal of the American Medical Association (JAMA).

Key finds from studying protein structure:

  • The RAF family of proteins is an integral component of the RAS signaling module involved in cell growth, differentiation and survival.  This new structural study on BRAF revealed that its catalytic function is regulated by a “side-to-side” dimerization mode.  Interestingly, a mutation found in oncogenic versions of BRAF is located in this dimerization interface and promotes aberrant activation.  Surely, the side-to-side dimer interface of BRAF will be a potential target for therapeutic intervention against BRAF-dependent tumorigenesis.  This exciting research was lead by a collaborative effort between Dr. Frank Sicheri at the Samuel Lunenfeld Research Institute in Toronto and Dr. Marc Therrien at Université de Montréal and published in the early edition of Nature.
  • New insight into how bacteria can steal iron from its host was revealed through structural studies of the bacteria’s transferrin receptor.  The bacterial transferrin receptor binds to the host’s iron containing transferrin protein, extracts the iron and transports it across the membrane.  When they mutated a critical residue at the interface of this interaction, binding was completely abolished.  Perhaps these results from Dr. Anthony Schryvers’ research team at the University of Calgary will lead to future directions for antimicrobial therapeutics.  The study was published in the recent edition of Molecular Cell.

Nervous system development in today’s issue of Cell…

  • Researchers revealed how the neural-specific SR-related protein of 100 kDa (nSR100) is responsible for facilitating alternative transcript splicing specifically in the nervous system.  nSR100 is required for neural cell differentiation and contributes to the greater complexity of the vertebrate nervous system.  The research was lead by Dr. Benjamin Blencowe at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research.

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Trends Update — Personalized Medicine: No Medicare Funding for Warfarin Testing, For Now

dna_sequenceThe WSJ Health Blog reports that Centers for Medicare and Medicaid Services (CMS) has decided there is not enough scientific evidence for Medicare to pay for genetic testing to customize Warfarin dosing.

CMS proposes paying for more research, and the New York Times story questions the cost effectiveness of a prospective study; but as we reported in February, NIGMS is already working on a prospective study that Frank Torti boosted at the time.

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Warfarin and Personalized Medicine

dna_sequenceThe optimal dose of Warfarin for an individual can vary across a 10-fold range, and depends in part on genetic variation in two genes, CYP2C9 and VKORC1.  In 2007, the FDA required a labelling change to warn of patients with increased risk of bleeding due to these variations.  However, population-wide assessments of outcomes based on genetic testing were not definitive.

A paper in the current issue of the New England Journal of Medicine uses retrospective data to build a new dosing algorithm and predicts significant benefit from the use of the algorithm for the 46% of patients who require lower- or higher-than-normal doses.  The algorithm and data used to derive it will be made available via PharmGKB, a database managed by researchers at Stanford, and the research has prompted a full-scale prospective study of the personalized approach.

Frank M. Torti, M.D., acting commissioner of Food and Drugs said that the prospective study

is precisely what is needed to advance the promise of personalized medicine, ensuring that patients receive the safest and most effective drug dose.

Read our other posts on personalized medicine.
 

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