February 26, 2010
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A few medical research applications this week…
Personalized Medicine – for Lung Cancer: To develop a personalized medicine approach to treating non-small cell lung cancer (NSCLC), researchers generated a xenograft model where they implant human tumour tissue into the renal capsule of a host mouse. As the tumour establishes itself, the mouse then becomes the platform for testing various chemotherapy regimes (cisplatin+vinorelbine; cisplatin+docetaxel; cisplatin+gemcitabine) to determine which one or combination therapy is the most effective against each of the different tumours. They compared the results of the treatments in mice to retrospective patient outcomes and found significant correlation to consider the xenograft model a success. Although it takes about 6-8 weeks for the results, they believe that it is quick enough to gain an insightful preliminary assessment of the potential therapeutic outcome. Dr. Yuzhuo Wang led his team at the BC Cancer Agency and reports their work in Clinical Cancer Research.
HIV-1 Molecular Manipulations: HIV-1 infected patients exhibit a loss of CD4+ T cells, which are essential players in the defense against viral infections. A new study reveals how the HIV-1 protein, Vpr, activates the Natural Killer (NK) cells by inducing the expression of stress-related proteins at the cell surface of CD4+ T cells. The NK cells recognize the stress signals on CD4+ T cells and attacks and destroy these cells, leaving the patient with severely reduced CD4+ T cells. Researchers also noticed that the continuous activation of NK cells eventually desensitizes them and they eventually lose their ability to perform their normal duties in attacking infected cells. The molecular mechanisms of Vpr discovered in this study should help in future research leading to new therapeutic strategies. Dr. Éric Cohen and his team at the Institut de recherches cliniques de Montréal describe their research in last week’s issue of Blood.
Protecting Your Heart: The blood pressure cuff you see in every doctor’s office can be used to limit the severity of heart attacks by triggering a molecular response in the body that protects the heart during an attack. It is called remote ischemic preconditioning where the blood pressure cuff is used to intermittently cut off blood flow to the arm during an attack. This triggers an innate response warning message throughout the body to release molecules to protect itself from the lack of blood flow. In this particular study, the size of the heart attacks were reduced by 30-50% compared to control groups. It is one of the most effective treatments and is relatively simple to administer. Dr. Andrew Redington at The Hospital for Sick Children led the international study and is published in the The Lancet.
November 13, 2009
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No bad luck here in unraveling new genetic and proteomic links in disease…
Gene Variants Linked to Hearing Loss: A genetic link to hearing loss in children who are being treated with the chemotherapy drug, cisplatin, has been identified. Cisplatin is a widely used anti-cancer drug but one of the harmful side effects is hearing loss experienced by over 60% of young cancer patients. In the study by Dr. Michael Hayden’s team (Child & Family Research Institute, Vancouver), they analyzed 220 drug metabolism genes and found variants in two particular genes that are associated to hearing loss in children – one gene is called TPMT (thiopurine methyltransferase) and the other is COMT (catechol-O-methyltransferase). With this information, doctors can perform genetic tests to determine the patient’s susceptibility to developing hearing loss and seek alternative treatment if necessary. Further studies investigating how these enzymes contribute to cisplatin-induced hearing loss could lead to drugs to counteract these effects while receiving the benefits of cisplatin therapy. The study appears in this week’s Nature Genetics.
The Missing Links in 5q- Syndrome: In patients with 5q- syndrome, a portion of chromosome 5 is deleted and the result is abnormal function of bone marrow cells leading to severe anemia. We now know what is missing in this region of chromosome 5 that have key roles in maintaining the integrity of bone marrow cells. In the investigation reported in Nature Medicine, Dr. Aly Karsan at the University of British Columbia and BC Cancer Agency discovered that two microRNAs (miRNAs), miR-145 and miR-146a, are lost in 5q- syndrome. MicroRNAs are short, single-stranded RNA that act to down regulate expression of specific target genes. The targets of miR-145 and miR-146a are two proteins called TIRAP and TRAF6, which play important roles in immune signalling but should be turned off in hematopoietic stem/progenitor cells during blood cell development. In support of their hypothesis, the researchers demonstrated in mice that forced expression of TRAF6 results in a condition that is similar to human 5q- syndrome.
Cancer Genes Now Linked: Researchers at Queen’s University studying C. elegans worms identified a connection between two genes involved in cancer. PTEN is a tumour suppressor and loss of function mutations are known to be involved in a number of cancers. Eph receptor signalling is required in developmental pathways and its expression level is elevated in some cancers. New evidence now connects PTEN and Eph receptors in development and cancer. The research led by Dr. Ian Chin-Sang’s team demonstrated an inverse relationship where Eph receptors can phosphorylate and downregulate PTEN. Conversely, PTEN activity can modulate Eph receptor signaling. If there is an imbalance in this relationship, then the (negative) effects may be amplified quickly. The study report appears in the current issue of Developmental Cell.
Determining Thryoid Hormone Receptor Complexes in Yeast: This is a neat genetic array assay using yeast as a simple model system to unravel co-regulators in thyroid hormone receptor (TR) activity. A yeast strain expressing TR was systematically crossed with each of 384 yeast strains bearing deletions of known genes. From this unbiased assay, researchers identified four genes that are deemed essential for thyroid hormone function and are also conserved in humans. Dr. Paul Walfish (Toronto Mount Sinai Hospital) and his team focused on one of these genes, CCR4. They validated its role in thyroid hormone receptor action by performing a series of CCR4 expression and deletion analyses in cultured human cells and proved its association with TR in response to thyroid hormone. Details of their findings appear in the early online edition of The Proceedings of the National Academy of Sciences.
FGFR3 Phosphorylation Network in Disease: An emerging field in proteomic studies is large-scale phospho-proteomic analyses using mass spectrometry to map signalling pathways. This technique was applied to define the FGFR3 phosphorylation network in multiple myeloma and other cancers. The researchers also demonstrated in their work the ability to quantitatively detect the upregulation or downregulation of over 60 phosphorylation sites on proteins that either responded to growth factor stimulation or inhibition by the pharmacologic drug PD173074. One could apply this general method for pharmacodynamic monitoring of any drug inhibitor to fully understand its implications in the cell. Dr. Michael Moran’s research team at the Hospital for Sick Children and University of Toronto published their report in this week’s Proceedings of the National Academy of Sciences.