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Biotechnology, Health and Business in Canada, the United States and Worldwide

Tag Archives: Mount Sinai Hospital

Friday Science Review: October 29, 2010

One announcement to make this week before delving into the FSR – Gordon Ramsay and a handful of well known Canadian chefs, including Toronto’s Mark McEwan, Jamie Kennedy, and Lynn Crawford, will be attending Mount Sinai Hospital on November 20th for the Chef’s Challenge. Participants must raise $2500 to attend the event and the top 50 fundraisers get to go head to head with Ramsay in a kitchen battle. Proceeds raised will go towards funding breast and ovarian cancer research at the Samuel Lunenfeld Research Institute and the Marvelle Koffler Breast Centre both of Mount Sinai Hospital. Check it out.

Oxygen Sensors Down: Preeclampsia is a serious pregnancy disorder, affecting 5-10% of all pregnancies, and results from the dysregulation of oxygen sensing mechanisms during early formation of the placenta. Ultimately, this defective development leads to hypertension and drastic increases in urinary protein that can damage the kidney and liver of women who suffer from the disorder. The Hypoxia Inducible Factor (HIF) family transcription factors have a key role in physiological response to acute and chronic hypoxia. One member of this family, HIF-1, is important for healthy placental development and is found in abnormally high concentrations in preeclamptic placental tissue. By establishing cultures of villous explants derived from human placental tissue and growing them under varying oxygen tensions, researchers at the Samuel Lunenfeld Research Institute were able to demonstrate that HIF-1 accumulation results from the diminished function of the oxygen sensing molecules PHD2, FIH, and the SIAHs. Under normal circumstances, PHD2 controls the abundance of HIF-1 by marking it for degradation. In the absence of a functional oxygen sensing mechanism, HIF-1 accumulates beyond normal levels and alters the expression of molecules necessary for proper modeling of maternal arteries at the maternal-placental interface, leading to preeclamptic symptoms. The study was led by Dr. Isabella Caniggia, and is published in PloS ONE.

Microsatellites Need Repair: In a large-scale multi-center study, published in PLoS ONE, researchers describe how single nucleotide polymorphisms contribute to colorectal cancer (CRC).  Typically CRC arises either through abnormalities in the APC/wingless signaling pathway causing somatic mutations in oncogenes (~80% of the time), or results from deficiencies in a mismatch-repair (MMR) system causing genome-wide microsatellite instability (~20% of the time). Building on their previous work which identified several single nucleotide polymorphisms (SNPs) associated with microsatellite instability-colorectal cancer (MSI-CRC), researchers have elucidated a mechanism that explains how these SNPs contribute to the onset and formation of the disease. After removing lymphocytes from the blood of patients, researchers genotyped SNPs located in a specific region of chromosome 3 surrounding the mismatch repair gene MLH1. They were then able to use logistical regression to test for the association between these SNPs and MLH1 gene expression in CRC, and DNA methylation in CRC. Results of this analysis suggest that SNPs near or in the promoter of the MLH1 gene make this segment of DNA more susceptible to methylation, which reduces its expression causing mismatch-repair deficiency and eventually genome-wide instability. This study, led by Dr. Bharati Bapat of the Samuel Lunenfeld Research Institute, included large patient samples from Ontario, Newfoundland, and the Seattle metropolitan area.

Death by Synergy: Researchers have discovered yet another way to sensitize drug resistant cancer cells to chemotherapeutics. A group at the University of Ottawa, led by Dr. Mary-Ellen Harper, has found that a molecule known as genipin can sensitize drug-resistant cancer cells (MX2) to a number of cancer fighting small molecule drugs including menadione, doxorubicin, and epirubicin. How does it do this? Drug resistant cancer cells respond to oxidative stresses by activating uncoupling protein-2 (UCP2). This protein, a component of the mitochondrial membrane, is responsible for ushering reactive oxygen species (ROS) from the cytoplasm into the matrix of the mitochondria. By activating UCP2, drug-resistant cancer cells have a way of evading oxidative damage to essential cellular macromolecules by storing these ROS in the mitochondria. Genipin happens to be an inhibitor of UCP2 and its presence increases the concentration of ROS in the cytoplasm leading to increased cell death in the presence of cytotoxic drugs. Find the study in PLoS ONE.

Friday Science Review: October 15, 2010

A world first

It has been almost 12 years since James Thomson published his groundbreaking paper in Science providing details on how he and his colleagues had managed to isolate embryonic stem cells from human blastocysts, and maintain them indefinitely in culture. This work provided the foundation upon which future therapies could be built. Stem cells are once again in the spotlight as we begin to transcend conventional medical therapies into unchartered waters. Earlier this week, Geron Corp. initiated the world’s first embryonic stem cell-based clinical trial in patients suffering spinal cord injury. In this phase 1 study, oligodendrocyte progenitor cells (GRNOPC1) derived from human embryonic stem cells will be investigated for their safety, and potentially for their ability to remyelinate neurons and stimulate nerve growth in the spinal column of patients.

The stem cell community is no doubt experiencing a whirlwind of conflicting emotions in the face of this progress – excitement and relief, that a new milestone in stem cell-based therapy has been reached; hope, that the patients may indeed benefit from the treatment; and fear, that the study may have arrived too early and could prove unsafe in its course. While the outcome of the study remains uncertain, what is more clear is that its results will have far reaching effects and set the tone for stem cell transplantation therapy for years to come. No doubt, the study will agitate the already heated interchange between stem cell proponents (researchers, advocates, and otherwise) and those staunchly opposed due to ethical and moral objections. It seems it may not be long before one side or the other has new material to buoy its argument.

A recently published letter in Cell Stem Cell, focusing on induced pluripotent stem (iPS) cells, discusses a transplantation approach that may help the scientific and medical communities maximize the value of early stem cell transplantation studies in humans, like that of Geron’s.

Moving iPS cells to the clinic: It has been well established in the scientific community that if induced pluripotent stem (iPS) cells are to be of therapeutic value in the clinic they must be free of any genetic factors used in the reprogramming process. If left behind, reactivation of any of these ‘stem cell’ genes could result in tumor formation following transplantation. In line with this goal, the Canadian research community was taken aback last year when Dr. Andras Nagy of Mount Sinai Hospital in Toronto managed to create human iPS cells using a jumping gene which allowed for complete excision of reprogramming factors (this was also some of the first work illustrating that iPS cells could be generated without viruses, find it here).

In a recent letter in Cell Stem Cell, James Ellis of the Ontario Human iPS Cell Facility reinforces the importance of transgene-free iPS cell lines like Nagy’s for future therapeutic use. In addition, Ellis points out that in the absence of cell tracking technology in early autologous transplantation procedures in humans we will have difficulty in knowing whether transplanted cells survive, localize to pathological sites, or exert positive or negative effects on the recipient. Gene therapy is an example of a field that would have benefited early on from basic information related to clinical outcome. An NIH review of gene therapy trials published in the mid-90′s noted that of over 100 approved clinical protocols virtually none had demonstrated definitive clinical efficacy.  To ensure that stem cell transplantation protocols do not meet the same end, Ellis proposes that transgenes be investigated for their ability to act as reporters to facilitate monitoring of therapeutic cells following transplantation. It’s only early days, but this is excellent foresight.

In other Canadian research news we find therapeutic value in natural compounds..

It’s in the skin: Studies show that a ‘Mediterranean diet’ reduces the incidence of certain age-related diseases such as heart disease, cancer, and dementia. Efforts to deconstruct this effect have put scientists on to polyphenols, a class of compounds found in abundance in Mediterranean foods with pronounced anti-oxidant and protective activity. One highly potent polyphenol, resveratrol, happens to be found in the skins of grapes (another reason to enjoy wine). Dr. Remi Quirion and his colleagues at McGill University previously showed that polyphenols bind receptors in the brain. This observation led them to believe that resveratrol may exert positive effects on the skin. Indeed, experiments revealed that resveratrol has specific binding sites in human skin tissue and is able to reduce the incidence of apoptosis in toxicity models. The molecule is currently being investigated by many groups around the globe for use in life extension, prevention of cancer, and a number of other disease-related applications.

Extracts for insulin: After scanning a library of 1319 marine invertebrate extracts using a high-throughput platform, researchers identified a number of compounds that modulate insulin and pdx1 expression in human pancreatic islet cells. In order to confirm up-regulation of relevant genes, pancreatic islet cells were transfected with a dual-reporter lentivirus containing eGFP driven by the insulin promoter and mRFP driven by the pdx1 promoter. Each compound was examined for four parameters, including insulin promoter activity, pdx1 promoter activity, nuclear morphology, and cell number. Bivittoside D was identified as a positive regulator of insulin gene expression. This study is the first example of a high-throughput, high-content, multi-parameter screen in living pancreatic beta-cells, and was led by Dr. James Johnson of the Department of Cellular and Physiological Sciences at the University of British Columbia.

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