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Friday Science Review: April 16, 2010

An amazing week of Canadian research advancements…

Cancer Genome Project is Well Underway: The Ontario Institute for Cancer Research (OICR), who is leading the International Cancer Genome Consortium (ICGC), published a report this week in Nature outlining the international effort to sequence 25,000 cancer genomes – 500 genomes from each of the 50 most common cancers such as breast, colon, liver, lung, and pancreatic cancers.  Some partial datasets are already available to the global research community at www.icgc.org.  This is truly a Herculean effort that is only possible because of the international collaborative effort of over 200 members around the globe.  Whole cancer genome sequencing will provide a fundamental base to advance personalized medicine to the next level.  Here is the original OICR press release and you can read a more comprehensive ‘Scientific American’ style news feature article on the cancer genome project here in the same issue of Nature.

Seek and Destory: Non-Hodgkins lymphoma cancer is taking a big hit from a newly discovered compound that destroys lymphoma cells.  The small molecule compound targets and blocks a transcription factor called BCL6, which is responsible for half of non-Hodgkins lymphoma cases.  Scientists started with the 3D structure of the BCL6 protein and used computer-aided drug design to perform in silico screening of over a million compounds.  They eventually narrowed it down to this one compound that proved to be efficacious and also non-toxic.  Dr. Gilbert Prive at the University Health Network led the innovative project that demonstrates the success of a computational approach to drug design and the ability to target transcriptions factors with minimal side effects.  Read all about it! – in the free full text article in Cancer Cell.

Divide and Conquer: Cell division is a complicated process with the synchronized dance of chromosomes segregating to each new cell.  It is a poorly understood process but research is this field is advancing with the discovery of new essential proteins involved in cell divisionDr. Laurence Pelletier (Samuel Lunenfeld Research Institute) and his collaborators in Europe used a combination of RNAi tools and mass spectrometry techniques to identify the components of protein complexes involved in cell division.  As cancer cells are hyperactive dividing cells, this new information will also aid in the advancement of cancer targeting therapeutics.  The study appears in the journal Science.

The Missing Link: Many have suspected that there must be some link or relationship between stress, anxiety and depression.  Now there is molecular evidence that this is true.  The connection involves the interaction between corticotropin releasing factor receptor 1 (CRFR1) and certain types of serotonin receptors (5-HTRs).  CRFR1 activity leads to stress related anxiety and it also stimulates an increase in the number of 5-HTRs in the brain, which can lead to signaling abnormalities causing depression.  The team headed by Dr. Stephen Ferguson at the University of Western Ontario also developed a small molecule inhibitor that blocks 5-HTRs.  Let’s hope this inhibitor and knowledge of the molecular links lead to more effective treatments for these disorders.  Check out the free full-text article in Nature Neuroscience.

Smart Buggers:  Understanding how bacteria become resistant to last-resort antibiotic drugs just got a boost from a McMaster University study.  Vancomycin resistant methicillin-resistant staphylococcus aureus (VMRSA), also known as the hospital superbug, is a rapidly growing problem with limited effective solutions.  The research team identified the histidine kinase VanSsc protein as the direct vancomycin detector in bacteria, which then triggers the expression of three genes that provide the drug resistance.  This is the first important step in redesigning antibiotic drugs to effectively fight these little buggers.   Dr. Gerry Wright and his collaborators published their exciting work in Nature Chemical Biology.

Not Just a Bad Golf Shot: Scientists have identified mutations in the SHANK3 gene that are associated with schizophrenia.  SHANK3 is a scaffolding protein involved in the formation of the synapse and maintains the structure of nerve cells.  Dr. Guy Rouleau’s team at the Université de Montréal discovered the new mutations (R1117X and R536W) in two families with schizophrenia patients where one of these families had three affected brothers.  Further molecular and genetic studies in zebrafish models confirmed that the R1117X mutation causes behavioural defects.  Earlier studies linked SHANK3 mutations to autism, which suggests that there is a molecular connection between the two neurological disorders.  The findings are reported in this week’s edition of the Proceedings of the National Academy of Sciences.

Gene Therapy is Still Alive: The promise of gene therapeutics to cure diseases may not have lived up to the hype presented a decade ago but there are still some hopeful successes using gene therapy.  One recent example comes from Laval University where researchers repaired the defective dystrophin gene responsible for Duchenne muscular dystrophy (DMD). In some cases of DMD, the dystrophin gene is misread causing a frame-shift mutation.  These frame-shift mutations may be targeted and repaired by enzymes called meganucleases.  A proof-of-principle project by Dr. Jacques Tremblay demonstrated that expression of specific meganucleases in the muscle of a DMD mouse model can restore the normal reading frame of a mutated dystrophin gene.  More details in this week’s edition of Gene Therapy.

Friday Science Review: March 12, 2010

Good viruses, bad viruses, biomarkers and protein structures in this week’s research highlights…

Biomarker for Hodgkin’s Lymphoma Subset: Using a high-throughput genomic approach to associate gene expression profile with treatment outcomes for Hodgkin lymphoma, researchers identified an overexpression of genes typically expressed by macrophages in samples from patients who had experienced a relapse after treatment.  This was confirmed histologically by looking at stained tissue samples and tallying the number of macrophages – high numbers of macrophages are associated with treatment resistance in Hodgkin lymphoma.  About 25% of patients fall into this category where a biomarker test could shuttle them into a more aggressive or experimental treatment option and may prevent them from being exposed to the side effects of primary treatments that are likely to fail.  The study, led by B.C. Cancer Agency researcher Dr. Randy Gascoyne, is reported in The New England Journal of Medicine with an editorial that is touting this as the “breakthrough we have been looking for.”

Immune System Boost for HIV Patients:  A very important molecular discovery may give a boost to restoring immune function in HIV infected patients.  Renowned HIV scientist, Dr. Rafick-Pierre Sékaly, and his cross-border research teams at the Université de Montréal and Vaccine and Gene Therapy Institute of Florida identified that the protein PD-1 is up-regulated by the release of bacterial products from the gut.  Another factor, IL-10, is subsequently increased and together this is what shuts down the CD4+ T-cell immune system in HIV patients.  Therefore, the scientists suggest that new immunotherapies should aim to block PD-1 and IL-10 to help restore the debilitated immune system in HIV infected patients.  The research article appears in this week’s Nature Medicine.

Not All Viruses are Bad: The ubiquitous reovirus has oncolytic actions against different types of cancer when used as a therapeutic approach.  Now, prostate cancer may be added to the growing list of cancers, which includes ovarian, breast, pancreatic and gliomas, that may be treated with a reovirus based strategy.  In fact, the Calgary-based Oncolytics Biotech Inc. technology platform and pipeline are based on the reovirus and contributed to the prostate study.  In the prostate cancer clinical study, a viral concoction was injected into prostate cancer nodules and three weeks later, the prostates were resected.  There was evidence of cancer cell death and overall, the procedure was deemed safe with only mild side effects experienced by the patients.  The success of this pilot study should draw interest to expand the clinical trial novel treatment for prostate cancer.  Dr. Donald Morris led the research and medical team at the University of Calgary and reports the study in Cancer Research.

Having Fun with Names: This study provides more molecular and structural details than you probably need to know but I want to point out the cool protein domain name: Really Interesting New Gene or RING domain.  It is an important component of a group of proteins that regulate the potent oncogene called eIF4E (eukaryotic translation initiation factor).  The details of the Université de Montréal study are described in the Proceedings of the National Academy of Sciences.

Pump It Up: Another structural study that I want to point out because of its importance: the V-ATPase.  This is a membrane proton pump that controls the acidity of the cellular environment and can play critical roles for the cell in promoting a diseased state.  SickKids Research Instiute scientist, Dr. John Rubinstein explains “In some types of cancer, the pumps are “hijacked” to acidify the external environment of tumours, allowing the cancer to invade surrounding tissues and spread throughout the body.  The cells that take up bone minerals also use V-ATPases to dissolve bone, a process that must be limited in treating osteoporosis.”  More details on the study are found here in the Proceedings of the National Academy of Sciences.

Paradoxical Signalling Interaction: The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a well studied signaling module and its aberrant activity is implicated in a number of diseases including cancer.  It is also the target of a handful of therapeutic drugs currently under study or in trials.  However, the new study led by Dr. Deborah Anderson at the Saskatchewan Cancer Agency throws a new twist into the pathway.  Their data identifies a paradoxical interaction between the p85 regulatory subunit of PI3K and the PTEN phosphatase enzyme since these two enzymes have opposing actions.  This is certainly food for thought for researchers in this field to rethink their signalling models.  A recent news article headlines this study as the “on switch” for cancer cell growth but it is really a much more complicated puzzle than that.  The data is presented in the early edition of the Proceedings of the National Academy of Sciences.

Friday Science Review: January 29, 2010

A productive week of international collaborations leading to new drugs or targets…

Genetic Map of Yeast: A large-scale, genome-wide interaction map of yeast genes was constructed in an international study.  The extensive network of genetic interactions lays out a functional map of the cell where similar biological processes can be grouped together. Yeast has been studied in the past and present because their molecular signaling is similar to human cells and is easy to manipulate.  The detailed “genetic atlas” in this project, a first for any organism, provides important information to better understand genetic functions in relation to diseases.  Their technique also allowed the scientists to map interactions between genes and chemicals, which will aid in choosing drug targets by predicting the extent of the interaction with other genes and how it may affect the cell.  The multi-national project was led by University of Toronto researchers Drs. Brenda Andrews and Charles Boone.  Details of the yeast map study appear in the prestigious journal, Science.

Mutations in Lymphomas: The identity of new mutations associated with specific types of lymphomas is described in this latest Nature Genetics article.  Sequencing of genes involved in the NF-kappaB signalling pathway led to the identification of recurrent mutations affecting the EZH2 histone methyltransferase enzyme.  The oncogene is the second member of this enzyme group found to be mutated in different types of cancer.  Mutations were found in over 21% of a lymphoma subtype, affecting amino acid Tyrosine 641 that renders the enzyme with lower activity.  Dr. Marco Marra at the Michael Smith Genome Sciences Centre (BC Cancer Agency) conducted the sequencing project.

Stopping Alzheimer’s Disease: Inhibition of ACAT1, an enzyme directly involved in cholesterol metabolism, significantly decreases the accumulation of amyloid plaques when tested in a mouse model of Alzheimer.  To gain deeper knowledge of how this works, researchers deleted the ACAT1 gene in mice predisposed to develop Alzheimer’s disease.  The brains of these mice had fewer amyloid plaques with improved cognitive function.  The key finding is that without ACAT1 function, cholesterol accumulates in a subcellular compartment of the cell where it is converted and no longer available to be involved in amyloid plaque formation.  These data supports the use of ACAT1 inhibitors in the battle against Alzheimer’s disease and lends insight into future improvement.  Dr. Nabil Seidah at the Institut de Recherches Cliniques de Montréal collaborated with researchers in the U.S. and published the study in the Proceedings of the National Academy of Sciences.

New Treatment to Stop Malaria: Two enzymes important to the survival of Plasmodium falciparum, the parasite causing malaria, have been discovered in an international collaboration aimed at stopping the drug-resistant parasite.  Malaria parasites invade red blood cells and digest the proteins for fuel to grow and divide until they burst out of the red blood cell and repeat the process again.  The discovery of the parasitic enzymes, PfA-M1 and PfA-M17, which are keys to the digestive process in red blood cells, was the first step in designing therapeutic drugs.  Building three-dimensional structures of the enzymes was the next step in determining how best to target and inhibit the enzyme.  The study suggests that blocking PfA-M1 and Pfa-M17 would prevent the parasite from feasting on the red blood cell and represents a new wave of promising anti-malarial drugs.  McGill University’s Dr. John Dalton led the international research project and is reported in this week’s The Proceedings of the National Academy of Sciences.

Vitamin D fights Crohn’s Disease: Vitamin D deficiency in individuals may contribute to the development of Crohn’s disease, as suggested in this new research report.  Mismanagement of intestinal bacteria triggers an inflammatory response that develops into the autoimmune disorder.  The action of Vitamin D, as the study suggests, is to directly promote the expression of NOD2, which signals to the body of a microbial invasion.  NOD2 then activates NF-kappaB to induce expression of DEFB2 (defensin beta2), an anti-microbial peptide.  To further support Vitamin D’s role, both DEFB2 and NOD2 have been linked to Crohn’s disease in earlier studies.  This is significant to the management of the disease because Vitamin D deficiency is easy to test for through a simple blood test and Vitamin D supplements (and sunlight!) are readily available.  Dr. John White and his team at McGill University and the Université de Montréal published their study in the Journal of Biological Chemistry.

Friday Science Review: October 23, 2009

A lucky find and two very different genomics projects…

Connective Tissue Disorder Linked to Defects in Ltbp4:  A McGill University researcher collaborating on two independent projects, one from Washington University School of Medicine and the other from New York University School of Medicine, made the coincidental link between the two after realizing that the tissue defects were identicalDr. Elaine Davis, an electron microscopy expert at McGill, analyzed tissue from children born with abnormally developed lungs, gastrointestinal and urinary systems, skin, skull, bones and muscles.  The underlying cause is a connective tissue disorder called cutis laxa that also causes skin to hang loosely from the body.  At the same time, Dr. Davis was analyzing tissue taken from Ltbp4 gene knockout mice from New York University when she realized that the connective tissue defects in the human and mouse samples were identical.  This connection was confirmed when they sequenced the Ltbp4 gene in human patients and discovered recessive mutations.  With this discovery, they now have a molecular target to understand the disease and to design therapeutic strategies.  The study is reported in The American Journal of Human Genetics.

A Deep-sea Microbe Genome: The microbe, SUP05, lives in the deep ocean “dead zone” where oxygenated water is minimal. It survives by using other compounds instead of oxygen, such as nitrates, sulphates and metals.  A recent surge in population suggests an expanding low-oxygen ocean ecosystem and is an indicator of global climate change.  University of British Columbia professor Dr. Steve Hallam and his research group analyzed the entire genome of SUP05 and identified a number of genes mediating carbon assimilation, sulfur oxidation, and nitrate respiration.  This study provides the first insight into the metabolism of these microbes and their effects on nutrients and gases in the deep-ocean ecosystem and will also lead to further understanding of their ecological and biogeochemical role.  The report appears in this week’s edition of Science.

Allelic Expression Genomic Map: Illumina genomics technology was used in this study to map global allelic expression differences associated with cis-acting variants.  Cis-acting elements can affect gene expression and variations due to single nucleotide polymorphisms (SNPs) explain a large percentage of the phenotypic differences in the population.  It is very informative to have this global map of the cis-acting variants and helps researchers identify variants associated with diseases.  To demonstrate this, they finely mapped cis-regulatory SNPs in a region in chromosome 8 associated with lupus.  The study was performed by Dr. Tomi Pastinen and his Genome Quebec team at McGill University and the report was published in Nature Genetics.

DNA Repair Suppresses c-Myc Lymphoma:  Overexpression of c-Myc in B cells is associated with lymphomas but requires secondary mutation events for the disease to develop.  In this study, immunologist Dr. Alberto Martin and his research team at the University of Toronto identified that the DNA repair protein, Msh2, plays an important role in mitigating c-Myc associated cancer.   To demonstrate this, they generated mice that overexpress c-Myc but with Msh2 mutations such that they are deficient in DNA mismatch repair.  These mice rapidly develop B cell lymphomas, which suggests that Msh2-dependent DNA repair actively suppresses c-Myc associated oncogenesis.  The report appears in the early edition of The Proceedings of the National Academy of Sciences.

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