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 8, 2010

I am starting the new year and decade by recognizing the accomplishments of two distinguished scientists…

Two outstanding Canadian scientists were recognized for their valuable contributions to the global research community.

Dr. Andras Nagy’s innovative technique to reprogram mature body cells into stem cells – called induced pluripotent stem cells or iPS cells – was named Method of the Year by the prestigious journal Nature Methods.  Earlier in the year, Dr. Nagy was selected as one of Scientific American magazine’s top 10 – Guiding Science for Humanity.

Dr. Tony Pawson was honoured as one of ten “Nation Builders of the Decade” by the Globe and Mail.  His breakthrough research over the past decade and beyond has propelled our understanding of the intricate communication that goes on within a cell and between cells.  Dr. Pawson was also awarded the Kyoto Prize this year.

Bypassing PTEN Mutants in Cancer Cells: The discovery of a novel link between the proteins PTEN and PKR may lead to new approaches forncer treatments.  Dr. Antonis Koromilas’ research at McGill University identified that the tumour suppressor function of PTEN requires it to activate the PKR-eIF2alpha pathway, which applies an inhibitory control on protein synthesis.  In a cancer cell where PTEN is mutated, PKR also loses its ability to control protein synthesis and the cell continues growing into a tumour.  The significance of this is that they can now try to bypass the PTEN mutation and find alternate ways to activate PKR and regain control of cell growth.  The research is reported in the journal Science Signaling.

Distinguishing Sister Chromatids: In studying cell division, scientists have long desired to follow the fate of sister chromatids – the identical chromosome copies that is distributed to each cell during the process of cell division.  Researchers used the CO-FISH (chromosome orientation fluorescence in situ hybridization) technique with unidirectional probes.  When they observed the process in different cell types, they found that the chromatids segregated randomly in some cell types but not in others.  The non-randomness may be a mechanism to direct cells to be slightly different from its sister cell and is one of many layers of complexity in developing higher organisms.  The solution to this biological phenomenon by Dr. Peter Lansdorp at the BC Cancer Agency deserves the recognition in the prestigious journal Nature.

Prognostic Marker for Bone Cancer Survival: Genetic deletion mutations in a specific chromosome region called osteo3q13.31 may be predictive of a poor prognosis for osteosarcoma patients.  The copy number alteration (CNA) marker was identified in subsets (80%) of osteosarcoma patients where their bone cancers appeared to be more difficult to treat.  With this genetic marker, patients may be screened to identify candidates who should be treated more aggressively from the onset of diagnosis.  Furthermore, the osteo3q13.31 region contains 3 genes that were not previously associated with the disease and requires further investigation that may lead to additional therapeutic options.  The study was conducted by Dr. David Malkin’s team at The Hospital for Sick Children and is published in Cancer Research.

Friday (the 13th) Science Review: November 13, 2009

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.