Stem Cell Transplantation Halts Multiple Sclerosis
Multiple sclerosis is a debilitating neurological condition and those afflicted with this illness face recurrent episodes of disability that come and go (relapses and remissions) as well as the prospect of significant and progressive permanent disabilities that can impair their abilities’. The damage to the nervous system is caused by the immune system, which mistakenly recognizes the brain as “foreign”. In a 2016 paper published in The Lancet, Dr Harold Atkins, Scientist Cancer Therapeutics and Medical Director, Regenerative Medicine at the OHRI, Attending Physician Blood Bone Marrow Transplant Program at the Ottawa Hospital and Associate Professor in the Department of Medicine and Dr. Mark Freedman, Senior Scientist Neuroscience Program at the OHRI, Director Multiple Sclerosis Research Unit, Neurology at the Ottawa Hospital and Professor in the Department of Medicine, have shown that strong doses of chemotherapy can eliminate the misguided immune system and regenerate a new immune system following a blood stem cell transplant. Together these treatments halt all evidence of ongoing immune mediated damage in patients with multiple sclerosis and prevent progressive permanent disabilities in 70% of patients. In the absence of ongoing immune mediated damage, the nervous system can repair itself and about 40% of patients at least partially recover from previous longstanding disabilities. Ongoing use of this procedure continues to help that subset of patients that present with the most aggressive multiple sclerosis.
Designing Viruses to Kill Cancer Cells
Cancers arise within our bodies because of genetic changes that occur during our lifetimes in a relatively small number of cells. These so-called “cancer cells” interact with the normal tissues of our body and using a variety of strategies trick “normal cells” into creating a new disorganized or malignant tissue which is commonly referred to as a tumour. Indeed there is a back and forth communication between the normal and cancer cells within a tumour which influences how well the tumour hides from the immune system, how rapidly it can grow and how effectively it can resist cancer therapy. A study led by Dr. John Bell, Senior Scientist Cancer Therapeutics Program at the OHRI, Program Director Ontario Regional Biotherapeutics, Director Canadian Oncolytic Virus Consortium, Terry Fox New Frontiers Program Project Grant, Scientific Director, BioCanRx Biotherapeutics for Cancer Treatment and Professor in the Departments of Medicine and Biochemistry, Microbiology and Immunology, and published in Nature Medicine deciphered the communication between normal and cancer cells within pancreatic tumours and discovered signals that predict if the cancer can be treated with innovative cancer killing viruses that the group are developing. This discovery also provided insights into how to better design viruses that specifically kill pancreatic tumours.
Less Is More in Detecting Cancer for Patients with Blood Clots
People with cancer are more susceptible to blood clots in the veins (venous thrombosis). In some cases, a blood clot with no apparent risk factors (unprovoked) can be the first sign of cancer. Conducting tests to identify whether a patient with unprovoked thrombosis has an underlying cancer is appealing for physicians and common in clinical practice. However, it is unknown if more screening lead to an earlier cancer diagnosis and earlier treatment.
In a study published in the New England Journal of Medicine, a team led by Dr. Marc Carrier, Senior Scientist at the Ottawa Hospital Research Institute (OHRI), Director of the Thrombosis Fellowship Program, and Associate Professor at the Department of Medicine, compared two strategies for detecting cancer in patients with unprovoked blood clots to determine how many cases of cancer are discovered using both of these strategies – one strategy was more extensive and involved a CT scan of the abdomen and pelvis while the other strategy was simpler and only included physical examination and basic blood work. The results of this study showed that routine screening with CT scan of the abdomen/pelvis does not lead to fewer missed cancers when compared to a limited screening strategy and that this method of screening does not appear to detect significantly more underlying cancers. These results could lead to major cost savings for the Canadian health-care system by reducing the number of CT Scans performed to detect underlying cancer.
Novel Insights into the Genetic Architecture of Coronary Artery Disease
Researchers from the University of Ottawa Heart Institute (UOHI), together with teams at Oxford University and the Broad Institute, have found the answer to an ongoing debate in the cardiovascular scientific world. Dr. Ruth McPherson Director of the Ruddy Canadian Cardiovascular Genetics Centre, Atherogenomics Laboratory and the Lipid Clinic, Cardiologist at the University of Ottawa Heart Institute, Professor in the Departments of Medicine and Biochemistry and Dr. Majid Nikpay, Post-Doctoral Fellow at the University of Ottawa Heart Institute , report that the genetic basis of heart disease is largely derived from the cumulative effect of multiple common genetic variants, rather than from a few rare variants with large effects.
The study, published in Nature Genetics, used the data from the 1000 Genomes project in order to obtain information on close to 10 million genetic variants (called SNPs). The analysis involved 60,000 heart disease patients, 120,000 healthy individuals, from a total of 48 studies around the world. Not only is the number of genetic variants much greater than the approximately 1 million previously studied, this is the first time that researchers have been able to study the link of rare genetic variants present in as few as 1 in 1000 people at risk of heart disease.
“Our analysis provides a comprehensive survey of the fine genetic architecture of coronary artery disease (CAD), showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size rather than just a few rare variants with large effects,” say the authors of this important study. This research team has produced a list of 202 genetic variants in 129 gene regions that together explain approximately 22% of the heritability of coronary heart disease as compared to only 11% reported in previous studies.
Discovery Could Reduce the Need for Preventive Mastectomy in BRCA1-mutated Breast Cancer
One in nine Canadian women is expected to develop breast cancer throughout her lifetime, and one in 30 will die from it. Preventing breast cancer at the cellular level, however, may be a possibility, after research published in Cell Stem Cell by Dr. Christine Pratt Associate Professor in the Department of Cellular and Molecular Medicine uncovered why breast cells with the BRCA1 gene mutation are at high risk for evolving into tumours. When a woman inherits a mutation of the BRCA1 gene, the gene may not be able to repair faulty DNA, increasing the risk of genetic mutations and cancer. During a monthly cycle in humans, stem cells within the breast undergo a phase called proliferation, where cells rapidly multiply in response to the hormone progesterone. Dr. Pratt and her team have discovered that if these cells lack BRCA1, they accumulate DNA damage as they multiply, which triggers NF-κB, a protein complex normally involved in the proliferation of immune cells. “The activation of NF-κB leads to increased cell proliferation that no longer requires progesterone, resulting in even more DNA damage which can lead to cancer,” says Pratt. “In cells with a BRCA1 mutation, the DNA cannot be properly repaired. Importantly, evidence suggests that other forms of familial breast cancer are also associated with mutations in different DNA repair proteins. Therefore this response to DNA damage in breast cells may be a common mechanism underlying the development of breast cancer”. The finding that NF-κB is pivotal to the development of breast cancer in BRCA1 mutation carriers opens the door for prevention therapies targeting the NF-κB protein.
Researchers Discover that Duchenne Muscular Dystrophy is a Stem Cell Disease
Dr. Michael Rudnicki is a Professor in the Departments of Medicine and Cellular and Molecular Medicine and Director and Senior Scientist of the Regenerative Medicine Program at the Ottawa Hospital Research Institute. A new study from Dr. Rudnicki’s group is poised to completely change our understanding of Duchenne muscular dystrophy and pave the way for far more effective treatments. The study, published in Nature Medicine, is the first to show that Duchenne muscular dystrophy directly affects muscle stem cells. “For nearly 20 years, we’ve thought that the muscle weakness observed in patients with Duchenne muscular dystrophy is primarily due to problems in their muscle fibres, but our research shows that it is also due to intrinsic defects in the function of their muscle stem cells,” said Dr. Rudnicki. Duchenne muscular dystrophy is the most common form of muscular dystrophy, affecting approximately one in 3,600 boys. It is caused by genetic mutations that result in the loss of the dystrophin protein, leading to progressive muscle weakness and death by the second or third decade of life.
Who Let the FoxO Out?
Forkhead box O (FoxO) transcription factors have been identified to function as a molecular link between ageing and tumor suppression. In mammals, there are four separate FoxO genes (FoxO1, FoO3, FoxO4 and FoxO6). Genetic variation within the FoxO3a gene has been shown to strongly impact human longevity, and inactivation of FoxO3a gene has been shown to correlate with the development of acute myeloid leukemia in humans. In a recent Nature Communications article, Dr. Subash Sad’s group (Department of Biochemistry, Microbiology and Immunology) has revealed that FoxO3a signaling promotes host survival during infection with a chronic, virulent pathogen. They have shown that FoxO3a signaling promotes host survival by engaging two key mechanisms: 1) FoxO3a promotes expression of genes that are involved in detoxification of reactive oxygen species and DNA repair, 2) FoxO3a signaling induces termination of mitogen activated protein kinase, ERK, signaling, which results in maintenance of a pro-inflammatory state that is necessary for control of virulent pathogens. The authors concluded that modulation of the toxic reactive oxygen species load and the anti-inflammatory signaling, FoxO3a tilts the balance towards increased inflammatory responses which results in host survival.
Mitochondria Regulate Stem Cells in the Brain
Extensive evidence now reveals that adult neural stem and progenitor cells, which support the generation and integration of newborn neurons into adult hippocampus, play an important role in cognitive function. The continuous generation of neurons in the adult brain requires a sustained population of stem cells, which relies on a regulated balance of cell fate decisions. Thus understanding the regulation of stem cell maintenance is key to preventing stem cell depletion in neurodegenerative diseases and aging. Recently, Dr. Ruth Slack from the Department of Cellular and Molecular Medicine and University of Ottawa’s Brain and Mind Research Institute (uOBMRI), have made an important discovery that uncovers a major role for mitochondria in the regulation of stem cell fate decisions, which was published in Cell Stem Cell. They have discovered a novel signaling pathway, whereby changes in mitochondrial structure or function can signal directly to the nucleus, to direct neural stem cell fate decisions, having a major impact on neural stem cell longevity, neurogenesis and cognitive function. These findings have important implications in our understanding and treatment of neurological deficits associated with aging, stroke and neurodegenerative diseases, where mitochondrial dysfunction is integral to disease progression.
Predicting Recovery Following Concussion
One-third of children with concussion have ongoing physical, thinking, emotional or behavioral symptoms beyond one month, known as persistent post-concussion symptoms (PPCS). PPCS may result in missed school, depressed mood, and lower quality of life. In a 2016 paper published in JAMA, Dr. Roger Zemek, Scientist at CHEO Research Institute and Associate Professor in the Departments of Pediatrics and Emergency Medicine, and his team developed a PPCS risk score that was significantly better than the child’s physician at predicting future PPCS. The score incorporates nine clinical variables containing information from demographics, past medical history, initial signs and symptoms, and physical examination. Clinicians are now able to provide accurate information to patients and families regarding the expected recovery, and researchers may target children at high risk for PPCS in new trials with the goal of preventing PPCS.