Myelodysplastic syndromes (MDS) are diseases of the blood and bone marrow. MDS originate when a stem cell, from which all other blood cells originate, becomes mutated and then overgrows and crowds out other cells. This results in reduced numbers of red cells (anemia), white cells (leukopenia) and platelets (thrombocytopenia) circulating in the blood. As the disease progresses, bone marrow may completely fail to produce normal cells, and the myelodysplastic stem cell may develop into cancer, Acute myeloid leukemia (AML). The exact molecular causes for MDS are unknown; however, a common feature of MDS is chromosomal abnormality, the loss of the long arm (q) of the chromosome 5 being one of the most common in a subtype of MDS called 5q- syndrome. This lost region of 5q likely harbors several important genes, which may prevent MDS.
Dr. Joanna Wegrzyn Woltosz's research project will decipher the molecular mechanism of the disease and identify targets of a new drug (lenalidomide) currently used in MDS treatment. She is studying two important factors that are located on the 5q arm and are involved in the development of MDS (1) the RPS14 gene, which is thought to be responsible for the anemia seen in MDS patients, and (2) microRNAs, whose loss allows the abnormal MDS stem cells to survive and grow more than the other bone marrow cells. Since lenalidomide reverses symptoms resulting from loss of the microRNAs, she will also study whether lenalidomide increases the expression of these microRNAs. Currently, the only treatment for MDS is high-dose chemotherapy with stem cell transplantation, which is risky and challenging for patients to endure.
The information Dr. Wegrzyn Woltosz expects to obtain from this study will not only help to better understand the molecular mechanism underlying MDS, but will suggest novel steps towards the development of better therapies that will improve treatment and quality of life and increase survival for MDS patients.
Multiple sclerosis (MS) is a relatively common neurological disease. Because of its chronic nature and because it typically first appears in people in their mid 20s to 30s, people with MS are usually expected to live for many years following disease onset. Little is known about survival expectations, predictors of long-term survival, how survival is influenced by MS drug therapies, and causes of death in this population. Ever since immunomodulatory therapies first became available to Canadian MS patients in the mid 1990s, there has been a rapid uptake of these drugs. These medications appear to be at least partially effective in modifying some aspects of the disease, such as relapses, but they are associated with significant side effects, require frequent injections, and are expensive. The long-term impact of treatment is unknown and opportunities to study treatment-naïve patients have diminished over the years, as there are fewer patients with MS who have not taken these therapies. In British Columbia, we have a valuable data resource that includes both unexposed (untreated) and treated MS patients.
Dr. Elaine Kingwell is combining several large, powerful, clinical and administrative longitudinal datasets, including the population-based BC MS clinical database (containing data from approximately 7,000 MS patients over a 30-year period), BC Ministry of Health medical services plan registration data, BC Vital Statistics death data and BC Cancer Agency data. She will use this data set to determine the long-term health impacts of MS and how they are influenced by immunomodulatory drugs. She will specifically compare the causes of death (including cancer, suicide, heart disease and infection) between people with MS and the general population.
Dr. Kingwell will also investigate cancer survival of MS patients in comparison to the general population, which is an area of some controversy. She will determine how frequently MS is listed as an underlying or contributing cause of death, which will help to facilitate planning and interpretation of population-based studies of MS mortality trends. Findings from this study will further our understanding of the role that MS plays in long-term health outcomes, such as cancer survival, and will broaden our existing knowledge of factors associated with longevity in MS. These results will also provide a vital estimate of the impact of immunomodulatory therapy on survival and specific causes of death for MS. The findings from this research will have a profound impact on the care, monitoring and treatment of the disease.
The traditional view of cancer is that tumours are composed of identical cells, and thus the goal of treatment is to kill every one of those cancer cells in the body. In a tumour, it is estimated that a very small fraction of cells (perhaps 1 in 10,000) are ""cancer stem cells"", which are the cells that have the capacity to self-renew or to create progeny that carry the same properties as the parent cell. A new cancer treatment theory hypothesizes that to treat cancer, the only cells that need to be killed off are these cancer stem cells, and once they are gone the rest of the tumour should regress on its own. The challenge becomes to first identify the cancer stem cells and then design a drug that would specifically kill those cancer stem cells only. Dr. Vincenzo Giambra's lab has recently shown that cancer stem cells exist in a particular type of blood cancer called T-cell acute lymphoblastic leukemia (T-ALL). Although T-ALL is not a common form of cancer, it is unique in that more than 50 per cent of cases carry mutations that inappropriately activate a gene called Notch1, which plays an important role in normal stem cell maintenance. Dr. Giambra's research objectives are to identify how cancer stem cells are able to evade the immune system and thrive in T-ALL, and to design a drug that specifically kills those cancer stem cells. He will be isolating cancer stem cells from a unique mouse model that has Notch1-induced T-ALL, using specific molecules on the surface of cancer stem cells. He will also compare leukemias generated from mice of different ages to see if they express different genes, with the goal of using this information to design new drugs that may help to cure more patients with leukemia. These studies will allow Dr. Giambra to define the genetic programs and pathways that are responsible for conferring self-renewal upon the leukemia stem cells; they will also provide rationale for the design of new therapies that specifically target the stem cells. In focusing his efforts toward killing only the cancer stem cells, Dr. Giambra expects these therapies will be more effective for achieving a cure and less toxic to the patient. Finally, he anticipates that some of the genetic programs and pathways he will identify will be critical for self-renewal of Notch T-ALL stem cells and may be important for self-renewal of all cancer stem cells in general. Thus, these results may prove useful to investigators studying other cancers as well.
The development of effective HIV/AIDS treatment has resulted in dramatic improvements in the health of people infected with the virus. Taken regularly, highly active antiretroviral therapy (HAART) interrupts the viral life cycle, suppresses the level of HIV in a patient's bloodstream, and promotes health improvements. The recent finding that individuals undergoing effective treatment are far less likely to transmit the virus to others has spurred the development of a new strategy aimed at preventing new HIV infections. Dubbed "Seek, Test and Treat", the goal of this initiative is to increase the number of people on HIV treatment in Prince George and in Vancouver's Downtown Eastside.
Dr. M-J Milloy is specifically focusing on the expansion of HIV treatment among people of Aboriginal ancestry who use illicit drugs. In Canada, young Aboriginal people are a growing sector of the HIV/AIDS pandemic, and Aboriginal people are highly over-represented among HIV-positive drug users. Dr. Milloy’s research will look at treatment for HIV and health outcomes for Aboriginal drug users and, in light of increasing calls by Aboriginal leaders for research that focuses on health and wellness among Aboriginal people, will try to identify the characteristics of successful treatment.
Dr. Milloy's research will address a number of outstanding concerns:
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Are Aboriginal individuals who are HIV-positive and use illicit drugs being effectively treated with HAART?
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What are some of the broader factors, such as stable housing or employment, that promote effective treatment?
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What is the level of viral resistance to HIV medications among Aboriginal drug users?
Much of the data for this study will come from the AIDS Care Cohort to Evaluate access to Survival Services, an ongoing study of approximately 750 HIV-positive drug users in Vancouver. The research will be supervised by Dr. Evan Adams, Physician Advisor to the First Nations Health Council, who will ensure that the research is respectful and responsible to Aboriginal participants and communities.
The information gained could be used to improve existing systems to provide HAART as well as inform new Aboriginal-led efforts to improve health and wellness. By improving HAART delivery and expanding the number of people receiving effective care for HIV infection, it is hoped that the number of new infections will also drop.
One in every eight Canadian men will be diagnosed with prostate cancer in their lifetime. Androgens, which are male sex hormones, are the primary driving force behind the development of prostate cancer and are synthesized in the testes, prostate, and in the prostate cancer tumour itself. Although once the standard of care, orchiectomy is rarely performed; continuous androgen deprivation is necessary when the cancer is very advanced. In these cases, the cancer becomes more aggressive and progresses to a stage called castration-resistant prostate cancer, which does not respond to hormonal agents. Dutasteride and abiraterone acetate are two current treatments for prostate cancer. The actions of these therapies are complementary, targeting different androgen metabolizing enzymes. Currently, dutasteride is successfully used for benign prostate hyperplasia, which is non-cancerous enlargement of the prostate. Abiraterone acetate, which was been approved in April 2011, is a promising treatment option for advanced prostate cancer patients. Clinical studies have shown that a subset of prostate cancer patients manifested resistance to abiraterone, and this suggests that there are compensatory mechanisms at work, either by supplying androgens via alternative biosynthetic pathways and/or by altering the signaling pathways involved in prostate cancer progression. The purpose of Dr. Subrata Deb’s research is to investigate the effects of abiraterone and dutasteride on pathways of androgen biosynthesis in castration-resistant prostate cancer. Mouse models of human prostate cancer, human prostate cancer cells, and human prostate tissues will be used to determine the effect of dutasteride and abiraterone acetate, either alone or in combination, on androgen formation during castration-resistant prostate cancer or in resistance to abiraterone. The aim of this research is to find the potential reasons for treatment failure in prostate cancer and aid in the development of potential treatment strategies.
The billions of cells in your body share the same DNA sequence and yet display a vast array of morphologies and functions. Understanding how this same genetic material is interpreted in diverse cell types remains a challenge. Epigenetic modifications are those that change how DNA is expressed without altering the genome sequence. For example, chemical modification of histones, the proteins that bind DNA into the large chromosome structures, can influence how genes are expressed.
In a related process, DNA itself can become methylated, which is typically thought to be a gene-silencing signal. Understanding how epigenetic modification influences gene expression has significant therapeutic potential and may provide us with insights into how we can disrupt abnormal cell divisions in cancer or promote self-renewal in stem cells for clinical use in repairing damaged or diseased tissue.
Dr. Cydney Nielsen aims to characterize epigenetic changes of stem cells, from which all other cells in the body arise. Stem cells can either self-renew to form identical daughter cells or can divide and differentiate into specialized cell types. Dr. Nielsen will use next-generation sequencing technologies and develop new data analysis techniques to examine the epigenetic changes and determine gene expression patterns in stem cells before and after differentiation.
Using these data sets, she will determine if characteristic epigenetic modification patterns exist for self-renewing cells. She will also use this information to determine if certain therapeutics are able to induce self-renewal in stem cells, to determine what the epigenetic changes are in this case, and if this ''reprogramming'' of cellular state opens up promising therapeutic applications. Such an approach will be valuable in evaluating the extent to which chemically induced cells have been reprogrammed and are appropriate for therapeutic use for regenerative medicine.
Informal caregiving is defined as care provided by family and friends to a relative or friend residing in a long-term residential care (LTRC) situation. The role of informal caregivers is significant. Informal caregivers contribute more than 44 million hours of care work in LTRC facilities each year; a number that will more than double to 107 million hours in 2038 (source: Canadian Alzheimer Society). These contributions are essential given the current pressures on LTRC, which include an increasingly acute and medically/socially complex resident population and staffing levels that are typically below industry standards. Dr. Jennifer Baumbusch is conducting a series of studies focused on understanding how informal caregivers currently participate in LTRC. Dr. Baumbusch is asking the following research questions in order to better understand the role of informal caregiving and to develop and refine policies and practices to improve the integration of informal caregiving in LTRC. In what ways do informal caregivers contribute to the care of their relative? In what ways do informal caregivers contribute to the care of other residents? How do the informal caregivers’ contributions affect the everyday facility routines, such as recreational activities and meal times? Research will take place on regular units and on Special Care Units for residents with Alzheimer disease and related dementias and will recognize the unique needs of this specialized population. This program will incorporate ethnographic approaches and will be guided by input from community stakeholders. Research findings will be consolidated with existing literature to provide the basis for knowledge translation activities which will include policy forums that foster a national dialogue about caregiving in LTRC, collaborative knowledge translation research, and arts-based knowledge translation approaches. The aim of this program is to improve the integration and recognize the unique contributions of both informal caregivers and formal caregivers (staff) to care provision. Generating new policy directions will contribute to more effective healthcare services within LTRC and will ultimately improve the health of aging Canadians living in LTRC.
Nine out of ten Canadians who are killed by cancer die because their tumour has metastasized, or spread, to other parts of their body. Metastasis occurs when tumour cells escape from the original, or primary, tumour and then grow into life-threatening metastatic tumours in other organs. Despite the fact that thousands of tumour cells can escape from a primary tumour every day, most cells do not live long enough to grow into metastatic tumours. As well, metastatic tumour cells can only grow in specific organs. Most primary tumours contain cells at lower oxygen levels than normal tissues, and these low-oxygen tumour cells make tumours more aggressive and metastatic.
Based on these facts, Dr. Bennewith's team is developing new approaches to help identify tumours that contain low-oxygen tumour cells in patients. In addition, Dr. Bennewith and his colleagues have recently discovered that proteins made by low-oxygen tumour cells cause the body's normal bone marrow cells to enter the bloodstream and build up in specific organs. These cells create an environment where metastasizing tumour cells can survive and grow into metastatic tumours. Dr. Bennewith’s team intends to identify the specific proteins that control bone marrow cell behavior in order to develop targeted therapies that will prevent the build-up of bone marrow cells in organs and thus inhibit metastatic tumour growth. Metastatic tumours are very difficult to treat, but by studying how tumour cells spread and grow into tumour metastases, more effective cancer treatments can be designed. Dr. Bennewith's expertise in metastasis research combined with his unique research program will improve our understanding of how low-oxygen tumour cells promote metastasis. Importantly, his work will help to create more effective methods to both detect and to treat metastatic cancer in the clinic.
Vaccines and immunization programs are the best way to prevent infectious diseases, improve child health, and save lives. According to the Public Health Agency of Canada, vaccines have saved the lives of more babies and children than any other medical intervention in the past 50 years. Through immunization, we have eliminated smallpox and have nearly eliminated eight other deadly diseases of childhood, including chickenpox and some kinds of pneumonia and meningitis. We need to continue to immunize all children so that we maintain high levels of protection throughout communities, which will prevent these diseases from re-emerging. Despite having province-wide immunization programs in place, not everyone gets vaccinated, as shown by several disease outbreaks in the past few years.
Dr. Julie Bettinger is working to address key questions about vaccines and immunization programs to ensure optimal disease protection in the population. Her research assesses the effectiveness of existing vaccination programs, evaluates the effectiveness of new vaccines, and also studies the best way to deliver them to children, adults and communities. Her approach uses quantitative and qualitative methods and includes collecting and analyzing surveillance data on select vaccine-preventable diseases and vaccine-adverse events from the Canadian Immunization Monitoring Program Active, an active surveillance network in 12 pediatric centers across Canada.
Dr. Bettinger’s research also focuses on evaluating the safety and effectiveness of vaccines through grant-funded clinical trials and observational studies and promoting improved immunization uptake through qualitative studies that assess the factors affecting vaccine use. Her work is used by local, provincial, and national public health decision makers, other research scientists, health care providers, and the public. This work, which is conducted at the Vaccine Evaluation Center at the Child and Family Research Institute and BC Children's Hospital, will create a centre for applied, population-based immunization research unique to BC and Canada.
In Canada, severe infection, or sepsis, is the most common acute illness causing death. Patients with severe infections can go into shock as a result of progressive cardiac collapse and can die within 24 to 48 hours. The mortality rate of sepsis is 40%. The fact that this rate has not changed in the last 30 years illustrates that very little is known about how infection causes cardiovascular dysfunction and that very little is known about the best ways to prevent this from occurring.
Dr. John Boyd's research program is using a two-pronged approach to understand how sepsis causes progressive cardiac collapse. The objective of his clinical research program is to identify prognostic factors and to characterize the cardiac response to infection in patients with sepsis. Specifically, he is focusing on very early enrollment of acutely ill patients with infection presenting to the St. Paul's Hospital emergency department in order to identify prognostic factors such as new biomarkers and the presence of emerging infections. He will characterize their cardiovascular response to infection using a bedside cardiac ultrasound. Although previous work in this area has been done, patients were recruited from critical care units 24 to 36 hours following admission, too late to identify prognostic markers and intervene to improve outcome.
As a complementary approach, Dr. Boyd's pre-clinical (basic) research program is taking a molecular approach and using the immune system as a tool in the fight against cardiovascular collapse. He has identified a "counter-regulatory" receptor which appears able to reverse the heart damage induced by other receptors in the same family. The identification of this receptor will hopefully lead to the development of a targeted intervention for sepsis-related cardiovascular dysfunction. Dr. Boyd's clinical research program aims to answer simple but as-yet unstudied questions such as the optimal volume of IV fluid and how one can reliably diagnose infection. Although the results of his laboratory work are not yet close to reaching the bedside, they may potentially lead to therapies in the future.
