Year: 2008

Substance use among youth continues to be a large public health concern, including alcohol consumption among underage youth. While much research has explored youth involvement in substance use and on the negative impacts of that use, there is a lack of consensus in the literature about how to approach the prevention and treatment of youth substance use. A focus on abstinence as the only acceptable outcome is a key controversy in prevention and treatment approaches. While Canada’s laws support abstinence as the desired stance for substance use, studies show that zero-tolerance approaches to drug and alcohol prevention are often ineffective. There is some evidence of the effectiveness of harm-reduction strategies, which focus on reducing youth’s levels of risk and experiences of harm from substance use. While there are low-risk drinking guidelines for adults in British Columbia, there are currently no accepted low-risk drinking guidelines for youth, nor a clear consensus on whether any alcohol consumption by youth below legal drinking age can be considered acceptable and low risk. Kara Murray is drawing on existing research literature and survey data to explore the issues of underage alcohol consumption and its health outcomes. She’s assessing the risk of harm at different levels of alcohol consumption, specifically at low frequency and low quantity of use as outlined in the Canadian low-risk drinking guidelines. She’s also identifying whether there are age or gender differences at different levels of alcohol consumption. Murray’s research will contribute to the advancement of knowledge by attempting to formulate a continuum of risk that identifies distinct levels of hazardous and non-hazardous alcohol use for youth. Ultimately, her work could inform changes to the current prevention and educational strategies that are used.

The social relationships that residents form within long-term care facilities (LTCF) are believed to buffer them from loneliness and depression to a greater degree than relationships with family and friends outside of facilities. Furthermore, support from friends and social groups has been associated with positive outcomes for older people living with chronic and serious health conditions. Traditional social activities in LTCF are not usually led by residents and are often passive entertainment programs that don’t provide the necessary supportive environment for residents to interact beyond surface social interactions. These activities are not usually grounded in research evidence, and some programs intended to foster resident well-being actually have adverse effects, including the perception among residents that activities offered are “childlike.” Currently, there is a lack of research evidence showing the benefits of specific social activity programs provided to residents in LTCF. One aspect of particular interest is the use of co-led self-support groups, which aim to enhance residents’ sense of belonging, self-development and self-determination. In this format, an activity staff member co-leads the groups with a resident group member, and acts in the role of a facilitator in order to assist with any special needs of the residents. Kristine Theurer is studying the benefits of co-led mutual support groups. Her assessments of resident well-being will be based on measures of sense of belongingness, loneliness, life satisfaction and happiness. From her findings, she will provide recommendations for co-led group formation, number of participants, suggested theme topics and supportive materials. Ultimately, her work will help LTCF provide appropriate evidence-based programming that supports residents to achieve a better quality of life.

Within the intravenous drug user (IDU) population of Vancouver’s Downtown Eastside (DTES), female commercial sex workers and Aboriginal women are overrepresented. These two groups are especially vulnerable to unique sets of health and social challenges that may be related to their substance dependency, including increased susceptibility to sexually transmitted infections, physical violence, psychological trauma and malnutrition. Their social challenges can include increased contact with law enforcement, lower education, unemployment and inability to access community support. The needs of these two groups both intersect and diverge based on a series of factors. There are currently numerous services and interventions that target intravenous drug using women, including emergency mental health counselling, addictions treatment and recovery, harm reduction (both for IDU and commercial sex work) and general support groups. However, the rates of use of these services by commercial sex workers and Aboriginal women are relatively low. This suggests that many women either choose not to or cannot make use of the available health services and interventions. In order for these interventions to effectively help these two groups of women in coping with deeply interconnected health and social challenges, these factors must be investigated, addressed and understood within a complex matrix. Ashley White is conducting an in-depth study to explore the characteristics, perceptions of health services, and needs of commercial sex workers and Aboriginal women practising intravenous drug use. Her findings will provide essential insight into potential ways that health planners can offer accessible services that better meet the requirements of these women.

Flow cytometry (FCM) is a method of sorting and measuring types of cells by fluorescent labelling of markers on the surface of the cells. It plays a critical role in basic research and clinical therapy in the areas of cancer, HIV and stem cell manipulation. For example, it can be used to diagnose some types of cancer, based on which labelled antibodies bind to a particular cell’s surface. It is widely recognized that one of the main stumbling blocks for FCM analysis is in data processing and interpretation, which heavily relies on manual processes to identify particular cell populations and to find correlations between these cell populations and their clinical diagnosis and outcome (e.g. survival). Manual analysis of FCM data is a process that is highly tedious, time-consuming (to the level of impracticality for some datasets), subjective and based on intuition rather than standardized statistical inference. Dr. Ali Bashashati has developed a “pipeline” for automatic analysis of FCM data – a computational platform that can identify cell populations, find biomarkers that correlate with clinical outcomes, and label the samples as normal or diseased. Preliminary evaluations of this pipeline have shown accuracy levels of more than 90 per cent in identifying some sub-types of lymphoma. Moreover, a biomarker that contributes to a more aggressive behaviour of a specific sub-type of lymphoma has been discovered. Bashashati is now testing and refining the platform to improve its analytical power and applicability to a range of FCM data, testing its performance across a number of ongoing FCM studies in BC. Ultimately, he hopes to provide an accurate, powerful computational platform to increase the efficiency of using FCM for research and clinical purposes.

Ever since its discovery more than 20 years ago, the CD34 antigen has been widely used as a marker to identify stem cells, precursor cells that give rise to all types of specialized cells. However, the exact function of CD34 expression on hematopoietic precursors and mature cells is still not well understood. Dr. Marie-Renée Blanchet and colleagues have uncovered some fascinating details about the role of CD34 in allergy and asthma. The team recently demonstrated that CD34 is expressed on mature mast cells and eosinophils – two types of cell that respond to injury during inflammation of the body’s tissues – and that the CD34 antigen is involved in their recruitment to the lung and peritoneum. They showed that mice without the CD34 antigen are protected against development of airway hyper-responsiveness and airway inflammation, which are two major hallmarks of allergic asthma. Finally, in preliminary experiments, these mice also showed protection in hypersensitivity pneumonitis, another model of lung inflammation. Now, Blanchet is working to better understand the mechanisms behind these recent findings. Many cell types involved in asthma and hypersensitivity pneumonitis express CD34, some in which the role of this protein remains unknown (eg. fibrocytes and dendritic cells). She plans to use models to elucidate the role of CD34 expression in these cells. Ultimately, she hopes her studies will reveal potential targets for treatment of allergy and inflammation.

A major obstacle in the treatment of fear-related anxiety disorders is their likelihood for relapse. Fear-related behaviour can be inhibited with extinction therapy (repeated exposure to specific fear-inducing cues). This is, however, a temporary fix because fear often returns after exposure to cues associated with the original learning. In the case of post-traumatic stress disorder, fear can also “incubate” or sensitize over time and further exacerbating symptoms of the disorder. These phenomena likely reflect long-term neural adaptation that occurs during learning – changes that may be based on lasting epigenetic modification of genes responsible for maintaining fear memories. Epigenetic modifications influence the way a gene functions without altering the underlying DNA sequence- processes now recognized to participate in the regulation of gene expression in the adult brain. Rapidly emerging evidence suggests that epigenetic mechanisms play an important role in psychiatric disease and in disorders of learning and memory. Dr. Timothy Bredy is employing state-of-the-art technologies to investigate the fundamental epigenetic mechanisms of associative fear memory. He is using a genome-wide approach to examine epigenetic machinery involved in regulating critical gene targets during the acquisition and extinction of conditioned fear. Dr. Bredy hopes his findings will provide insight into the molecular basis of relapse and its prevention and that this research will ultimately contribute to the design of novel pharmacotherapeutic treatment approaches for fear-related anxiety disorders.

Non-Hodgkin lymphoma (NHL) is a specific type of cancer where an abnormal growth of immune cells produces what is known as a lymphoid tumour. Since the 1970s, NHL has become increasingly common, indicating that lifestyle and environment are likely causative factors. However, certain individuals may also have a genetic make-up that makes them more susceptible. NHL tumours often show a type of DNA damage called a translocation, where two chromosomes are incorrectly joined together. In NHL tumours, translocations are generally found near genes that are important for the development of immune cells. They cause changes in how these genes are regulated (turned on or off), that result in abnormal cell growth. Certain genes are responsible for repairing damaged DNA. If these genes are not functioning properly, DNA breaks will not be repaired and harmful translocations may occur. Previous studies have found that a common DNA sequence change at one of these DNA repair genes, called H2AX, was much more frequent among the NHL patients than unaffected individuals. Individuals who carry this gene variant have twice the risk of NHL as those who do not carry it. Dr. Karla Bretherick is interested in how common genetic variants influence risk for complex diseases. MSFHR has previously funded her graduate training, which involved studying the genetic factors that contribute to premature menopause. Now, she is looking at why individuals with the H2AX gene variant have increased risk of NHL. She will look at how this DNA sequence change affects H2AX gene regulation, modifies protein binding, and affects the ability of the cell to repair DNA damage. Ways to understand, prevent, and avoid NHL and other cancers are of increasing importance for the Canadian healthcare system. Understanding how and why this specific gene variant increases risk for NHL will lead to a better knowledge of how this cancer develops. This information will eventually be useful for identifying new drug targets and therapies for NHL, and may also provide insight into the development of cancers in general.

Cutaneous malignant melanoma is a life-threatening skin cancer that is very resistant to conventional radio- and chemotherapy and has a low survival rate. Thus, it is important to understand the molecular changes underlying the onset and progression of the disease. The novel tumour suppressor ING3 acts to inhibit cell growth. A number of previous studies have demonstrated that ING3 switches on and off during normal cell division, and that it enhances cell death in melanoma cells when they are exposed to UV-light. Dr. Guangdi Chen has identified that the expression of ING3 degrades (or decreases) much faster in melanoma cells than in regular melanocytes (healthy melanin-producing cells) during the cell cycle. This rapid degradation may be an important cause of aberrant ING3 expression and the loss of its tumour suppressing function. However, the mechanism of ING3 protein degradation and its role in cell cycle progression remain unclear. Chen is investigating the pathway of ING3 protein degradation and assessing its role in cell cycle progression. By understanding the molecular mechanisms of ING3 tumour suppressive functions in cell cycle progression, he hopes his work could help in the design of novel strategies for cancer prevention and treatment. Chen’s post-doctoral fellowship is jointly funded by MSFHR and the VGH & UBC Hospital Foundation.

A heart that has become enlarged in response to a pressure overload, such as with high blood pressure, has reduced function compared to a normal heart. This impaired function is particularly apparent during and after interruption of the blood supply, which can occur when a blood clot blocks a diseased coronary artery, or during open heart surgery. This reduced heart function can be very dangerous for the patient. Enlarged hearts use glucose to a greater extent than normal, a situation that appears to contribute to their exaggerated dysfunction. The mechanisms responsible for the accelerated utilization of glucose in enlarged hearts are not yet known. Dr. Minnie Dai was previously funded by MSFHR for her doctoral training. Currently, she is working to determine the mechanisms behind accelerated rates of glucose utilization in enlarged hearts. Using molecular biology techniques, she will selectively and specifically alter the activity of potentially relevant proteins in order to determine their role in causing accelerated glucose utilization. Her studies are unique in that the activity of proteins will be altered at specific times and will be altered only in the heart – ensuring that changes observed are truly related to alterations in these proteins. Many people suffer ill health because of an enlarged heart. By understanding the mechanisms responsible for their accelerated use of glucose, researchers may be able to identify targets for the development of drugs designed to altered glucose use by enlarged hearts, thereby improving their function.

Chronic obstructive pulmonary disease (COPD) is a serious lung disease that is predicted to become the fifth leading cause of death by 2020. It is marked by inflammation of the airways. Currently, there is no efficient drug for treatment for this disease. A promising area of COPD research is focused on matrix metalloproteases (MMP), a family of proteins that digest or cut other proteins (known as substrates) into smaller pieces. These cleavages modify the biological functions of the substrate. MMPs are implicated in many inflammatory diseases, including COPD. Dr. Alain Doucet is studying how two specific MMPs, MMP-8 and MMP-12, contribute to the development of COPD. He is conducting studies to validate his hypothesis that MMP-8 and -12 regulate inflammation by cleaving immune cell mediators such as cytokines, chemokines and their cellular receptors. He is conducting a proteomic identification of MMP-8 and -12 biological substrates and assessing the effect of the substrate cleavage on its biological activity. This work could lead to identification of new, more refined targets for COPD treatment. The identification of MMP-8 and -12 biological substrates will indicate their cleavage specificity and will help in the design of more specific inhibitors. Anti-inflammatory drugs developed for COPD treatment also have the potential to be applied to other inflammatory-associated diseases, such as cancer and arthritis.