Cancer is one of the leading causes of death among Canadians, and therefore the identification of new cancer therapies is of great importance. To that end, researchers have found that the structurally diverse defence chemicals provided by sessile marine organisms offer great potential in the fight against cancer. In fact, in the past decade more than 30 natural products isolated from marine sources have entered preclinical and clinical trials as potential treatments for cancer. However, it is rarely ecologically or economically feasible to obtain the active ingredient by harvesting the natural source. Fortunately, synthetic organic chemistry – where molecules are fabricated in the laboratory through a series of chemical transformations – can serve as an alternative source of these compounds. Eleutherobin was originally isolated from a rare soft coral located of the coast of Western Australia in 1997, and in preliminary tests it has shown many promising anti-cancer properties. In fact, taxol, a member of the same class of agents, has already been used to treat more than one million patients suffering from advanced breast and ovarian cancers. Over the past two years, Jeffrey Mowat has spearheaded research centered on the development of a concise synthesis of eleutherobin and analogues of this substance as candidates for cancer treatment. However, so far, eleutherobin's preclinical evaluation has been hampered by lack of material from the natural source or chemical synthesis. Mr. Mowat's current research project addresses this situation through the development of a synthetic strategy that would significantly reduce the number of steps required to access eleutherobin and facilitate its preclinical evaluation. His research also provides a venue for the construction of analogues of eleutherobin, the biological evaluation of which may well lead to the discovery of new, improved antimitotic drugs for cancer therapy.
Year: 2009
Structural analysis of proteins involved in bacterial cell wall biosynthesis
Antibiotics play an essential role in the treatment of bacterial infections. However, the overuse of antibiotics has resulted in the emergence of numerous drug resistant strains of important human pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). These, and related bacteria, represent major threats to human health if tools cannot be developed to combat these so called “”superbugs””. Potential targets for the development of these new antibacterial treatments include the enzymes involved in the production of the bacterial cell wall. Robert Gruninger’s research is focused on characterizing distinct aspects of cell-wall biogenesis. By clarifying the three dimensional structure of these enzymes, it will be possible to design drugs that will block their function, and combat the development and spread of “superbugs”.
Targeting the Ras/MAPK pathway for treatment of high-grade pediatric brain tumors
Brain cancer is an extremely aggressive disease that remains difficult to cure and carries a high mortality rate. Every year, more than 3,500 children in North America are diagnosed with this disease. Brain tumours are the most common solid tumours and the second leading cause (after leukemia), of cancer-related deaths in children. The majority of patients (80 percent), with the more aggressive forms of brain tumours will survive less than two years. Surgical removal of brain tumours is challenging for a number of reasons, and complete removal of cancer cells is virtually impossible. The chemotherapeutic agent Temozolomide (TMZ), is used in patients with aggressive brain cancers however, in a subgroup of patients this drug does not work effectively because they are resistant to it. Furthermore, recent research shows that TMZ is not generally very effective at eliminating pediatric brain tumour cells. Consequently, certain ‘survivor’ tumour cells become ‘seeds’, generating more cells that subsequently form a new tumour. Cathy Lee’s research focuses on a protein called PLK1, which is essential to the cell division process in cancer cells. Many researchers have shown that PLK1 levels are higher in cancer cells than in normal cells and that tumour cells require this protein for survival. When this protein is eliminated, cancer cells either die or their growth is suppressed. Importantly, normal cells do not seem to be greatly affected by PLK1. Ms. Lee’s research will provide a deeper understanding of this protein. In related research, Lee will examine the ‘seeds’ of brain tumours, called ‘brain tumour initiating cells’, with a view to determining a way to prevent their expansion and induce cell death. The results of her research will improve our understanding of pediatric brain cancers and allow future design of novel, alternative therapeutic strategies that benefit patients’ health and improve the way we currently treat this devastating disease.
Neural Mechanisms of Reward Learning and Cognitive Control in Children with Attention Deficit Hyperactivity Disorder
Attention Deficit Hyperactivity Disorder (ADHD), is characterized by its behavioural manifestations including difficulties with attention, hyperactivity and impulsivity. It is one of the most common childhood disorders with a prevalence rate of three to seven percent of school-aged children. ADHD carries a significant impact not only on children diagnosed with this disorder, but also on their families, schools, communities and the health care system. Numerous theories of ADHD have focused on deficits in executive functions, specifically cognitive control and the inability to inhibit inappropriate behaviours. Neuropsychological and neuroimaging studies in children with ADHD support a theory of frontal-subcortical dysfunction: specifically, a dysfunction in the midbrain dopamine (DA) system that may result in an impaired midbrain DA system and reinforcement learning, or the ability to learn to modify behaviour on the basis of rewarding and punishing stimuli in the environment. Furthermore, recent developments in reinforcement learning theory indicate that the midbrain DA system carries Reward Prediction Error (RPE) signals. Carmen Lukie is investigating how a midbrain DA system for reinforcement learning may be impaired in children with ADHD. This study follows on from her earlier research which showed that children with ADHD are particularly sensitive to the saliency of rewards. Specifically, she found that RPE signals in children with ADHD are modulated by the context in which feedback is given, and differs from what is observed in typically developing children. The current study will replicate this finding, while correcting for the limitations of the earlier study. Ultimately, the results of this research could lead to the development of novel, more effective behavioural and pharmacological treatments. Further, the research may expand to include individuals with substance abuse, pathological gambling, conduct and borderline personality disorders.
Optimal timing of delivery for pregnancies with pre-existing hypertension
Chronic high blood pressure in pregnant women is associated with serious maternal and fetal complications such as poor growth, early separation of the placenta, and stillbirth. Consequently, the recommendation has been made that all women with chronic high blood pressure be considered candidates for induced delivery to reduce the risk of complications that may occur with allowing pregnancies to continue to later gestational ages. However, the optimal gestational age at which the infants should be delivered is currently unknown: delivering too early may increase the risk of respiratory complications for the infant at birth, while delaying the induction of delivery increases the risk of stillbirth. Dr. Hutcheon’s research centres on the development of a methodology to help determine the optimal gestational week for delivery. Data on maternal characteristics and pregnancy outcomes obtained from the US population birth registry as well as Canadian Birth Registries will be reviewed with a focus on the occurrence of either a serious birth complication for the newborn (such as seizures or need for prolonged assisted ventilation), or stillbirth. Among women with pre-existing high blood pressure, the risks of a poor pregnancy outcome will be calculated for each week of gestation between 36 and 42 weeks of pregnancy. Statistical models will be used to determine the gestational age range for birth during which risks to the infants are lowest. These analyses will then be repeated to determine the timing of delivery that minimizes risks of serious complications for the mother. With childbearing at older maternal ages increasing in Canada, the number of pregnancies complicated by high blood pressure is expected to increase. The results of Dr. Hutcheon’s project will help provide guidance to physicians as to the best time to deliver pregnancies complicated by pre-existing high blood pressure and, as a result, help minimise the number of adverse pregnancy outcomes in the Canadian population.
Gender Differences in the Diagnosis and Management of Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD), has generally been thought of as a ""man's disease."" However, there has been a substantial increase in the prevalence and mortality of COPD in women recently, with a tripling of the female mortality rate over the past 20 years compared with a stable mortality rate in men over that same time period. The increased prevalence and mortality of COPD in women has been attributed to an increase in smoking rates in women, which began over 50 years ago. Recent studies have shown that women may be more susceptible to the effects of cigarette smoke compared to men. In addition, there is evidence to suggest that a gender bias may exist with respect to diagnosis; specifically, that women may be more likely to be diagnosed with asthma, and men with COPD, regardless of their underlying condition. Furthermore, studies have shown that a smaller proportion of women compared to men are not referred for diagnostic testing for COPD, or do not receive optimal pharmacotherapy. Using data from the BC Linked Health Database and the PharmaNet database, Dr. Pat Camp is conducting an in-depth analysis of the management and health outcomes of COPD in women compared with men. The goals of Dr. Camp's research are designed to identify gender differences with respect to diagnostic test utilization, hospitalization rates and medication usage. Dr. Camp is also investigating what, if any, impact age and region of residence have on diagnostic testing, medications and hospitalizations in people with COPD. The results of Dr. Camp's research will allow for specific messages and targeted interventions to be developed that facilitate better care and improved quality of life of people living with COPD.
Visual-spatial attention and falls risk in seniors: Do fallers show impairments in reflexive orienting?
Seniors who fall and sustain injuries or worse, injury-related deaths, represent a major health concern. Approximately one-third of seniors over the age of 65 experience one or more falls per year, 20 percent of which require medical attention. In Canada, falls result in over $2.4 billion annually in direct health care costs. A growing body of research suggests that cognitive factors, such as visual-spatial attention, play a major role in a person's risk for falling.
In an earlier study, Lindsay Nagamatsu found that seniors who are prone to falling (fallers), may be less likely or slower to notice hazards while navigating within their environment. In other words, fallers appear to have a narrowed focus of attention compared to non-fallers. This may cause them to overlook hazards or obstacles and prevent them from safely navigating the immediate environment, and avoid falling. Failing to notice a step or a curb, for example, may lead to a fall.
In this, her second, follow-up study, Ms. Nagamatsu will determine whether other aspects of attention are also related to falls. Her research focuses on examining automatic attention in senior fallers through a series of carefully designed experiments. Identifying the causes of falls in seniors is important because success will guide strategic interventions to prevent falls and consequently reduce individuals' injuries and societal health care costs. The results of this study could also be applied to develop novel risk screening strategies for fallers.
Assessing Protective Factors for Self-harm: Development of the Barriers to Self-harm Inventory
Deliberate self-harm (DSH) is the deliberate, direct destruction of body tissue without suicidal intent. Common forms of DSH include cutting, burning or hitting oneself and, not surprisingly, it is associated with a variety of negative health outcomes. DSH often begins in adolescence. Without treatment it can persist for several years and decades. Although promising treatments exist, studies indicate that many individuals in treatment fail to reduce their DHS behaviours. To date, few studies have examined factors that directly prevent someone from engaging in DSH, either over the short- or long-term. Brianna Turner’s research is focusing on factors that directly prevent DSH, as well as the development of a novel psychometric measure that can be used easily within busy health care settings to assess protective barriers against DSH and predict future DSH. These are novel research directions that fit within two larger investigational projects underway that looking at the emotional, individual and environmental factors that predict changes related to self harm. Additionally, and importantly, the results of this study have the potential to improve the quality of care and health outcomes for individuals who engage in deliberate self-harm.
An ethno-epidemiological investigation of social and environmental contexts of HIV vulnerability among injection drug users
Outside of Africa, an estimated two-thirds of new Human Immunodeficiency virus (HIV), infections are believed to occur among people who inject illicit drugs. While an urgent need exists for tailored interventions to address HIV risk behaviour within vulnerable groups such as adult injection drug users (IDU), there are major knowledge gaps that must first be addressed if interventions are to be successful. Innovative approaches to examine how participation in particular social contexts and environments foster vulnerability to HIV are crucial to the development of effective intervention strategies among highly vulnerable populations of IDUs. William Small is conducting research to address this need using ethnographic methods to develop empirical information regarding transitions into particular high-risk social contexts, including drug markets and sex trade activities. Specifically, his research focuses on the risk environments in two different geographical settings, Vancouver, Canada and Sydney, Australia. The results will provide critical insight regarding how participation in these high-risk settings influences HIV risks as well as an individual’s ability to engage in risk reduction in the context of injection drug use. The information will be integrated with findings from ongoing epidemiological studies in the same locales to test socially-oriented hypotheses regarding the relationship between HIV vulnerabilities and particular social contexts. Ultimately, the findings from Mr. Smalls’ research will help advance the study of HIV risks among IDUs, and inform the development of social and community interventions designed to reduce HIV transmission.
The Role of Gap Junction Proteins in cytoskeletal rearrangements in B-lymphocytes
B-cell lymphomas are the most common type of blood cancer, accounting for 80-90 percent of non-Hodgkin’s lymphomas. Because lymphoma cancer cells can so readily spread from the blood stream to other tissues in the body, it is also a highly fatal form of disease. The key to preventing the spread of B-lymphomas is to prevent the proliferation and migration of these cancerous cells. To that end, an understanding of the underlying cellular processes is essential to the development of effective therapies. Recently, the Gap junction protein connexin43 (Cx43), was shown to cause neuronal migration in the brain. This novel role for gap junctions has led to speculation that Cx43 may be important for the migration of other cell types. Further, Cx43 expression on B-cells is important for hematopoiesis in the bone marrow, however the function of Cx43 on mature, circulating B-cells has remained elusive. Letitia Falk’s research involves a systematic dissection of the role of different protein domains of Cx43. Additionally, she is investigating the migration of B-lymphoid tumour cells expressing wild type and mutated forms of Cx43 in mouse models of tumour metastasis. These experiments will provide insight into processes that underlie normal lymphocyte development as well as the regulatory processes involved in the metastasis of B-cell leukemias, lymphomas and myelomas. Understanding in this area has the potential to aid in the development of novel anti-cancer therapeutics for the treatment of lymphoma cancers.