WE-SPARK Health Institute

INTRODUCTION: Clinical trials, although academically accepted as the most effective treatment available for cancer patients, poor accrual to clinical trials remains a significant problem. A clinical trials navigator (CTN) program was piloted where patients and/or their healthcare professionals could request a search and provide a list of potential cancer clinical trials in which a patient may be eligible based on their current status and disease. OBJECTIVES: This study examined the outcomes of a pilot program to try to improve clinical trials accrual with a focus on patients at medium to small sized cancer programs. Outcomes examined included patient disposition (referral to and accrual to interventional trials), patient survival, sites of referral to the CTN program. METHODS: One 0.5 FTE navigator was retained. Stakeholders referred to the CTN through the Canadian Cancer Clinical Trials Network. Demographic and outcomes data were recorded. RESULTS: Between March 2019 and February 2020, 118 patients from across Canada used the program. Seven per cent of patients referred were enrolled onto treatment clinical trials. No available trial excluded 39% patients, and 28% had a decline in their health and died before they could be referred or enrolled onto a clinical trial. The median time from referral to death was 109 days in those that passed. CONCLUSION: This novel navigator pilot has the potential to increase patient accrual to clinical trials. The CTN program services the gap in the clinical trials system, helping patients in medium and small sized cancer centres identify potential clinical trials at larger centres.

BACKGROUND: Translational research is an ideology focussed on streamlining the transition of novel research into clinical practice to ultimately benefit populations. Central to this approach is overcoming barriers to research involvement and interdisciplinary collaboration. Identifying barriers has been the subject of several studies focused on communities with large academic hospitals. The Windsor-Essex region is currently built around community hospitals which have less of an emphasis on research, employ fewer physicians holding academic appointments and generally do not provide incentivised time for research and training. In this study, we surveyed clinicians and researchers working in Windsor-Essex to gain insight into barriers to translational research important to those working in smaller sized, community-based research networks. METHODS: Using an anonymous close-ended Qualtrics survey distributed via email, we surveyed faculty members from The University of Windsor and clinical care providers from Windsor-Essex (n = 68). This included 24 physicians, 14 allied health professionals, and 30 non-clinician researchers. RESULTS: Managing competing interests, lack of time, funding, infrastructure, and networks were identified by greater than 75% of participants as barriers to research involvement. 62% of physicians identified the lack of permanent post-graduate medical trainees as a barrier. Clinicians were consistently less experienced in research skills compared to others; particularly in publishing results and applying for funding (p < 0.001). Schedule incompatibility, funding issues and identifying interested collaborators with overlapping interests were identified as barriers to interdisciplinary collaboration by 80% of participants. Moreover, 46% of those surveyed were unhappy with their research involvement and these individuals were 13% more likely to perceive research as important for their career progression (p = 0.244). CONCLUSIONS: This study identifies several important barriers to translational research in Windsor-Essex and suggests that many motivated researchers are unhappy with their current involvement. These results will inform decision making in the research community of Windsor-Essex and provides insight for communities of similar size and research capacity. Ultimately, enabling the translation of clinical research in all communities is required to ensure equitable access to cutting edge care.

Unacceptable impurities emerge in hand sanitizers due to oxidation chemistry facilitated by mandated additives coupled with heat and metal salts.

PURPOSE: Exercise offers benefits for people with a disability, yet environmental barriers hinder their participation in gyms. Universal design (UD) may enhance gym accessibility by addressing diverse users' needs, but greater empirical evidence is needed. This mixed methods study compared diverse participants' experiences of barriers and facilitators in a conventional gym and a gym adapted with UD. METHODS: Participants were instructed to think aloud as they completed five tasks in each gym while being audio and video recorded. Video observations were used to assign data points to floor plans of each gym, documenting where and how often barriers and facilitators occurred. Directed content analysis of transcripts captured participants' perceptions of each gym. Joint display tables integrated behavioural mapping and think aloud data. RESULTS: Thirty-nine participants with and without a disability participated. The adapted gym yielded fewer barriers and more facilitators than the conventional gym. Seven themes encompassed participants' perceptions of each gym environment. Data integration identified key physical, social, cognitive, sensory, and environmental factors that affect accessibility and inclusion in gyms. CONCLUSIONS: UD can improve gym accessibility, while fostering inclusive environments that support exercise for people with diverse abilities. Gyms implementing UD may reduce health inequities by accommodating diverse users.

. Furthermore, we found a direct correlation between Arg forks' interaction energies and the number of phosphates involved, which is more delicately modulated by other factors, like the types of hydrogen bonds and cation-π interactions that constitute the Arg fork. Additionally, we observed a positive correlation between the average interaction energies of Arg forks and the frequency of their occurrence in available crystal structures. At the broader level, this work establishes the groundwork for more precise modeling and understanding of RNA-protein interfaces, which could have potential implications in advancing the knowledge of biomolecular recognition patterns.

Fatty acid binding protein 1 (FABP1) is a lipid transporter primarily expressed in the liver where it helps move fatty acids between lipid membranes. Inhibition of FABP1 has potential therapeutic implications for nonalcoholic fatty liver disease, metabolic syndrome &amp; obesity, diabetes, and inflammatory &amp; cardiovascular diseases. Curiously, FABP1 is known to bind to both endocannabinoids (ECs) and the major phytocannabinoids (PCs) with moderately high affinities. We have developed an in-silico model of the protein and validated it against experimental data. We then employed the model to predict the binding mode and affinities of minor cannabinoids (MCs) to FABP1. Our study predicts that the top ranked MCs 5-acetyl-4-hydroxy-CBG and CBGA bind stronger than fatty acids (FAs), ECs or PCs, and participate in the key interactions used to stabilize FABP1-FA complexes. This makes them promising starting points for the development of new therapeutics. The implications this has on considering the minor cannabinoids as low entropy isosteres of the fatty acids is also discussed.

208 Background: Young-onset sporadic CRC is an important yet understudied heterogeneous group of aggressive cancers with distinct clinical and histopathological features. There is a steady increase in the incidence of cancer in this group of patients and currently, there are no screening guidelines to identify these patients due to a lack of understanding of the molecular mechanisms driving cancer in this patient group. Introduction: Despite screening guidelines and recent advances in cancer treatment, colorectal cancer (CRC) remains the second most diagnosed cancer and the second and third leading cause of cancer-related mortality in Canadian men and women, respectively [Canadian Cancer Statistics 2017.]. More striking is the rise in incidence of CRC in young adults in the United States [Siegel, R.L., et al, Bailey, C.E., et al., Dozois, E.J., et al., Deen, K.I., et al.], and the expectation that by the year 2030, the incidence rate will increase by 90% in this patient population. Data from the Surveillance and Cancer registry at Cancer Care Ontario shows a similar trend with increased rates in younger adults (ages 30 to 49) by 5.2 per cent per year between 2005 and 2012 [Ontario, C.C., Cancer Fact.]. Moreover, these younger patient groups are often diagnosed with aggressive forms and advanced stages of the disease [Ontario, C.C., Cancer Fact.]. Methods: In this study, using a total of 30 colorectal cancer patient samples from Windsor Regional Hospital Cancer Program, we performed comprehensive targeted gene sequencing to identify single nucleotide variants, small insertions/deletions, copy number variants in over 500 genes that are implicated in cancer. Mean age of the patients in this study was 44 years and only patients without any personal or family history of colon cancer /other malignancies or IBD were enrolled in the study. Results: While identifying previously known colorectal cancer associated genetic variants, our preliminary data shows distinct missense mutations in several genes potentially contributing to the development and progression of cancer in these patients. In addition to showing pathogenic mutations in colorectal cancers associated genes, such as PIK3CA (H1047R, E545K, E545G, R93W, V344A), KRAS (G12V, G12D, A146T) and APC, our study showed recurring missense mutations in several genes including AXIN2, ALK, CDKN1A, MAP3K1, ROS1, EPCAM, KDM5A and AURKA in over 50% of our samples. Conclusions: The genomic profiling performed using biopsies from young colorectal cancer patients through this study provides a unique ability to identify the potential “genomic triggers” for the development and progression of cancer in young sporadic colorectal cancer patients. This information can not only be used to develop targeted treatment options for these patients but also to design new screening protocols as well as optimal surveillance strategies.

People with a disability encounter a surfeit of barriers to exercising in fitness and recreational facilities. While barriers and facilitators are well documented, few efforts have been made to synthesize recommendations that can facilitate the development of accessible and inclusive facilities. This rapid review addresses this gap by developing recommendations that encompass factors pertinent to physical, cognitive, and social accessibility. The research is reported according to the PRISMA-ScR guidelines. Searches of 11 databases related to architecture, health, and sociobehavioral sciences yielded 41 articles that were analyzed using an inductive content analysis. Six recommendations were derived: (1) Increase education and awareness, (2) advocate for accessibility, (3) collaborate with interest groups, (4) implement strategies for inclusion, (5) establish evaluation and improvement plans, and (6) adopt guidelines or best practices. The recommendations encompass guiding principles and strategic advice that can be implemented in facilities to enable diverse people to engage in physical activity.

Background As the antivaccine movement has increased, vaccine preventable illnesses have also increased. The resurgence of measles globally has been noted, specifically the United States received 1200 new cases of measles in 2019, which is the highest number of cases since 1994. Measles is a highly contagious pathogen; the virus has an attack rate of up to 90% in susceptible individuals. Standard of care for patients post hematopoietic cell transplant (HCT) includes repeating all childhood vaccinations. However, compliance with recommendations is unknown. No previous reports have been created measuring the difference in measles, mumps, and rubella (MMR) reactivity between autologous and allogeneic HCT patients post treatment. Methods A retrospective chart review investigated HCT patients between 2000-2019 from the Windsor Regional Hospital (WRH) cancer centre. Patients were excluded from data collection if they were deceased before an MMR reactivity test could be done or if they were lost to follow up. A total of 83% of autologous HCT (N=57) and 66% of allogeneic HCT (N=47) patients had serology tested to measure MMR reactivity post-transplant prior to live vaccinations. MMR titres were drawn from autologous patients a median of 395 days after HCT and a median of 907 days after HCT for allogeneic patients. Results Overall, allogeneic HCT patients had more reactivity than autologous HCT patients as seen in Table 1. Conclusion All patients not reactive to measles need to be re-vaccinated 24 months after treatment according to 2019 American Society for Transplantation and Cellular Therapy guidelines. Our patients are treated in a variety of transplant centers in Ontario, Canada as well as Detroit, Michigan; which is of concern because measles cases have been reported in Detroit. The majority (66%) of allogeneic HCT patients had a myeloid malignancy, while 70% of autologous patients has a diagnosis of multiple myeloma. As evidenced by the poor MMR response, less robust immune systems may be accounted for by multiple myeloma patients. This does emphasize the need for MMR vaccinations post HCT for multiple myeloma patients and raises the question regarding immunization for at risk non-transplant eligible patients. We suggest that it may be reasonable to assess MMR immune status in all myeloma patients to determine if this is a transplant effect or an effect of the underlying immune status of the myeloma patient. This study does emphasize the need to assess MMR status post transplant in all myeloma patients, as the vast majority in our study did not demonstrate immunity post stem cell transplant. Figure Disclosures Hamm: Amgen: Consultancy.

c-MET (c-mesenchymal-epithelial transition factor) is dysregulated across multiple cancers yet reports of prospectively validated ATP-competitive inhibitor chemotypes remain limited. We sought to discover new c-MET inhibitors by coupling scaffold-aware machine learning with explicit-solvent structure-based triage and targeted assays. A curated activity set yielded a tuned support vector machine that enriched ~5 million molecules. Docking and pose filtering produced 114 candidates; 36 were analyzed using 200 ns molecular dynamics (MD) simulations, from which six were advanced to experimental validation, including two candidates that inhibited c-MET with IC50 values of 1.2 and 18 μM and demonstrated cellular activity consistent with MET dependence (gastric &gt; NSCLC &gt; HeLa). MD revealed stable class-I poses that pack the ligand at the hinge (Tyr1159/Met1160), traverse the Val1092/Met1211 hydrophobic groove, and engage the activation-loop edge (Tyr1230 with auxiliary Asp1222/Arg1208 contacts). Variant docking suggested tolerance to the common mutations D1228N/H/V and D1231Y with moderate sensitivity to Y1230C/H. This work delivers validated and structurally innovative class-I c-MET chemotypes demonstrating that a multi-stage workflow integrating machine learning, docking, and physics-based scoring for ultra-large libraries can accelerate hit identification. The same strategy is directly applicable to other receptor tyrosine kinases that share flanking, hinge-anchoring, hydrophobic sub pockets, and to protein ligand discovery more broadly.

High-impact practices (HIPs) are educational practices that foster student success. HIPs have not been widely used in cancer education and research despite the need for students to develop key transferable skills and cultivate social responsibility. Our study addresses this need by implementing four community-based learning HIPs within the context of cancer education and research. Each HIP was classified as having low, moderate, or high alignment with the traits of effective HIPs. Undergraduate science students participated in one to four HIPs as a Feedback Participant, General Volunteer, Student Leader, or Cancer Undergraduate Research and Education (CURES) Class Student. We then studied the effect of these HIPs on students' development of knowledge and skills; career interest and preparedness; and social responsibility. Results from self-reported questionnaires showed that HIPs increased students' cancer knowledge and developed their transferable and technical skills. Many students reported that these HIPs strongly impacted their career preparedness; positively influenced their interest in pursuing careers in health or biomedical sciences; and encouraged them to participate in community service activities. Thus, these findings provide new insights into the perceived benefits of HIPs in cancer education and research by undergraduate students.

Protein homeostasis depends on many fundamental processes including mRNA synthesis, translation, post-translational modifications, and proteolysis. In the late 70s and early 80s the discovery that the small 76 amino acid protein ubiquitin could be attached to target proteins via a multi-stage process involving ubiquitin-activating enzymes, ubiquitin conjugating enzymes, and ubiquitin ligases, revealed an exciting new post-translational mechanism to regulate protein degradation. This cellular system was uncovered using biochemical methods by Avram Hershko, who would later won the Nobel prize for this discovery; however, the biological functions of ubiquitin ligases remained unknown for many years. It was initially described that ubiquitin modifies proteins at one or more lysine residues and once a long ubiquitin chain was assembled, proteins were degraded by the proteasome. Now we know that proteins can be mono-, multimono-, homotypic poly-, or heterotypic poly-ubiquitylated, each of which confers a specific signal that goes beyond protein degradation regulating additional key cellular functions such as signal transduction, protein localization, recognition of damaged proteins, etc.