Search

Supplemental Digital Content is available in the text., The COVID-19 pandemic caused substantial disruptions in medical education. The University of British Columbia (UBC) MD Undergraduate Program (MDUP) is the sixth-largest medical school in North America. MDUP students and faculty developed a joint response to these disruptions to address the curriculum and public health challenges that the pandemic posed. After clinical activities were suspended in March 2020, third- and fourth-year MDUP students formed a COVID-19 Medical Student Response Team (MSRT) to support frontline physicians, public health agencies, and community members affected by the pandemic. A nimble organizational structure was developed across 4 UBC campuses to ensure a rapid response to meet physician and community needs. Support from the faculty ensured the activities were safe for the public, patients, and students and facilitated the provision of curricular credit for volunteer activities meeting academic criteria. As of June 19, 2020, more than 700 medical students had signed up to participate in 68 projects. The majority of students participated in projects supporting the health care system, including performing contact tracing, staffing public COVID-19 call centers, distributing personal protective equipment, and creating educational multimedia products. Many initiatives have been integrated into the MDUP curriculum as scholarly activities or paraclinical electives for which academic credit is awarded. This was made possible by the inherent flexibility of the MDUP curriculum and a strong existing partnership between students and faculty. Through this process, medical students were able to develop fundamental leadership, advocacy, communication, and collaboration skills, essential competencies for graduating physicians. In developing a transparent, accountable, and inclusive organization, students were able to effectively meet community needs during a crisis and create a sustainable and democratic structure capable of responding to future emergencies. Open dialogue between the MSRT and the faculty allowed for collaborative problem solving and the opportunity to transform disruption into academic innovation.

Background Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, particularly at the individual tumor level. We selected a cohort of 25 high-risk prostate tumors, representing the lethal phenotype, and applied deep RNA-sequencing and matched whole genome sequencing, followed by detailed molecular characterization. Results Ten tumors were exposed to neo-adjuvant hormone therapy and expressed marked evidence of therapy response in all except one extreme case, which demonstrated early resistance via apparent neuroendocrine transdifferentiation. We observe high inter-tumor heterogeneity, including unique sets of outlier transcripts in each tumor. Interestingly, outlier expression converged on druggable cellular pathways associated with cell cycle progression, translational control or immune regulation, suggesting distinct contemporary pathway affinity and a mechanism of tumor stratification. We characterize hundreds of novel fusion transcripts, including a high frequency of ETS fusions associated with complex genome rearrangements and the disruption of tumor suppressors. Remarkably, several tumors express unique but potentially-oncogenic non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression. Finally, one ETS-negative tumor has a striking tandem duplication genotype which appears to be highly aggressive and present at low recurrence in ETS-negative prostate cancer, suggestive of a novel molecular subtype. Conclusions The multitude of rare genomic and transcriptomic events detected in a high-risk tumor cohort offer novel opportunities for personalized oncology and their convergence on key pathways and functions has broad implications for precision medicine. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0426-y) contains supplementary material, which is available to authorized users.

Patients with triple-negative breast cancers (TNBCs) have very poor prognosis in terms of relapse and overall survival. There is currently no targeted therapy for this heterogeneous group of patients and it presents a pressing unmet medical need. Recent data suggest that Polo-like kinase 1 (PLK1) is a plausible target for treating TNBCs, and many small-molecule inhibitors are currently under development for targeting this kinase. Since clinical data have shown that single-agent treatment often leads to resistance and relapse of the cancer, it is essential to identify potential resistance mechanisms of TNBCs to PLK1 inhibition such that combination therapy can be rationally designed to increase treatment efficacy. We have selected ten individual cell clones from a TNBC cell line, MDA-MB-231, through long-term incubation of the cells with increasing concentrations of a PLK1 inhibitor BI 2536. We hypothesized that increased expression and/or activities of other kinases can compensate for the PLK1 inhibition. To identify these kinases, we screened the expression levels of >500 human kinases in the resistant clones in comparison to the parental cells, using the Nanostring platform, and generated a list of candidate kinases. Among the candidates, NEK9, a downstream effector of PLK1, was confirmed to be over-expressed in all resistant cell clones through Western blotting. MDA-MB-231 parental cells were then infected with a lentiviral over-expression vector that contains NEK9 and GFP. When a mixed population of NEK9-over-expressing cells (GFP+) and parental cells (GFP-) were incubated in the presence of BI 2536, increased proportion of GFP+ cells and increased mean GFP fluorescence intensity was observed over time through flow cytometry. Increase of NEK9 expression was also confirmed with Western blotting in the mixed cell culture experiment, indicating the selection of the NEK9-over-expressing cells in the presence of BI 2536. In conclusion, we have constructed a list of over-expressed kinase candidates that may contribute to the resistance to PLK1 inhibition. We further identify that over-expression of NEK9 contributes to the resistance phenotype. Our data prompt the need to further study the biology around NEK9 and suggest the possibility of combination therapy through inhibition of PLK1 and NEK9 in treating TNBCs. Citation Format: Nelson K. Y. Wong, Devon Mitchell, Mohamed K. Khan. Compensatory up-regulation of NEK9 contributes to resistance to PLK1 inhibition in triple-negative breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 303.