An ex vivo model of human colon cancer enables study of the drivers of tumor development and invasion. Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.

Telemedicine training was not a substantial element of most residency programmes prior to the COVID-19 pandemic. Social distancing measures changed this. The Cleveland Clinic Internal Medicine Residency Programme (IMRP) is one of the largest programmes in the USA, which made the task of implementing a telemedicine curriculum more complex. Here we describe our experience implementing an effective, expedited telemedicine curriculum for our ambulatory resident clinics. This study was started in April 2020 when we implemented a resident-led curriculum and training programme for providing ambulatory telemedicine care. The curriculum was finalised in less than 5 weeks. It entailed introducing a formal training programme for residents, creating a resource guide for different video communication tools and training preceptors to safely supervise care in this new paradigm. Residents were surveyed before the curriculum to assess prior experience with telemedicine, and then afterward to assess the curriculum's effectiveness. We also created a mini-CEX assessment for residents to solicit feedback on their performance during virtual appointments. Over 2000 virtual visits were performed by residents in a span of 10 weeks. Of 148 residents, 38% responded to the pre-participation survey. A majority had no prior telemedicine experience and expressed only slight comfort with the modality. Through collaboration with experienced residents and faculty, we expeditiously deployed an enhancement to our ambulatory care curriculum to teach residents how to provide virtual care and help faculty with supervision. We share our insights on this experience for other residency programmes to use.

Introduction: The role of medical students in catalyzing and leading curricular change in US medical schools is not well described. Here, American Medical Association student and physician leaders in the Accelerating Change in Medical Education initiative use qualitative methods to better define student leadership in curricular change. Methods: The authors developed case studies describing student leadership in curricular change efforts. Case studies were presented at a national medical education workshop; participants provided worksheet reflections and were surveyed, and responses were transcribed. Kotter’s change management framework was used to categorize reported student roles in curricular change. Thematic analysis was used to identify barriers to student engagement and activators to overcome these barriers. Results: Student roles spanned all eight steps of Kotter’s change management framework. Barriers to student engagement were related to faculty (e.g. view student roles narrowly), students (e.g. fear change or expect faculty-led curricula), or both (e.g. lack leadership training). Activators were: (1) recruiting collaborative faculty, staff, and students; (2) broadening student leadership roles; (3) empowering student leaders; and (4) recognizing student successes. Conclusions: By applying these activators, medical schools can build robust student–faculty partnerships that maximize collaboration, moving students beyond passive educational consumption to change agency and curricular co-creation.

Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1β and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1β, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80⁺ macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of K_i-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response.

Porous silicon (pSi) microparticles, in diverse sizes and shapes, can be functionalized to present pathogen-associated molecular patterns that activate dendritic cells. Intraperitoneal injection of MPL-adsorbed pSi microparticles, in contrast to free MPL, resulted in the induction of local inflammation, reflected in the recruitment of neutrophils, eosinophils and proinflammatory monocytes, and the depletion of resident macrophages and mast cells at the injection site. Injection of microparticle-bound MPL resulted in enhanced secretion of the T helper 1 associated cytokines IFN-γ and TNF-α by peritoneal exudate and lymph node cells in response to secondary stimuli while decreasing the anti-inflammatory cytokine IL-10. MPL-pSi microparticles independently exhibited anti-tumor effects and enhanced tumor suppression by low dose doxorubicin nanoliposomes. Intravascular injection of the MPL-bound microparticles increased serum IL-1β levels, which was blocked by the IL-1 receptor antagonist Anakinra. The microparticles also potentiated tumor infiltration by dendritic cells, cytotoxic T lymphocytes, and F4/80⁺ macrophages, however, a specific reduction was observed in CD204⁺ macrophages.