Student Engagement: The Effects of Goals, Personality, Relations, and Society

Undergraduate Applie

The SMAC mimetic LCL-161 selectively targets JAK2V617F mutant cells.

Background:Evasion from programmed cell death is a hallmark of cancer and can be achieved in cancer cells by overexpression of inhibitor of apoptosis proteins (IAPs). Second mitochondria-derived activator of caspases (SMAC) directly bind to IAPs and promote apoptosis; thus, SMAC mimetics have been investigated in a variety of cancer types. particularly in diseases with high inflammation and NFĸB activation. Given that elevated TNFα levels and NFĸB activation is a characteristic feature of myeloproliferative neoplasms (MPN), we investigated the effect of the SMAC mimetic LCL-161 on MPN cell survival in vitro and disease development in vivo. Methods:To investigate the effect of the SMAC mimetic LCL-161 in vitro, we utilized murine and human cell lines to perform cell viability assays as well as primary bone marrow from mice or humans with JAK2V617F-driven MPN to interrogate myeloid colony formation. To elucidate the effect of the SMAC mimetic LCL-161 in vivo, we treated a JAK2V617F-driven mouse model of MPN with LCL-161 then assessed blood counts, splenomegaly, and myelofibrosis. Results:We found that JAK2V617F-mutated cells are hypersensitive to the SMAC mimetic LCL-161 in the absence of exogenous TNFα. JAK2 kinase activity and NFĸB activation is required for JAK2V617F-mediated sensitivity to LCL-161, as JAK or NFĸB inhibitors diminished the differential sensitivity of JAK2V617F mutant cells to IAP inhibition. Finally, LCL-161 reduces splenomegaly and may reduce fibrosis in a mouse model of JAK2V617F-driven MPN. Conclusion:LCL-161 may be therapeutically useful in MPN, in particular when exogenous TNFα signaling is blocked. NFĸB activation is a characteristic feature of JAK2V617F mutant cells and this sensitizes them to SMAC mimetic induced killing even in the absence of TNFα. However, when exogenous TNFα is added, NFĸB is activated in both mutant and wild-type cells, abolishing the differential sensitivity. Moreover, JAK kinase activity is required for the differential sensitivity of JAK2V617F mutant cells, suggesting that the addition of JAK2 inhibitors to SMAC mimetics would detract from the ability of SMAC mimetics to selectively target JAK2V617F mutant cells. Instead, combination therapy with other agents that reduce inflammatory cytokines but preserve JAK2 signaling in mutant cells may be a more beneficial combination therapy in MPN

COVID-19: Using Social Media to Promote Mental Health in Medical School During the Pandemic

The Asian Pacific American Medical Student Association (APAMSA) is a national student organization that advocates for the health of the Asian American Pacific Islanders. In May 2020, our APAMSA chapter at Oakland University William Beaumont (OUWB) School of Medicine located in Michigan, USA hosted a virtual mental health campaign titled, “Socially Distant but Emotionally Connected: 6ft Closer During Quarantine.” We reached out to medical students and faculty within the OUWB community to share their experiences during the initial phases of quarantine. Our goal was to create a space for everyone at OUWB to engage in meaningful conversations about mental health and support each other during the pandemic. The responses we received varied across numerous topics, including xenophobia, loneliness, and lack of motivation. Participants also followed up with words of encouragement for their peers and guidance on how to cope with social isolation. Our virtual campaign was very feasible and successful under the constraints of social distancing, and we urge other medical schools to implement their own mental health awareness initiatives to destigmatize the topic in their communities. General steps on how to start your own campaign include: collaborating with interest groups, deciding on social media platforms, and sharing with your community.&nbsp

EGFR is required for Wnt9a-Fzd9b signalling specificity in haematopoietic stem cells.

Wnt signalling drives many processes in development, homeostasis and disease; however, the role and mechanism of individual ligand-receptor (Wnt-Frizzled (Fzd)) interactions in specific biological processes remain poorly understood. Wnt9a is specifically required for the amplification of blood progenitor cells during development. Using genetic studies in zebrafish and human embryonic stem cells, paired with in vitro cell biology and biochemistry, we determined that Wnt9a signals specifically through Fzd9b to elicit β-catenin-dependent Wnt signalling that regulates haematopoietic stem and progenitor cell emergence. We demonstrate that the epidermal growth factor receptor (EGFR) is required as a cofactor for Wnt9a-Fzd9b signalling. EGFR-mediated phosphorylation of one tyrosine residue on the Fzd9b intracellular tail in response to Wnt9a promotes internalization of the Wnt9a-Fzd9b-LRP signalosome and subsequent signal transduction. These findings provide mechanistic insights for specific Wnt-Fzd signals, which will be crucial for specific therapeutic targeting and regenerative medicine

Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic, and Chemogenic Manipulations

The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. In rodents, MCH acts on MCHR1, a G protein-coupled receptor, which is widely expressed in the brain and abundantly localized to neuronal primary cilia. Cilia act as cells’ antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different experimental models and methodologies, including organotypic brain slice cultures from rat prefrontal cortex (PFC) and caudate–putamen (CPu), in vivo pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (designer receptors exclusively activated by designer drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation or indirectly through optogenetic and chemogenetic-mediated excitation of MCH-neuron, caused cilia shortening, detected by the quantification of the presence of ADCY3 protein, a known primary cilia marker. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations — germline deletion of MCHR1 and conditional ablation of MCH neurons — induced cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions and implicate MCHR1 present at primary cilia as a potential therapeutic target for the treatment of pathological conditions characterized by impaired primary cilia function associated with the modification of its length

Incubateur de Santé Communautaire et de Médecine Sociale : un cadre d’apprentissage par le service pour des projets menés par des étudiants en médecine

Implication Statement The Community Health and Social Medicine (CHASM) Incubator is a social impact venture that gives medical and other health care students the opportunity to develop initiatives that sustainably promote health equity for, and in partnership with, community partners and historically marginalized communities. Students learn how to develop projects with project management curricula, are paired with community health mentors, and are given seed micro-financing. As the first community health incubator driven by medical students, CHASM provides a framework for students interested in implementing sustainable solutions to local health disparities which extends the service-learning opportunities offered in existing curricula.Énoncé des implications de la recherche L’incubateur CHASM (Community Health and Social Medicine) est une initiative visant à créer un impact social en donnant aux étudiants en médecine et des autres sciences de la santé la possibilité de développer des initiatives durables en collaboration avec des partenaires communautaires et des communautés historiquement marginalisées. CHASM met en valeur l’équité en matière de santé. Les étudiants apprennent à élaborer des projets via un cursus de gestion de projet, sont jumelés à des mentors en santé communautaire et bénéficient de micro-financement de départ. Ce premier incubateur de santé communautaire mené par des étudiants en médecine fournit un cadre aux étudiants qui souhaitent mettre en œuvre des solutions durables aux inégalités en matière de santé. Il élargit également les possibilités d’apprentissage par le service offertes dans les cursus existants

Image Registration of In Vivo Micro-Ultrasound and Ex Vivo Pseudo-Whole Mount Histopathology Images of the Prostate: A Proof-of-Concept Study

Early diagnosis of prostate cancer significantly improves a patient's 5-year survival rate. Biopsy of small prostate cancers is improved with image-guided biopsy. MRI-ultrasound fusion-guided biopsy is sensitive to smaller tumors but is underutilized due to the high cost of MRI and fusion equipment. Micro-ultrasound (micro-US), a novel high-resolution ultrasound technology, provides a cost-effective alternative to MRI while delivering comparable diagnostic accuracy. However, the interpretation of micro-US is challenging due to subtle gray scale changes indicating cancer vs normal tissue. This challenge can be addressed by training urologists with a large dataset of micro-US images containing the ground truth cancer outlines. Such a dataset can be mapped from surgical specimens (histopathology) onto micro-US images via image registration. In this paper, we present a semi-automated pipeline for registering in vivo micro-US images with ex vivo whole-mount histopathology images. Our pipeline begins with the reconstruction of pseudo-whole-mount histopathology images and a 3-dimensional (3D) micro-US volume. Each pseudo-whole-mount histopathology image is then registered with the corresponding axial micro-US slice using a two-stage approach that estimates an affine transformation followed by a deformable transformation. We evaluated our registration pipeline using micro-US and histopathology images from 18 patients who underwent radical prostatectomy. The results showed a Dice coefficient of 0.94 and a landmark error of 2.7 mm, indicating the accuracy of our registration pipeline. This proof-of-concept study demonstrates the feasibility of accurately aligning micro-US and histopathology images. To promote transparency and collaboration in research, we will make our code and dataset publicly available

Development and Psychometric Properties of Surveys to Assess Provider Perspectives on the Barriers and Facilitators of Effective Care Transitions

Background The quality of the discharge process and effective care transitions between settings of care are critical to minimize gaps in patient care and reduce hospital readmissions. Few studies have explored which care transition components and strategies are most valuable to patients and providers. This study describes the development, pilot testing, and psychometric analysis of surveys designed to gain providers’ perspectives on current practices in delivering transitional care services. Methods We underwent a comprehensive process to develop items measuring unique aspects of care transitions from the perspectives of the three types of providers (downstream, ambulatory, and hospital providers). The process involved 1) an environmental scan, 2) provider interviews, 3) survey cognitive testing, 4) pilot testing, 5) a Stakeholder Advisory Group, 6) a Scientific Advisory Council, and 7) a collaborative Project ACHIEVE (Achieving Patient-Centered Care and Optimized Health in Care Transitions by Evaluating the Value of Evidence) research team. Three surveys were developed and fielded to providers affiliated with 43 hospitals participating in Project ACHIEVE. Web-based survey administration resulted in 948 provider respondents. We assessed response variability and response missingness. To evaluate the composites’ psychometric properties, we examined intercorrelations of survey items, item factor loadings, model fit indices, internal consistency reliability, and intercorrelations between the composite measures and overall rating items. Results Results from psychometric analyses of the three surveys provided support for five composite measures: 1) Effort in Coordinating Patient Care, 2) Quality of Patient Information Received, 3) Organizational Support for Transitional Care, 4) Access to Community Resources, and 5) Strength of Relationships Among Community Providers. All factor loadings and reliability estimates were acceptable (loadings ≥ 0.40, α ≥ 0.70), and the fit indices showed a good model fit. All composite measures positively and significantly correlated with the overall ratings (0.13 ≤ r ≤ 0.71). Conclusions We determined that the items and composite measures assessing the barriers and facilitators to care transitions within this survey are reliable and demonstrate satisfactory psychometric properties. The instruments may be useful to healthcare organizations and researchers to assess the quality of care transitions and target areas of improvement across different provider settings