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Abstract Background Experts in the field of medical education emphasized the need for curricula that improve students’ attitudes toward the underserved. However, some studies have shown that medical education tends to worsen these attitudes in students. We aimed at systematically reviewing the literature assessing the change in medical students’ attitudes toward the underserved and intention to work with the underserved throughout medical education, the sociodemographic and educational factors associated with favorable medical student attitudes toward and/or intention to work with the underserved and the effectiveness of educational interventions to improve medical student attitudes toward and/or intention to work with the underserved. Method We conducted a systematic review on MEDLINE, Scopus, and Web of Science databases. Three investigators independently conducted the electronic search. We assessed the change in medical students attitudes toward the underserved by computing a weighted mean effect size of studies reporting scores from validated scales. The research team performed a meta-analysis for the sociodemographic and educational factors associated with medical students attitudes toward and/or intention to work with the underserved. Results Fifty-five articles met the inclusion criteria, including a total of 109,647 medical students. The average response rate was 73.2%. Most of the studies were performed in the USA (n = 45). We observed a significant decline of medical students attitudes toward the underserved throughout medical education, in both US and non-US studies. A moderate effect size was observed between the first and fourth years (d = 0.51). Higher favorable medical students attitudes toward or intention to work with the underserved were significantly associated with female gender, being from an underserved community or ethnic minority, exposure to the underserved during medical education and intent to practice in primary care. Regarding educational interventions, the effectiveness of experiential community-based learning and curricula dedicated to social accountability showed the most positive outcome. Conclusions Medical students attitudes toward the underserved decline throughout medical education. Educational interventions dedicated to improving the attitudes or intentions of medical students show encouraging but mixed results. The generalizability of our results is impeded by the high number of studies from the global-North included in the review.

The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ’s effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer and suppressed the progression of established tGLI1-positive BCBM without liver toxicities. We further developed six KCZ derivatives, two of which (KCZ-5 and KCZ-7) retained tGLI1-selectivity in vitro. KCZ-7 exhibited higher blood–brain barrier penetration than KCZ/KCZ-5 and more effectively reduced the BCBM frequency. In contrast, itraconazole, another FDA-approved antifungal, failed to suppress BCBM. The mechanistic studies suggest that KCZ and KCZ-7 inhibit tGLI1’s ability to bind to DNA, activate its target stemness genes Nanog and OCT4, and promote tumor proliferation and angiogenesis. Our study establishes the rationale for using KCZ and KCZ-7 for treating and preventing BCBM and identifies their mechanism of action.

Despite advances in systemic therapies for solid tumors, the development of brain metastases remains a significant contributor to overall cancer mortality and requires improved methods for diagnosing and treating these lesions. Similarly, the prognosis for malignant primary brain tumors remains poor with little improvement in overall survival over the last several decades. In both primary and metastatic central nervous system (CNS) tumors, the challenge from a clinical perspective centers on detecting CNS dissemination early and understanding how CNS lesions differ from the primary tumor, in order to determine potential treatment strategies. Acquiring tissue from CNS tumors has historically been accomplished through invasive neurosurgical procedures, which restricts the number of patients to those who can safely undergo a surgical procedure, and for which such interventions will add meaningful value to the care of the patient. In this review we discuss the potential of analyzing cell free DNA shed from tumor cells that is contained within the cerebrospinal fluid (CSF) as a sensitive and minimally invasive method to detect and characterize primary and metastatic tumors in the CNS.

Purpose: Radiation-induced cognitive decline is relatively common after treatment for primary and metastatic brain tumors; however, identifying dosimetric parameters that are predictive of radiation-induced cognitive decline is difficult due to the heterogeneity of patient characteristics. The memory function is especially susceptible to radiation effects after treatment. The objective of this study is to correlate volumetric radiation doses received by critical neuroanatomic structures to post–radiation therapy (RT) memory impairment. Methods and materials: Between 2008 and 2011, 53 patients with primary brain malignancies were treated with conventionally fractionated RT in prospectively accrued clinical trials performed at our institution. Dose-volume histogram analysis was performed for the hippocampus, parahippocampus, amygdala, and fusiform gyrus. Hopkins Verbal Learning Test-Revised scores were obtained at least 6 months after RT. Impairment was defined as an immediate recall score ≤15. For each anatomic region, serial regression was performed to correlate volume receiving a given dose (VD(Gy)) with memory impairment. Results: Hippocampal V53.4Gy to V60.9Gy significantly predicted post-RT memory impairment (P

JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.

Abstract Introduction Clinical reasoning is a fundamental skill in medicine. Teaching of this important skill spans much of formal medical training and encompasses both the acquisition of medical knowledge (i.e., content-oriented learning) and the integration of sufficient clinical experience (i.e., process-oriented learning). This course incorporates clinically relevant clerkship content to deliver a process-oriented (as opposed to content-oriented) approach to learning. Methods This course involves two 60-minute sessions distributed over the 4-week required Neurology Core Clerkship rotation at our institution. In Session 1, the instructor leads students in the generation of a framework for evaluating neurologic disease. Students are introduced to the concepts underlying clinical reasoning in neurology, including the process of lesion localization, development of categorization of the case, and differential diagnosis formation. In Session 2, students engage in a heavily peer-mediated, learner-centered approach to applying the concepts learned in Session 1 to clinical scenarios. Clinically relevant cases, either provided by the instructor or from student-driven clinical encounters, are used to apply the framework and build models for efficiently evaluating neurologic disease. Results Approximately 1 year following implementation, the course has been exceedingly well received. Student satisfaction has been high. The course has also not negatively impacted student performance in the clerkship. National Board of Medical Examiners Neurology Shelf Exam scores were not different in the year following implementation of the course, nor were there differences in mean rating of student clinical performance as assessed by faculty and resident clinical evaluations as observed in the years prior to and following institution of the course. Discussion Initial student feedback was largely positive and suggested the existing format was sufficient to meet the course objectives. Student participation with the noncompulsory clinical case vignettes has remained low, and additional incentives have been sought to encourage self-directed student participation. While course content is most relevant to neurology, the skills acquired are generalizable to all of medicine and are particularly applicable to the clinical clerkship.

Glioblastoma (GBM) is one of most aggressive forms of brain cancer, with a median survival time of 14.6 months following diagnosis. This low survival rate could in part be attributed to the lack of model systems of this type of cancer that faithfully recapitulate the tumor architecture and microenvironment seen in vivo in humans. Therapeutic studies would provide results that could be translated to the clinic efficiently. Here, we assess the role of the tumor microenvironment physical parameters on the tumor, and its potential use as a biomarker using a hyaluronic acid hydrogel system capable of elastic modulus tuning and dynamic elastic moduli changes. Experiments were conducted to assess the sensitivity of glioblastoma cell populations with different mutations to varying elastic moduli. Cells with aberrant epithelial growth factor receptor (EGFR) expression have a predilection for a stiffer environment, sensing these parameters through focal adhesion kinase (FAK). Importantly, the inhibition of FAK or EGFR generally resulted in reversed elastic modulus preference. Lastly, we explore the concept of therapeutically targeting the elastic modulus and dynamically reducing it via chemical or enzymatic degradation, both showing the capability to reduce or stunt proliferation rates of these GBM populations.

Abstract Introduction Numerous transitions exist in medical school—from undergraduate to medical education, from didactic to problem-based learning, from institutionally generated to national standardized examinations, from classroom study to clinical clerkship training, and from learning clinical medicine to determining a future career path. These transitions can have significant impact on academic performance, cynicism, dishonesty, substance abuse, depression, and suicidality. While faculty- and staff-led support programs are often offered to assist students, peer-led programs may provide even more support for coping with these transitions. Student mentoring has also been identified as an important factor in student satisfaction and career development during medical school. Methods Herein we describe a 4-year, noncompulsory course, Transitions in Medicine, that provides a mechanism for peer-led support and guidance through the many transitions in medical school. Recurring seminars focusing on process-oriented as opposed to content-oriented preparation are offered at key points within a student's medical school career. During each session, upper-class students provide targeted guidance and discussion about the important concepts, strategies, and preparation necessary at each transition. This resource includes an instructor's guide, PowerPoint and narrative descriptions of each seminar session, and a sample student survival guide designed to complement the 4-year course. Results This course has been effective and had significant impact on the culture of our institution. Several prior publications outlined in the resource have documented the effect of the course on student anxiety and academic performance. In addition, we offer further explanation of the tangible benefits that have been realized, including but not limited to benefits on student anxiety, early student planning, student preparedness, and student-to-student mentoring. Discussion The principle of “paying it forward” underlies student participation in this course. Students and faculty and have commented that as an apparent indirect benefit of the course, this important principle has been fostered and emphasized in its incorporation into the curriculum.

Abstract Introduction Medical school curricula are specifically designed to address issues related to content competency and knowledge-based preparation. The USMLE Step 1 examination is a major indicator of basic science content competency. Studies have shown, and students at our institution have indicated, that success on this examination requires efficient preparation and adequate student confidence in addition to content competency. This course is designed to address issues relating to student guidance, support, early awareness, and confidence. Methods In this resource, we provide a session-by-session manual and accompanying PowerPoint presentations for the development and implementation of a five-part seminar series offered during the first 2 years of medical school. The series is composed of five 1-hour seminars, beginning with a short presentation followed by an interactive discussion between first- and second-year medical students. Two sessions are held in the first year and focus on general topics addressing the personalization of study strategies. Three sessions are held in the second year and focus more specifically on planning and preparation strategies for the USMLE Step 1 examination. Results In the first 2 years of implementation, we have observed profound improvement in student confidence. Course participants praised the series for addressing important stressors in medical education and providing not only helpful solutions to these challenges but also an interactive environment for communicating with upperclassmen. Students have found communication with these colleagues to be extremely beneficial. In a review survey of the course, with over 70% of students responding, more than 80% of students agreed or strongly agreed that the course was helpful in providing guidance for early USMLE Step 1 study planning. Discussion This course complements existing medical school curricula and provides formal student guidance on early planning and preparation strategies for success throughout medical school, with particular emphasis on the USMLE Step 1 examination. The course is designed to impact all medical students; however, particular focus is aimed at students who may be at risk of poor performance. We encourage the implementation of this course in existing medical school curricula.