Dynamic Opportunities for Medical Students to Assume the Roles of "Medical Teacher".

The traditional undergraduate medical education curriculum focuses on bolstering knowledge for practice and building clinical skills. However, as future clinicians, medical students will be tasked with teaching throughout their careers, first as residents and then as attendings. Here, we describe teaching opportunities for students that foster their development as future teachers and potential clinician educators. These offerings are diverse in their focus and duration and are offered across various levels of the curriculum - including course-based learning, longitudinal electives, and extra-curricular opportunities for medical students who have a passion for teaching.

Impact of Experiential Learning of Nutrition Therapy on Medical Students.

Despite the recognition that nutrition is a critical component of health and disease, many medical schools struggle to incorporate nutrition education into their dense curriculum. We designed this study to determine whether a brief, experiential learning project would be an effective option for teaching this content. Medical students voluntarily enrolled in the study, agreeing to (1) attempt a 2-week "medically prescribed" diet and (2) participate in small group lunch discussions related to their diet experience. Data on student perception of nutrition in medicine was collected through validated surveys. Custom surveys were designed to capture student confidence in using nutrition counseling, while qualitative analysis of lunch discussions revealed themes of experiential learning. Participants reported an overall positive sentiment and named the most impactful learning component as actively attempting the diet. Student participants showed a variety of adherence to their assigned diet, yet as a cohort demonstrated increased confidence over their non-participant peers in the use of nutrition counseling in a clinical setting. In addition, diet participants demonstrated an increased perception of the importance of physician efficacy and the physician-patient relationship in the broader landscape of nutrition in patient care (compared to the control group). This study demonstrates the educational value of a short, immersive, extracurricular opportunity in bolstering an already demanding undergraduate medical education curriculum.

Effective and Time-Efficient Implementation of a Flipped-Classroom in Preclinical Medical Education.

The flipped classroom (FC) model of instruction has inherent barriers to implementation in medical education due to amount of content taught versus time allotted, the widespread adoption of interdisciplinary course structure causing a plethora of instructors responsible for content delivery, and trends to reduce the number of weeks to teach preclinical foundational science. Here we report on a FC model executed in an interdisciplinary endocrinology block in a time-saving manner, while preserving student preferences and satisfaction and improving written assessment performance. In this study, traditional lectures were 100% replaced with pre-session assignments (custom video modules) resulting in less time (- 9 h) spent on first pass learning. In-person, active-learning, case-based sessions were created (+ 8 h) to complete the FC model and achieve higher level understanding. Written assessment performance in the endocrinology block was compared between two cohorts: the FC model and traditional lecture model. The FC model cohort outperformed the traditional lecture cohort on written, multiple-choice assessments (both in-house and NBME assessments). Furthermore, a measured (survey data) student preference for the FC model was observed.

Participation in Dissection Affects Student Performance on Gross Anatomy Practical and Written Examinations: Results of a Four-Year Comparative Study.

The role of human dissection in modern medical curricula has been a topic of intense debate. In part, this is because dissection can be time-consuming and curricular hours are being monitored more carefully. This has led some to question the efficacy and importance of dissection as a teaching method. While this topic has received considerable attention in the literature, the question of how dissection impacts learning has been difficult to evaluate in a real-world, high-stakes setting since participation in dissection is often one of many variables. In this study, this challenge was overcome due to a change in the curriculum of a Special Master Program (SMP) that permitted a comparison between two years of students that learned anatomy using prosection only and two years of students that participated in dissection laboratories. Since each class of SMP students took courses in the medical school, and the medical school anatomy curriculum was constant, medical student performance served as a control throughout the study period. Results demonstrate that SMP students who learned through prosection had lower performance on anatomy practical and written examinations compared to medical students. When the SMP program changed and students started participating in dissection, there were measurable improvements in both practical and written examinations. These findings provide evidence of dissection's role in learning and applying anatomy knowledge both within and outside the gross anatomy laboratory.

Serotonin and serotonin transport in the regulation of lactation.

Serotonin (5-HT), classically known as a neurotransmitter involved in regulating sleep, appetite, memory, sexual behavior, neuroendocrine function and mood is also synthesized in epithelial cells located in many organs throughout the body, including the mammary gland. The function of epithelial 5-HT is dependent on the expression of the 5-HT receptors in a particular system. The conventional components of a classic 5-HT system are found within the mammary gland; synthetic enzymes (tryptophan hydroxylase I, aromatic amino acid decarboxylase), several 5-HT receptors and the 5-HT reuptake transporter (SERT). In the mammary gland, two actions of 5-HT through two different 5-HT receptor subtypes have been described: negative feedback on milk synthesis and secretion, and stimulation of parathyroid hormone related-protein, a calcium-mobilizing hormone. As with neuronal systems, the regulation of 5-HT activity is multifactorial, but one seminal component is reuptake of 5-HT from the extracellular space following its release. Importantly, the wide availability of selective 5-HT reuptake inhibitors (SSRI) allows the manipulation of 5-HT activity in a biological system. Here, we review the role of 5-HT in mammary gland function, review the biochemistry, genetics and physiology of SERT, and discuss how SERT is vital to the function of the mammary gland.

Estrogen receptor alpha deletion enhances the metastatic phenotype of Ron overexpressing mammary tumors in mice.

BACKGROUND: The receptor tyrosine kinase family includes many transmembrane proteins with diverse physiological and pathophysiological functions. The involvement of tyrosine kinase signaling in promoting a more aggressive tumor phenotype within the context of chemotherapeutic evasion is gaining recognition. The Ron receptor is a tyrosine kinase receptor that has been implicated in the progression of breast cancer and evasion of tamoxifen therapy. RESULTS: Here, we report that Ron expression is correlated with in situ, estrogen receptor alpha (ERα)-positive tumors, and is higher in breast tumors following neoadjuvant tamoxifen therapy. We also demonstrate that the majority of mammary tumors isolated from transgenic mice with mammary specific-Ron overexpression (MMTV-Ron mice), exhibit appreciable ER expression. Moreover, genetic-ablation of ERα, in the context of Ron overexpression, leads to delayed mammary tumor initiation and growth, but also results in an increased metastasis. CONCLUSIONS: Ron receptor overexpression is associated with ERα-positive human and murine breast tumors. In addition, loss of ERα on a Ron overexpressing background in mice leads to the development of breast tumors which grow slower but which exhibit more metastasis and suggests that targeting of ERα, as in the case of tamoxifen therapy, may reduce the growth of Ron overexpressing breast cancers but may cause these tumors to be more metastatic.

Intraluminal volume homeostasis: A common sertonergic mechanism among diverse epithelia.

Volume homeostasis is a common physiological phenomenon for fluid secreting organs, such as exocrine and endocrine glands. It is a manifestation of a finite intraluminal space and an ever changing demand for secretory fluids. Volume homeostasis addresses issues of fluid secretion, storage and clearance for efficient functioning. Here we discuss the evidence gathered over the past 2-3 decades on serotonin's role as a feedback inhibitor of secretion in the mammary gland, salivary gland, liver, pancreas, lung, thyroid gland and prostate gland. We propose that serotonin action is a common mechanism of regulating intraductal volume homeostasis.

Ron receptor tyrosine kinase activation confers resistance to tamoxifen in breast cancer cell lines.

Although tamoxifen treatment is associated with improved survival in patients with estrogen receptor (ER)-positive breast tumors, resistance remains an important clinical obstacle. Signaling through growth factor signaling pathways, in particular through receptor tyrosine kinases, has been demonstrated to confer tamoxifen resistance in an estradiol-independent manner. The Ron receptor tyrosine kinase, a member of the c-Met family of receptors, is expressed in a number of human epithelial tumors, and elevated expression of Ron is associated with poor prognosis in women with breast cancer. In this report, we evaluated the role of Ron receptor activation in conferring resistance to tamoxifen in human and murine breast cancer cell lines. Activation of Ron by its ligand, hepatocyte growth factor-like protein (HGFL) was associated with partial rescue from tamoxifen-induced growth inhibition in Ron-expressing cell lines. Western analysis revealed that treatment of the T47D human breast cancer cell line with tamoxifen and HGFL was associated with increased phosphorylation of mitogen-activated protein kinase (MAPK) 1/2 and phosphorylation of serine residue 118 of ER. Expression of ER-dependent genes was increased in cells treated with tamoxifen and HGFL by quantitative reverse transcription-polymerase chain reaction. All of these effects were inhibited by treatment with either a Ron-neutralizing antibody or a MEK1 inhibitor, suggesting the specificity of the effect to Ron, and the involvement of the MAPK 1/2 signaling pathway. In summary, these results illustrate a novel connection between the Ron receptor tyrosine kinase and an important mechanism of tamoxifen resistance in breast cancer.

Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution.

CONTEXT: Serotonin [5-hydroxytryptamine (5-HT)] is an important local regulator of lactation homeostasis; however, the roles for the serotonin reuptake transporter and monoamine oxidase have not been known. OBJECTIVE: The aim of the study was to determine whether drugs that impact 5-HT affect human lactation physiology. DESIGN AND SETTING: We conducted laboratory studies of human and animal models and an observational study of the onset of copious milk secretion in postpartum women at a university medical center. PARTICIPANTS: We studied women expecting their first live-born infant; exclusion criteria were: referred to the medical center for another medical condition, known contraindication to breastfeed, and less than 19 yr of age and unable to obtain parental consent. INTERVENTION(S): The mothers were interviewed. The cell and animal studies consisted of a variety of biochemical, pharmacological, and genetic interventions. MAIN OUTCOME MEASURE(S): The human subjects outcome was prevalence of delayed onset of copious milk secretion. The cell and animal outcomes were physiological and morphological. RESULTS: Inhibiting serotonin reuptake in mammary epithelial cells altered barrier function, and the effects were amplified by coadministering a monoamine oxidase inhibitor. Direct delivery of fluoxetine by slow-release pellets caused localized involution. TPH1 knockout mice displayed precocious secretory activation. Among a cohort of 431 women, those taking SSRI were more likely (P = 0.02) to experience delayed secretory activation. CONCLUSIONS: Medications that perturb serotonin balance dysregulate lactation, and the effects are consistent with those predicted by the physiological effects of intramammary 5-HT bioactivity. Mothers taking serotonergic drugs may need additional support to achieve their breastfeeding goals.

Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival.

INTRODUCTION: The breast microenvironment can either retard or accelerate the events associated with progression of latent cancers. However, the actions of local physiological mediators in the context of breast cancers are poorly understood. Serotonin (5-HT) is a critical local regulator of epithelial homeostasis in the breast and other organs. Herein, we report complex alterations in the intrinsic mammary gland serotonin system of human breast cancers. METHODS: Serotonin biosynthetic capacity was analyzed in human breast tumor tissue microarrays using immunohistochemistry for tryptophan hydroxylase 1 (TPH1). Serotonin receptors (5-HT1-7) were analyzed in human breast tumors using the Oncomine database. Serotonin receptor expression, signal transduction, and 5-HT effects on breast cancer cell phenotype were compared in non-transformed and transformed human breast cells. RESULTS: In the context of the normal mammary gland, 5-HT acts as a physiological regulator of lactation and involution, in part by favoring growth arrest and cell death. This tightly regulated 5-HT system is subverted in multiple ways in human breast cancers. Specifically, TPH1 expression undergoes a non-linear change during progression, with increased expression during malignant progression. Correspondingly, the tightly regulated pattern of 5-HT receptors becomes dysregulated in human breast cancer cells, resulting in both ectopic expression of some isoforms and suppression of others. The receptor expression change is accompanied by altered downstream signaling of 5-HT receptors in human breast cancer cells, resulting in resistance to 5-HT-induced apoptosis, and stimulated proliferation. CONCLUSIONS: Our data constitutes the first report of direct involvement of 5-HT in human breast cancer. Increased 5-HT biosynthetic capacity accompanied by multiple changes in 5-HT receptor expression and signaling favor malignant progression of human breast cancer cells (for example, stimulated proliferation, inappropriate cell survival). This occurs through uncoupling of serotonin from the homeostatic regulatory mechanisms of the normal mammary epithelium. The findings open a new avenue for identification of diagnostic and prognostic markers, and valuable new therapeutic targets for managing breast cancer.

In vitro multipotent differentiation and barrier function of a human mammary epithelium.

As demonstrated by a variety of animal studies, barrier function in the mammary epithelium is essential for a fully functioning and differentiated gland. However, there is a paucity of information on barrier function in human mammary epithelium. Here, we have established characteristics of a polarizing differentiating model of human mammary epithelial cells capable of forming a high-resistance/low-conductance barrier in a predictable manner, viz., by using MCF10A cells on permeable membranes. Inulin flux decreased and transepithelial electrical resistance (TEER) increased over the course of several days after seeding MCF10A cells on permeable membranes. MCF10A cells exhibited multipotent phenotypic differentiation into layers expressing basal and lumenal markers when placed on permeable membranes, with at least two distinct cell phenotypes. A clonal subline of MCF10A, generated by culturing stem-like cells under non-adherent conditions, also generated a barrier-forming epithelial membrane with cells expressing markers of both basal and lumenal differentiation (CD10 and MUC1, respectively). Progressive changes associated with differentiation, including wholesale inhibition of cell-cycle genes and stimulation of cell and tissue morphogenic genes, were observed by gene expression profiling. Clustering and gene ontology categorization of significantly altered genes revealed a pattern of lumenal epithelial-cell-specific differentiation.

Mammary gland homeostasis employs serotonergic regulation of epithelial tight junctions.

Homeostatic control of volume within the alveolar spaces of the mammary gland has been proposed to involve a feedback system mediated by serotonin signaling. In this article, we describe some of the mechanisms underlying this feedback based on studies of a human normal mammary epithelial cell line (MCF10A) and mouse mammary epithelium. Mammary serotonin was elevated during lactation and after injection of 5-hydroxytryptophan (5-HTP). The genes encoding the serotonin reuptake transporter (SERT) and the type 7 serotonin receptor (5-HT(7)) were expressed in human and mouse mammary epithelial cells, and serotonin caused a concentration-dependent increase of cAMP in MCF10A cells. Mouse and human mammary epithelial cells formed polarized membranes, in which tight junction activity was monitored. Treatment of mammary epithelial membranes with serotonin receptor antagonists increased their transepithelial electrical resistance (TEER). Antagonist and agonist effects on TEER were mediated by receptors on the basolateral face of the membranes. Our results suggest a process in which serotonin accumulates in the interstitial fluid surrounding the mammary secretory epithelium and is detected by 5-HT(7) receptors, whereupon milk secretion is inhibited. One mechanism responsible for this process is serotonin-mediated opening of tight junctions, which dissipates the transepithelial gradients necessary for milk secretion.