Personal Preparation of Medical Students for the Human Dissection Experience: A Systematic Review.

Anatomical dissection is a cause of distress for many medical students. Explicit pedagogical strategies are important in reducing student distress and supporting their personal development. A systematic review of PubMed, Ovid, PsycINFO, and Web of Science databases was conducted to examine quantitative data regarding medical school interventions to reduce the negative psychological and moral impact of anatomical dissection on medical students. Of 1189 unique abstracts, 14 papers met screening criteria. Student distress decreased with the use of educational audiovisual materials and graded exposure to donor bodies. Educational lectures, memorial ceremonies, and utilization of background music had mixed results.

IGF-dependent dynamic modulation of a protease cleavage site in the intrinsically disordered linker domain of human IGFBP2.

Functional regulation via conformational dynamics is well known in structured proteins but less well characterized in intrinsically disordered proteins and their complexes. Using NMR spectroscopy, we have identified a dynamic regulatory mechanism in the human insulin-like growth factor (IGF) system involving the central, intrinsically disordered linker domain of human IGF-binding protein-2 (hIGFBP2). The bioavailability of IGFs is regulated by the proteolysis of IGF-binding proteins. In the case of hIGFBP2, the linker domain (L-hIGFBP2) retains its intrinsic disorder upon binding IGF-1, but its dynamics are significantly altered, both in the IGF binding region and distantly located protease cleavage sites. The increase in flexibility of the linker domain upon IGF-1 binding may explain the IGF-dependent modulation of proteolysis of IGFBP2 in this domain. As IGF homeostasis is important for cell growth and function, and its dysregulation is a key contributor to several cancers, our findings open up new avenues for the design of IGFBP analogs inhibiting IGF-dependent tumors.

An assessment of racial differences in epidemiological, clinical and psychosocial factors among head and neck cancer patients at the time of surgery.

OBJECTIVE: Racial disparities have been well characterized and African American (AA) patients have 30% lower 5-year survival rates than European Americans (EAs) for head and neck squamous carcinoma (HNSCC). This poorer survival can be attributed to a myriad of different factors. The purpose of this study was to characterize AA-EA similarities and differences in sociodemographic, lifestyle, clinical, and psychosocial characteristics in HNSCC patients near the time of surgery. METHODS: Setting: Single tertiary care center. Participants: Thirty-nine newly diagnosed, untreated HNSCC patients (n = 24 EAs,n = 15 AAs) who were to undergo surgery were recruited. Study Design: Cross-sectional study Sociodemographic, lifestyle factors, and disease factors (cancer site, AJCC clinical and pathologic stage, and HPV status)were assessed. Risk factors, leisure time, quality of life and social support were also assessed using validated questionnaires. Exposures: EA and AA patients were similar in the majority of sociodemographic factors assessed. AAs had a higher trend toward pathologically later stage disease compared to EAs and significantly increased time to treatment. RESULTS: EA and AA patients were similar in the majority of sociodemographic factors assessed. AAs had a higher trend toward pathologically later stage disease compared to EAs. AAs also had significantly increased time to treatment (P = 0.05). The majority of AA patients (62%) had later stage pathologic disease. AA were less likely to complete high school or college (P = 0.01) than their EA counterparts. Additionally, AAs were more likely to report having a gap in health insurance during the past decade (37% vs. 15%). CONCLUSIONS: This preliminary study demonstrates a similar profile of demographics, clinical and psychosocial characteristics preoperatively for AAs and EAs. Key differences were AAs tending to have later pathologic stage disease, educational status, delays in treatment initiation, and gaps in health insurance.

The Continuing Evolution of Insulin-like Growth Factor Signaling.

The insulin-like growth factors (IGFs; IGF1/IGF2), known for their regulation of cell and organismal growth and development, are evolutionarily conserved ligands with equivalent peptides present in flies ( D. melanogaster), worms ( C. elegans) among others. Two receptor tyrosine kinases, the IGF1 receptor and the insulin receptor mediate the actions of these ligands with a family of IGF binding proteins serving as selective inhibitors of IGF1/2. This treatise reviews recent findings on IGF signaling in cancer biology and central nervous system function. This includes overexpression of IGF1 receptors in enhancing tumorigenesis, acquired resistance and contributions to metastasis in multiple cancer types. There is accumulating evidence that insulin resistance, a hallmark of type 2 diabetes, occurs in the central nervous system, independent of systemic insulin resistance and characterized by reduced insulin and IGF1 receptor signaling, and may contribute to dementias including Alzheimer's Disease and cognitive impairment. Controversy over the role(s) of IGF signaling in cancer and whether its inhibition would be of benefit, still persist and extend to IGF1's role in longevity and central nervous system function.

The peroxidase PRDX1 inhibits the activated phenotype in mammary fibroblasts through regulating c-Jun N-terminal kinases.

BACKGROUND: Reactive oxygen species (ROS), including hydrogen peroxide, drive differentiation of normal fibroblasts into activated fibroblasts, which can generate high amounts of hydrogen peroxide themselves, thereby increasing oxidative stress in the microenvironment. This way, activated fibroblasts can transition into cancer-associated fibroblasts (CAFs). METHODS: Mammary fibroblasts from either female 8 weeks old PRDX1 knockout and wildtype mice or Balb/c mice were studied for characteristic protein expression using immunofluorescence and immunoblotting. Cancer-associated fibroblasts was examined by transwell migration and invasion assays. The binding of PRDX1 to JNK1 was assessed by co-immuneprecipitation and JNK regulation of CAF phenotypes was examined using the JNK inhibitor SP600125. Extracellular hydrogen peroxide levels were measured by chemiluminescence via the reaction between hypochlorite and luminol. Statistical analyses were done using Students t-test. RESULTS: We show here PRDX1 activity as an essential switch in regulating the activated phenotype as loss of PRDX1 results in the development of a CAF-like phenotype in mammary fibroblasts. We also show that PRDX1 regulates JNK kinase signaling thereby inhibiting CAF-like markers and CAF invasion. Inhibition of JNK activity reduced these behaviors. CONCLUSIONS: These data suggest that PRDX1 repressed the activated phenotype of fibroblasts in part through JNK inhibition which may present a novel therapeutic option for CAF-enriched cancers such as breast cancer.

Vimentin and Non-Muscle Myosin IIA are Members of the Neural Precursor Cell Expressed Developmentally Down-Regulated 9 (NEDD9) Interactome in Head and Neck Squamous Cell Carcinoma Cells.

Here we demonstrate an interaction between neural precursor cell expressed, developmentally-downregulated 9 (NEDD9) and the cytoskeletal proteins vimentin and non-muscle myosin IIA (NMIIA), based on co-immunoprecipitation and mass spectrometric sequence identification. Vimentin was constitutively phosphorylated at Ser56 but vimentin associated with NEDD9-was not phosphorylated at Ser56. In contrast, NMIIA bound to NEDD9 was phosphorylated on S1943 consistent with its function in invasion and secretion. Treatment of cells with the vimentin-targeting steroidal lactone withaferin A had no effect on vimentin turnover as previously reported, instead causing NEDD9 cleavage and cell death. The NMIIA-selective inhibitor blebbistatin induced cells to form long extensions and attenuated secretion of matrix metalloproteinases (MMPs) 2 and 9. While the site of vimentin interaction on NEDD9 was not defined, NMIIA was found to interact with NEDD9 at its substrate domain. NEDD9 interactions with vimentin and NMIIA are consistent with these proteins having roles in MMP secretion and cell invasion. These findings suggest that a better understanding of NEDD9 signaling is likely to reveal novel therapeutic targets for the prevention of invasion and metastasis.

An ultra-stable redox-controlled self-assembling polypeptide nanotube for targeted imaging and therapy in cancer.

We introduce a self-assembling polypeptide-based nanotube system having the ability to specifically target cancer cells. The nanotubes target the cancer cell surface through integrin engagement with the help of multiple RGD units present along their surface. While the nanotubes are non-toxic towards cells in general, they can be loaded with suitable drugs to be released in a sustained manner in cancer cells. In addition, the nanotubes can be utilized for cellular imaging using any covalently tagged fluorescent dye. They are stable over a wide range of temperature due to intermolecular disulphide bonds formed during the self-assembly process. At the same time, presence of disulphide bonds provides a redox molecular switch for their degradation. Taken together this system provides a unique avenue for multimodal formulation in cancer therapy.

Climate Change Impacts on Yields and Soil Carbon in Row Crop Dryland Agriculture.

Dryland agroecosystems could be a sizable sink for atmospheric carbon (C) due to their spatial extent and level of degradation, providing climate change mitigation. We examined productivity and soil C dynamics under two climate change scenarios (moderate warming, representative concentration pathway [RCP] 4.5; and high warming, RCP 8.5), using long-term experimental data and the DayCent process-based model for three sites with varying climates and soil conditions in the US High Plains. Each site included a no-till cropping intensity gradient introduced in 1985, with treatments ranging from wheat-fallow ( L.) to continuous annual cropping and perennial grass. Simulations were extended to 2100 using data from 16 global circulation models to estimate uncertainty. Simulated yields declined for all crops (up to 50% for wheat), with small changes after 2050 under RCP 4.5 and continued losses to 2100 under RCP 8.5. Of the cropped systems, continuous cropping had the highest average productivity and soil C sequestration rates (78.1 kg C ha yr from 2015 to 2045 under RCP 4.5). Any increase in soil C for cropped rotations was realized by 2050, but grassland treatments increased soil C (up to 69%) through 2100, even under RCP 8.5. Our simulations indicate that reduced frequency of summer fallow can both increase annualized yields and store more soil C. As evapotranspiration is likely to increase, reducing fallow periods without live vegetation from dryland agricultural rotations may enhance the resilience of these systems to climate change while also increasing soil C storage and mitigating carbon dioxide emissions.

NEDD9 stimulated MMP9 secretion is required for invadopodia formation in oral squamous cell carcinoma.

Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a component of the metastatic signatures of melanoma, breast cancer, glioblastoma, lung cancer and head and neck squamous cell carcinoma (HNSCC). Here we tested the efficacy of NEDD9's domains in stimulating matrix metalloproteinase (MMP) secretion and invadopodia formation in cells stably expressing various NEDD9 mutants. Replacement of the 13 YxxP motif substrate domain (SD) tyrosines and the C-terminal Y629 with phenylalanines (F14NEDD9) eliminated tyrosine phosphorylation, MMP9 secretion and loss of invadopodia formation. Mutation of the N-terminal SH3 domain Y12 to glutamic acid (Y12ENEDD9) or phenylalanine (Y12FNEDD9) reduced MMP9 secretion and inhibited invadopodia formation. SH3 domain deletion (∆SH3NEDD9) resulted in the loss of MMP9 secretion and a lack of invadopodia formation. The SH3-SD domain (SSNEDD9) construct exhibited tyrosine phosphorylation and stimulated MMP9 secretion, as did ∆CTNEDD9 which lacked the C-terminus (∆C-terminal; ∆CT). E13NEDD9 expression blocked MMP9 secretion and invadopodia formation. MICAL1 (molecule interacting with Cas-L1) silencing with a short hairpin RNA reduced MMP9 secretion, vimentin and E-cadherin levels while increasing N-cadherin and Rab6 levels, consistent with reduced invasive behavior. These findings indicate that NEDD9 SD phosphorylation and SH3 domain interactions are necessary for increasing MMP9 secretion and invadopodia formation.

Acquired Resistance to Drugs Targeting Tyrosine Kinases.

Resistance to chemotherapeutic drugs exemplifies the greatest hindrance to effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over 50 years and have revealed the lack of a single cause, but instead, multiple mechanisms including induced expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system, and altered metabolism. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered. Chemotherapeutic agent resistance was initially assumed to be due to induction of mutations leading to a resistant phenotype. While this has occurred for molecularly targeted drugs, it is clear that drugs selectively targeting tyrosine kinases (TKs) cause the acquisition of mutational changes and resistance to inhibition. The first TK to be targeted, Bcr-Abl, led to the generation of several drugs including imatinib, dasatinib, and sunitinib that provided a rich understanding of this phenomenon. It became clear that mutations alone were not the only cause of resistance. Additional mechanisms were involved, including alternative splicing, alternative/compensatory signaling pathways, and epigenetic changes. This review will focus on resistance to tyrosine kinase inhibitors (TKIs), receptor TK (RTK)-directed antibodies, and antibodies that inactivate specific RTK ligands. New approaches and concepts aimed at avoiding the generation of drug resistance will be examined. Many RTKs, including the IGF-1R, are dependence receptors that induce ligand-independent apoptosis. How this signaling paradigm has implications on therapeutic strategies will also be considered.

The tumor suppressor capability of p53 is dependent on non-muscle myosin IIA function in head and neck cancer.

Over 300,000 patients develop squamous cell carcinoma of the head and neck (HNSCC) worldwide with 25-30% of patients ultimately dying from their disease. Currently, molecular biomarkers are not used in HNSCC but several genes have been identified including mutant TP53 (mutp53). Our recent work has identified an approach to stratify patients with tumors harboring high or low risk TP53 mutations. Non-muscle Myosin IIA (NMIIA) was recently identified as a tumor suppressor in HNSCC. We now demonstrate that low MYH9 expression is associated with decreased survival in patients with head and neck cancer harboring low-risk mutp53 but not high-risk mutp53. Furthermore, inhibition of NMIIA leads to increased invasion in cells harboring wildtype p53 (wtp53), which was not observed in high-risk mutp53 cells. This increased invasiveness of wtp53 following NMIIA inhibition was associated with reduced p53 target gene expression and was absent in cells expressing mutp53. This reduced expression may be due, in part, to a decrease in nuclear localization of wtp53. These findings suggest that the tumor suppressor capability of wtp53 is dependent upon functional NMIIA and that the invasive phenotype of high-risk mutp53 is independent of NMIIA.

How Do Medical Schools Identify and Remediate Professionalism Lapses in Medical Students? A Study of U.S. and Canadian Medical Schools.

PURPOSE: Teaching and assessing professionalism is an essential element of medical education, mandated by accrediting bodies. Responding to a call for comprehensive research on remediation of student professionalism lapses, the authors explored current medical school policies and practices. METHOD: In 2012-2013, key administrators at U.S. and Canadian medical schools accredited by the Liaison Committee on Medical Education were interviewed via telephone or e-mail. The structured interview questionnaire contained open-ended and closed questions about practices for monitoring student professionalism, strategies for remediating lapses, and strengths and limitations of current systems. The authors employed a mixed-methods approach, using descriptive statistics and qualitative analysis based on grounded theory. RESULTS: Ninety-three (60.8%) of 153 eligible schools participated. Most (74/93; 79.6%) had specific policies and processes regarding professionalism lapses. Student affairs deans and course/clerkship directors were typically responsible for remediation oversight. Approaches for identifying lapses included incident-based reporting and routine student evaluations. The most common remediation strategies reported by schools that had remediated lapses were mandated mental health evaluation (74/90; 82.2%), remediation assignments (66/90; 73.3%), and professionalism mentoring (66/90; 73.3%). System strengths included catching minor offenses early, emphasizing professionalism schoolwide, focusing on helping rather than punishing students, and assuring transparency and good communication. System weaknesses included reluctance to report (by students and faculty), lack of faculty training, unclear policies, and ineffective remediation. In addition, considerable variability in feedforward processes existed between schools. CONCLUSIONS: The identified strengths can be used in developing best practices until studies of the strategies' effectiveness are conducted.

Preserving third year medical students' empathy and enhancing self-reflection using small group "virtual hangout" technology.

BACKGROUND: Medical student professionalism education is challenging in scope, purpose, and delivery, particularly in the clinical years when students in large universities are dispersed across multiple clinical sites. We initiated a faculty-facilitated, peer small group course for our third year students, creating virtual classrooms using social networking and online learning management system technologies. The course emphasized narrative self-reflection, group inquiry, and peer support. METHODS: We conducted this study to analyze the effects of a professionalism course on third year medical students' empathy and self-reflection (two elements of professionalism) and their perceptions about the course. Students completed the Groningen Reflection Ability Scale (GRAS) and the Jefferson Scale of Empathy (JSE) before and after the course and provided anonymous online feedback. RESULTS: The results of the JSE before and after the course demonstrated preservation of empathy rather than its decline. In addition, there was a statistically significant increase in GRAS scores (p < 0.001), suggesting that the sharing of personal narratives may foster reflective ability and reflective practice among third year students. CONCLUSION: This study supports previous findings showing that students benefit from peer groups and discussion in a safe environment, which may include the use of a virtual group video platform.

Residents' and standardized patients' perspectives on empathy: issues of agreement.

OBJECTIVE: We investigated correlations between residents' scores on the Jefferson Scale of Empathy (JSE), residents' perceptions of their empathy during standardized-patient encounters, and the perceptions of standardized patients. METHODS: Participants were 214 first-year residents in internal medicine or family medicine from 13 residency programs taking standardized patient-based clinical skills assessment in 2011. We analyzed correlations between residents' JSE scores; standardized patients' perspectives on residents' empathy during OSCE encounters, using the Jefferson Scale of Patient Perceptions of Physician Empathy; and residents' perspectives on their own empathy, using a modified version of this scale. RESULTS: Residents' JSE scores correlated with their perceptions of their own empathy during encounters but correlated poorly with patients' assessments of resident empathy. CONCLUSION: The poor correlation between residents' and standardized patients' assessments of residents' empathy raises questions about residents' abilities to gauge the effectiveness of their empathic communications. The study also points to a lack of congruence between the assessment of empathy by standardized patients and residents as receivers and conveyors of empathy, respectively. PRACTICE IMPLICATIONS: This study adds to the literature on empathy as a teachable skill set and raises questions about use of OSCEs to assess trainee empathy.

Role of oxidative stress and the microenvironment in breast cancer development and progression.

Breast cancer is a highly complex tissue composed of neoplastic and stromal cells. Carcinoma-associated fibroblasts (CAFs) are commonly found in the cancer stroma, where they promote tumor growth and enhance vascularity in the microenvironment. Upon exposure to oxidative stress, fibroblasts undergo activation to become myofibroblasts. These cells are highly mobile and contractile and often express numerous mesenchymal markers. CAF activation is irreversible, making them incapable of being removed by nemosis. In breast cancer, almost 80% of stromal fibroblasts acquire an activated phenotype that manifests by secretion of elevated levels of growth factors, cytokines, and metalloproteinases. They also produce hydrogen peroxide, which induces the generation of subsequent sets of activated fibroblasts and tumorigenic alterations in epithelial cells. While under oxidative stress, the tumor stroma releases high energy nutrients that fuel cancer cells and facilitate their growth and survival. This review describes how breast cancer progression is dependent upon oxidative stress activated stroma and proposes potential new therapeutic avenues.