Investigating Gender Disparities in Internal Medicine Residency Awards

Background: Significant gender disparities persist in career advancement for physicians. Studies have highlighted the lack of female representation in awards from both academic institutions and professional societies; these awards play a role in promotions, making them a fundamental building block of success. Objectives: We aim to explore the gender breakdown among resident awards presented by several Internal Medicine residency programs across the United States in this pilot study. Our ultimate goals are to define disparities in award selection, determine what variables contribute to these disparities, and work to mitigate these variables. Methods/Research: We generated a survey in REDCap to collect retrospective data about resident award selection from academic Internal Medicine residency programs across the country. This survey gathered awards data from 2009-2019 and included variables such as gender breakdown of the program, gender of resident award recipients, and details about how awards are selected. Eight programs completed the survey; these programs were from six different states in various geographic regions. Overall 43.1 percent of residents were female. Across all residency programs and years, there were 51 distinct resident awards with 290 (39.7%) female winners. Of the 51 distinct awards, there were 10 which were awarded to female residents with the same or higher frequency as males; 6 of these mentioned words that have been differentially associated with women in medicine such as “ambulatory,” “community,” “compassion,” and “humanism.” In the 41 awards favoring males, there was only a single mention of the word “compassion,” and no mention of the others. Conclusions/Impact: This data shows a concerning disparity in gender of award winners. In the future we will collect data from more residency programs and perform a thorough investigation of selection mechanisms that may help mitigate bias in order to ultimately propose strategies to reduce these gender disparities.https://jdc.jefferson.edu/sexandgenderhealth/1007/thumbnail.jp

Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight

There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10-7. Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR. Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This study was supported by grant no. HD073978 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, and National Institute of Neurological Disorders and Stroke; and by the Beatrice and Samuel A. Seaver Foundation. The iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) team acknowledges funding from The Lundbeck Foundation (grant no. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (project no: 294838), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. This research has been conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation. J.M. and E.H. are supported by funding from the UK Medical Research Council (K013807).published version, accepted version, submitted versio

Silencing of IQGAP1 by shRNA inhibits the invasion of ovarian carcinoma HO-8910PM cells in vitro

<p>Abstract</p> <p>Background</p> <p>IQGAP1 is a scaffolding protein and overexpressed in many human tumors, including ovarian cancer. However, the contribution of IQGAP1 to invasive properties of ovarian cancer cells remains unknown. Here, we investigated the effect of IQGAP1-specific short hairpin RNA (shRNA) expressing plasmids on metastatic potential of ovarian cancer HO-8910PM cells.</p> <p>Methods</p> <p>We used RT-PCR and Western blot analysis to characterize expression of IQGAP1 in three human ovarian cancer-derived cell lines SK-OV-3, HO-8910 and HO-8910PM. We then determined whether expression of endogenous IQGAP1 correlated with invasive and migratory ability by using an in vitro Matrigel assay and cell migration assay. We further knocked down IQGAP1 using shRNA expressing plasmids controlled by U1 promoter in HO-8910PM cells and examined the proliferation activity, invasive and migration potential of IQGAP1 shRNA transfectants using MTT assay, in vitro Matrigel-coated invasion assay and migration assay.</p> <p>Results</p> <p>IQGAP1 expression level seemed to be closely associated with the enhanced invasion and migration in ovarian cancer cell lines. Levels of both IQGAP1 mRNA and protein were significantly reduced in HO-8910PM cells transfected with plasmid-based IQGAP1-specific shRNAs. RNAi-mediated knockdown of IQGAP1 expression in HO-8910PM cells resulted in a significant decrease in cell invasion and migration.</p> <p>Conclusion</p> <p>Our findings support the hypothesis that IQGAP1 promotes tumor progression and identify IQGAP1 as a potential therapeutic strategy for ovarian cancer and some other tumors with over-expression of the IQGAP1 gene.</p

Dissecting mitosis by RNAi in Drosophila tissue culture cells

Here we describe a detailed methodology to study the function of genes whose products function during mitosis by dsRNA-mediated interference (RNAi) in cultured cells of Drosophila melanogaster. This procedure is particularly useful for the analysis of genes for which genetic mutations are not available or for the dissection of complicated phenotypes derived from the analysis of such mutants. With the advent of whole genome sequencing it is expected that RNAi-based screenings will be one method of choice for the identification and study of novel genes involved in particular cellular processes. In this paper we focused particularly on the procedures for the proper phenotypic analysis of cells after RNAi-mediated depletion of proteins required for mitosis, the process by which the genetic information is segregated equally between daughter cells. We use RNAi of the microtubule-associated protein MAST/Orbit as an example for the usefulness of the technique

Prolonged Mechanical Ventilation Induces Cell Cycle Arrest in Newborn Rat Lung

Rationale: The molecular mechanism(s) by which mechanical ventilation disrupts alveolar development, a hallmark of bronchopulmonary dysplasia, is unknown. Objective: To determine the effect of 24 h of mechanical ventilation on lung cell cycle regulators, cell proliferation and alveolar formation in newborn rats. Methods: Seven-day old rats were ventilated with room air for 8, 12 and 24 h using relatively moderate tidal volumes (8.5 mL.kg-1). Measurement and Main Results: Ventilation for 24 h (h) decreased the number of elastin-positive secondary crests and increased the mean linear intercept, indicating arrest of alveolar development. Proliferation (assessed by BrdU incorporation) was halved after 12 h of ventilation and completely arrested after 24 h. Cyclin D1 and E1 mRNA and protein levels were decreased after 8-24 h of ventilation, while that of p27Kip1 was significantly increased. Mechanical ventilation for 24 h also increased levels of p57Kip2, decreased that of p16INK4a, while the levels of p21Waf/Cip1 and p15INK4b were unchanged. Increased p27Ki

Intracranial Administration of P Gene siRNA Protects Mice from Lethal Chandipura Virus Encephalitis

Background: In parts of India, Chandipura Virus (CHPV) has emerged as an encephalitis causing pathogen in both epidemic and sporadic forms. This pediatric disease follows rapid course leading to 55–75 % mortality. In the absence of specific treatment, effectiveness of RNA interference (RNAi) was evaluated. Methods and Findings: Efficacy of synthetic short interfering RNA (siRNA) or short hairpin RNA (shRNA) in protecting mice from CHPV infection was assessed. The target genes were P and M genes primarily because important role of the former in viral replication and lethal nature of the latter. Real time one step RT-PCR and plaque assay were used for the assessment of gene silencing. Using pAcGFP1N1-CHPV-P, we showed that P-2 siRNA was most efficient in reducing the expression of P gene in-vitro. Both quantitative assays documented 2logs reduction in the virus titer when P-2, M-5 or M-6 siRNAs were transfected 2hr post infection (PI). Use of these siRNAs in combination did not result in enhanced efficiency. P-2 siRNA was found to tolerate four mismatches in the center. As compared to five different shRNAs, P-2 siRNA was most effective in inhibiting CHPV replication. An extended survival was noted when mice infected intracranially with 100 LD 50 CHPV were treated with cationic lipid complexed 5 mg P-2 siRNA simultaneously. Infection with 10LD 50 and treatment with two doses of siRNA first, simultaneously and second 24 hr PI, resulted in 70 % survival. Surviving mice showed 4logs less CHPV titers in brain without histopathological changes or antibody response. Gene expression profiles of P-2 siRNA treated mice showed no interferon response. First dose of siRNA at 2h

Integrin β1 is required for the invasive behaviour but not proliferation of squamous cell carcinoma cells in vivo

Integrin β1 is both overexpressed and in an ‘active' conformation in vulval squamous cell carcinomas (VSCCs) compared to matched normal skin. To investigate the significance of integrin β1 deregulation we stably knocked-down integrin β1 expression in the VSCC cell line A431. In vitro analysis revealed that integrin β1 is required for cell adhesion, cell spreading and invasion. However, integrin β1 is not required for cell growth or activation of FAK and ERK signalling in vitro or in vivo. Strikingly, while control tumours were able to invade the dermis, integrin β1 knockdown tumours were significantly more encapsulated and less invasive

HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells

INTRODUCTION: Amplification of the HER-2 receptor tyrosine kinase has been implicated in the pathogenesis and aggressive behavior of approximately 25% of invasive human breast cancers. Clinical and experimental evidence suggest that aberrant HER-2 signaling contributes to tumor initiation and disease progression. Transforming growth factor beta (TGF-β) is the dominant factor opposing growth stimulatory factors and early oncogene activation in many tissues, including the mammary gland. Thus, to better understand the mechanisms by which HER-2 overexpression promotes the early stages of breast cancer, we directly assayed the cellular and molecular effects of TGF-β1 on breast cancer cells in the presence or absence of overexpressed HER-2. METHODS: Cell proliferation assays were used to determine the effect of TGF-β on the growth of breast cancer cells with normal or high level expression of HER-2. Affymetrix microarrays combined with Northern and western blot analysis were used to monitor the transcriptional responses to exogenous TGF-β1 in luminal and mesenchymal-like breast cancer cells. The activity of the core TGF-β signaling pathway was assessed using TGF-β1 binding assays, phospho-specific Smad antibodies, immunofluorescent staining of Smad and Smad DNA binding assays. RESULTS: We demonstrate that cells engineered to over-express HER-2 are resistant to the anti-proliferative effect of TGF-β1. HER-2 overexpression profoundly diminishes the transcriptional responses induced by TGF-β in the luminal MCF-7 breast cancer cell line and prevents target gene induction by a novel mechanism that does not involve the abrogation of Smad nuclear accumulation, DNA binding or changes in c-myc repression. Conversely, HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-β induced pro-invasive and pro-metastatic gene signature. CONCLUSION: HER-2 overexpression promotes the growth and malignancy of mammary epithelial cells, in part, by conferring resistance to the growth inhibitory effects of TGF-β. In contrast, HER-2 and TGF-β signaling pathways can cooperate to promote especially aggressive disease behavior in the context of a highly invasive breast tumor model

Sequencing of Pooled DNA Samples (Pool-Seq) Uncovers Complex Dynamics of Transposable Element Insertions in Drosophila melanogaster

Transposable elements (TEs) are mobile genetic elements that parasitize genomes by semi-autonomously increasing their own copy number within the host genome. While TEs are important for genome evolution, appropriate methods for performing unbiased genome-wide surveys of TE variation in natural populations have been lacking. Here, we describe a novel and cost-effective approach for estimating population frequencies of TE insertions using paired-end Illumina reads from a pooled population sample. Importantly, the method treats insertions present in and absent from the reference genome identically, allowing unbiased TE population frequency estimates. We apply this method to data from a natural Drosophila melanogaster population from Portugal. Consistent with previous reports, we show that low recombining genomic regions harbor more TE insertions and maintain insertions at higher frequencies than do high recombining regions. We conservatively estimate that there are almost twice as many “novel” TE insertion sites as sites known from the reference sequence in our population sample (6,824 novel versus 3,639 reference sites, with on average a 31-fold coverage per insertion site). Different families of transposable elements show large differences in their insertion densities and population frequencies. Our analyses suggest that the history of TE activity significantly contributes to this pattern, with recently active families segregating at lower frequencies than those active in the more distant past. Finally, using our high-resolution TE abundance measurements, we identified 13 candidate positively selected TE insertions based on their high population frequencies and on low Tajima's D values in their neighborhoods

The Great American Crime Decline : Possible Explanations

This chapter examines the most important features of the crime decline in the United States during the 1990s-2010s but also takes a broader look at the violence declines of the last three centuries. The author argues that violent and property crime trends might have diverged in the 1990s, with property crimes increasingly happening in the online sphere and thus traditional property crime statistics not being reflective of the full picture. An important distinction is made between ‘contact crimes’ and crimes that do not require a victim and offender to be present in the same physical space. Contrary to the uncertainties engendered by property crime, the declines in violent (‘contact’) crime are rather general, and have been happening not only across all demographic and geographic categories within the United States but also throughout the developed world. An analysis of research literature on crime trends has identified twenty-four different explanations for the crime drop. Each one of them is briefly outlined and examined in terms of conceptual clarity and empirical support. Nine crime decline explanations are highlighted as the most promising ones. The majority of these promising explanations, being relative newcomers in the crime trends literature, have not been subjected to sufficient empirical scrutiny yet, and thus require further research. One potentially fruitful avenue for future studies is to examine the association of the most promising crime decline explanations with improvements in self-control