Filling the Core EPA 10 assessment void: A framework for individual assessment of Core Entrustable professional activity 10 competencies in medical students.

Objectives: The goal of this study was to develop and evaluate a novel curriculum and assessment tool for Core Entrustable Professional Activity (EPA) 10 competencies and entrustment scoring in a cohort of medical students in their emergency medicine (EM) clerkship using a framework of individualized, ad hoc, formative assessment. Core EPA 10 is an observable workplace-based activity for graduating medical students to recognize a patient requiring urgent or emergent care and initiate evaluation and management.

Methods: This is a prospective, pretest-posttest study of medical students during their EM clerkship.

Direct Evidence of Plasticity within Human Primary Motor and Somatosensory Cortices of Patients with Glioblastoma.

Glioblastoma multiforme (GBM) is a devastating disease without cure. It is also the most common primary brain tumor in adults. Although aggressive surgical resection is standard of care, these operations are limited by tumor infiltration of critical cortical and subcortical regions.

Plasticity of the Primary Motor Cortex in Patients with Primary Brain Tumors.

There are two neuron-level mechanisms proposed to underlie neural plasticity: recruiting neurons nearby to support the lost function (ipsilesional plasticity) and uncovering latent pathways that can assume the function that was lost (contralesional plasticity). While both patterns have been demonstrated in patient groups following injury, the specific mechanisms underlying each mode of plasticity are poorly understood. In a retrospective case series of 13 patients, we utilize a novel paradigm that analyzes serial fMRI scans in patients harboring intrinsic brain tumors that vary in location and growth kinetics to better understand the mechanisms underlying these two modes of plasticity in the human primary motor cortex.

Breast Cancer Resistance Protein (BCRP/) Inhibits Extra Villous Trophoblast Migration: The Impact of Bacterial and Viral Infection.

Extravillous trophoblasts (EVT) migration into the decidua is critical for establishing placental perfusion and when dysregulated, may lead to pre-eclampsia (PE) and intrauterine growth restriction (IUGR). The breast cancer resistance protein (BCRP; encoded by ) regulates the fusion of cytotrophoblasts into syncytiotrophoblasts and protects the fetus from maternally derived xenobiotics. Information about BCRP function in EVTs is limited, however placental exposure to bacterial/viral infection leads to BCRP downregulation in syncitiotrophoblasts.

Gestational age-dependent gene expression profiling of ATP-binding cassette transporters in the healthy human placenta.

The ATP-binding cassette (ABC) transporters control placental transfer of several nutrients, steroids, immunological factors, chemicals, and drugs at the maternal-fetal interface. We and others have demonstrated a gestational age-dependent expression pattern of two ABC transporters, P-glycoprotein and breast cancer resistance protein throughout pregnancy. However, no reports have comprehensively elucidated the expression pattern of all 50 ABC proteins, comparing first trimester and term human placentae.

Glucocorticoids modulate multidrug resistance transporters in the first trimester human placenta.

The placental multidrug transporters, P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP, ABCG2) protect the foetus from exposure to maternally derived glucocorticoids, toxins and xenobiotics. During pregnancy, maternal glucocorticoid levels can be elevated by stress or exogenous administration. We hypothesized that glucocorticoids modulate the expression of ABCB1/P-gp and ABCG2/BCRP in the first trimester human placenta.

Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta.

Background/aims: The ATP-binding cassette (ABC) transporters mediate drug biodisposition and immunological responses in the placental barrier. In vitro infective challenges alter expression of specific placental ABC transporters. We hypothesized that chorioamnionitis induces a distinct pattern of ABC transporter expression.

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier.

Background/aims: Viral infection during pregnancy is known to affect the fetal brain. The toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viruses known to elicit adverse fetal neurological outcomes. The P-glycoprotein (P-gp) efflux transporter protects the developing fetus by limiting the transfer of substrates across both the placenta and the fetal blood-brain barrier (BBB).

Astrocyte-mediated regulation of multidrug resistance p-glycoprotein in fetal and neonatal brain endothelial cells: age-dependent effects.

Brain endothelial cells (BECs) form a major component of the blood-brain barrier (BBB). In late gestation, these cells express high levels of the multidrug transporter p-glycoprotein (P-gp; encoded by Abcb1), which prevents the passage of an array of endogenous factors and xenobiotics into the fetal brain. P-gp levels in the BECs increase dramatically in late gestation, coincident with astrocyte differentiation.

Neuroplasticity: Insights from Patients Harboring Gliomas.

Neuroplasticity is the ability of the brain to reorganize itself during normal development and in response to illness. Recent advances in neuroimaging and direct cortical stimulation in human subjects have given neuroscientists a window into the timing and functional anatomy of brain networks underlying this dynamic process. This review will discuss the current knowledge about the mechanisms underlying neuroplasticity, with a particular emphasis on reorganization following CNS pathology.

Glucocorticoids modify effects of TGF-β1 on multidrug resistance in the fetal blood-brain barrier.

Transforming growth factor-β1 (TGF-β1) increases P-glycoprotein (P-gp; encoded by Abcb1) activity in fetal brain endothelial cells (BECs). P-gp is important for fetal brain protection against xenobiotics including synthetic glucocorticoids (sGC). We hypothesized that antenatal sGC would modify P-gp responsiveness to TGF-β1 in fetal BECs.

Impact of bacterial and viral challenge on multidrug resistance in first- and third-trimester human placenta.

The ABC transporters P-glycoprotein (P-gp, official gene symbol ABCB1) and breast cancer resistance protein (BCRP, official gene symbol ABCG2) protect the conceptus from exposure to toxins and xenobiotics present in the maternal circulation. Viral or bacterial challenges alter expression of placental multidrug transporters in rodents. We hypothesized that exposure to lipopolysaccharide (LPS, bacterial antigen) and polyinosinic-polycytidylic acid (poly(I:C), viral antigen) would decrease P-gp and BCRP in the human placenta.

TGF-β1 regulation of multidrug resistance P-glycoprotein in the developing male blood-brain barrier.

P-glycoprotein (P-gp), an efflux transporter encoded by the abcb1 gene, protects the developing fetal brain. Levels of P-gp in endothelial cells of the blood-brain barrier (BBB) increase dramatically during the period of peak brain growth. This is coincident with increased release of TGF-β1 by astrocytes and neurons.

Prenatal endotoxemia and placental drug transport in the mouse: placental size-specific effects.

Lipopolysaccharide (LPS) in high doses inhibits placental multidrug resistance P-glycoprotein (P-gp--Abcb1a/b) and breast cancer resistance protein (BCRP--Abcg2). This potentially impairs fetal protection against harmful factors in the maternal circulation. However, it is unknown whether LPS exposure, at doses that mimic sub-lethal clinical infection, alters placental multidrug resistance.

A colorectal cancer classification system that associates cellular phenotype and responses to therapy.

Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering.

Effects of sertraline and fluoxetine on p-glycoprotein at barrier sites: in vivo and in vitro approaches.

Background And Purpose: Retention of substances from systemic circulation in the brain and testes are limited due to high levels of P-glycoprotein (P-gp) in the luminal membranes of brain and testes capillary endothelial cells. From a clinical perspective, P-gp rapidly extrudes lipophilic therapeutic agents, which then fail to reach efficacious levels. Recent studies have demonstrated that acute administration of selective serotonin reuptake inhibitors (SSRI) can affect P-gp function, in vitro and in vivo.

Expression of Nuclear Receptor Coactivators in the Human Fetal Membranes at Term before and after Labor.

Human fetal membranes play an important role in term and preterm labor and are responsive to steroids. We examined the expression of steroid receptor coactivators in fetal membranes obtained prior to and following labor at term. Proteins were localized by immunohistochemistry, Western analysis was carried out in nuclear extracts, and mRNA levels were determined by real-time RT-PCR.

Pro-inflammatory cytokine regulation of P-glycoprotein in the developing blood-brain barrier.

Placental P-glycoprotein (P-gp) acts to protect the developing fetus from exogenous compounds. This protection declines with advancing gestation leaving the fetus and fetal brain vulnerable to these compounds and potential teratogens in maternal circulation. This vulnerability may be more pronounced in pregnancies complicated by infection, which is common during pregnancy.

Sertraline alters multidrug resistance phosphoglycoprotein activity in the mouse placenta and fetal blood-brain barrier.

Phosphoglycoprotein (P-gp) is highly expressed in the placental syncytiotrophoblast and prevents xenobiotics from entering the fetus. In tumor cells, P-gp-mediated substrate efflux is inhibited by selective serotonin reuptake inhibitors (SSRIs). However, nothing is known regarding the effects of SSRIs on P-gp function in the placenta or fetal tissues.

Subtype and pathway specific responses to anticancer compounds in breast cancer.

Breast cancers are comprised of molecularly distinct subtypes that may respond differently to pathway-targeted therapies now under development. Collections of breast cancer cell lines mirror many of the molecular subtypes and pathways found in tumors, suggesting that treatment of cell lines with candidate therapeutic compounds can guide identification of associations between molecular subtypes, pathways, and drug response. In a test of 77 therapeutic compounds, nearly all drugs showed differential responses across these cell lines, and approximately one third showed subtype-, pathway-, and/or genomic aberration-specific responses.

An observational study of associations among maternal fluids during parturition, neonatal output, and breastfed newborn weight loss.

Background: Newborn weight measurements are used as a key indicator of breastfeeding adequacy. The purpose of this study was to explore non-feeding factors that might be related to newborn weight loss. The relationship between the intravenous fluids women receive during parturition (the act of giving birth, including time in labour or prior to a caesarean section) and their newborn's weight loss during the first 72 hours postpartum was the primary interest.

A cross-species analysis of a mouse model of breast cancer-specific osteolysis and human bone metastases using gene expression profiling.

Background: Breast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients suffer from bone metastasis. These metastases are predominantly osteolytic and develop when tumor cells interact with bone.

Glucocorticoid regulation of placental breast cancer resistance protein (Bcrp1) in the mouse.

Placental breast cancer resistance protein (Bcrp1; encoded by the Abcg2 gene) limits maternal-fetal transplacental transfer of numerous endogenous and exogenous substrates; however, the regulation of placental Abcg2 and Bcrp1 and is not well understood. Placental Abcg2 messenger RNA (mRNA) levels decrease with advancing gestation in the mouse, and this corresponds to increasing levels of maternal and fetal plasma glucocorticoid. Glucocorticoids, including dexamethasone (DEX), downregulate Bcrp1 expression and function in both breast cancer cell lines and the blood-brain barrier in vitro; whether this occurs in the placenta is not known.

Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond.