Identification of up- and down-regulated proteins in doxorubicin-resistant uterine cancer cells: reticulocalbin-1 plays a key role in the development of doxorubicin-associated resistance.

Drug resistance is a frequent cause of failure in cancer chemotherapy treatments. In this study, a pair of uterine sarcoma cancer lines, MES-SA, and doxorubicin-resistant partners, MES-SA/DxR-2μM cells and MES-SA/DxR-8μM cells, as a model system to investigate resistance-dependent proteome alterations and to identify potential therapeutic targets. We used two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to perform this research and the results revealed that doxorubicin-resistance altered the expression of 208 proteins in which 129 identified proteins showed dose-dependent manners in response to the levels of resistance.

Recent Developments in Molecular Simulation Approaches to Study Spherical Virus Capsids.

Viruses are a particularly challenging systems to study via molecular simulation methods. Virus capsids typically consist of over 100 subunit proteins and reach dimensions of over 100 nm; solvated viruses capsid systems can be over 1 million atoms in size. In this review, I will present recent developments which have attempted to overcome the significant computational expense to perform simulations which can inform experimental studies, make useful predictions about biological phenomena and calculate material properties relevant to nanotechnology design efforts.

Evaluating the Health "Hubs and Spokes" interprofessional placements in rural New South Wales, Australia.

Unlabelled: Australia has been relatively slow in adopting interprofessional learning (IPL) to prepare health professional students for future collaborative professional practice. A collaborative project between two universities placed senior health professional students in IPL teams in rural southeast New South Wales, Australia, to work on small, locally relevant projects with guidance from locally appointed IPL facilitators. This paper reports on the initial stages of an evaluation of this rural-based IPL intervention using the modified Freeth/Kirkpatrick's 4-level evaluation model.

Prevalence of ear disease in dogs undergoing multidetector thin-slice computed tomography of the head.

Previous reports describing the prevalence of ear diseases in dogs have primarily been based on dogs presenting with clinical signs of disease. The prevalence of subclinical ear disease remains unknown. The purpose of this cross-sectional retrospective study was to describe the prevalence of lesions consistent with middle and external ear disease in dogs presented for multidetector computed tomography (CT) of the head and/or cranial cervical spine at our hospital during the period of July 2011 and August 2013.

Adverse skin reactions to iodinated x-ray contrast agents in healthy rats.

Purpose: The aim of this preclinical study on healthy Sprague-Dawley rats was to determine whether differences exist in the induction of adverse skin reactions after the intravenous administration of a monomeric and 2 dimeric iodinated nonionic contrast agents.

Materials And Methods: After intravenous injection of iopromide (monomeric), iodixanol (dimeric), and iotrolan (dimeric) at a dose of 4 g iodine/kg of body weight, mechanical ear volume measurements (10 minute after injection) and intravital microscopy (baseline, 5 minutes after injection) of the ear with the near-infrared dye indocyanine green were performed to determine the volume change and plasma extravasation. Histopathological analysis (20 minutes, 1 hour, and 3 hours after injection) was performed to diagnose alterations in the skin.

Discovery of novel insulin-like growth factor-1 receptor inhibitors with unique time-dependent binding kinetics.

This letter describes a series of small molecule inhibitors of IGF-1R with unique time-dependent binding kinetics and slow off-rates. Structure-activity and structure-kinetic relationships were elucidated and guided further optimizations within the series, culminating in compound 2. With an IGF-1R dissociative half-life (t 1/2) of >100 h, compound 2 demonstrated significant and extended PD effects in conjunction with tumor growth inhibition in xenograft models at a remarkably low and intermittent dose, which correlated with the observed in vitro slow off-rate properties.

Analysis of SecA dimerization in solution.

The Sec pathway mediates translocation of protein across the inner membrane of bacteria. SecA is a motor protein that drives translocation of preprotein through the SecYEG channel. SecA reversibly dimerizes under physiological conditions, but different dimer interfaces have been observed in SecA crystal structures.

A protocol for conducting rainfall simulation to study soil runoff.

Rainfall is a driving force for the transport of environmental contaminants from agricultural soils to surficial water bodies via surface runoff. The objective of this study was to characterize the effects of antecedent soil moisture content on the fate and transport of surface applied commercial urea, a common form of nitrogen (N) fertilizer, following a rainfall event that occurs within 24 hr after fertilizer application. Although urea is assumed to be readily hydrolyzed to ammonium and therefore not often available for transport, recent studies suggest that urea can be transported from agricultural soils to coastal waters where it is implicated in harmful algal blooms.

Hepatic encephalopathy is associated with slowed and delayed stimulus-associated somatosensory alpha activity.

Objective: Hepatic encephalopathy (HE) is associated with motor symptoms and attentional deficits, which are related to pathologically slowed oscillatory brain activity. Here, potential alterations of oscillatory activity in the somatosensory system were investigated.

Methods: 21 patients with liver cirrhosis and varying HE severity and 7 control subjects received electrical stimulation of the right median nerve while brain activity was recorded using magnetoencephalography (MEG).

pH-induced stability switching of the bacteriophage HK97 maturation pathway.

Many viruses undergo large-scale conformational changes during their life cycles. Blocking the transition from one stage of the life cycle to the next is an attractive strategy for the development of antiviral compounds. In this work, we have constructed an icosahedrally symmetric, low-energy pathway for the maturation transition of bacteriophage HK97.

Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C.

Aim: To study the potential association between hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), cirrhosis and latent hepatitis B (LHB) infection, defined as the absence of detectable serum hepatitis B surface antigen (HBsAg) and the presence of hepatitis B core antibody (HBcAb).

Methods: This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody (HCV Ab) (+) and HBsAg(-) at Wayne State University between 1999 and 2008. From these, 108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining (77) were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease.

A systems chemical biology study of malate synthase and isocitrate lyase inhibition in Mycobacterium tuberculosis during active and NRP growth.

The ability of Mycobacterium tuberculosis (Mtb) to survive in low oxygen environments enables the bacterium to persist in a latent state within host tissues. In vitro studies of Mtb growth have identified changes in isocitrate lyase (ICL) and malate synthase (MS) that enable bacterial persistence under low oxygen and other environmentally limiting conditions. Systems chemical biology (SCB) enables us to evaluate the effects of small molecule inhibitors not only on the reaction catalyzed by malate synthase and isocitrate lyase, but the effect on the complete tricarboxylic acid cycle (TCA) by taking into account complex network relationships within that system.

Profound jaundice in a patient with acute hepatitis C.

A 52-year-old African-American woman with overall good health and medical history of asthma and depression presented with right lower quadrant abdominal pain, vomiting and icterus for 3 weeks. Her physical examination was remarkable for only sclera icterus and mild tenderness on palpation in the right lower quadrant. Investigations revealed marked hyperbilirubinemia and transaminitis, with other serological and radiological studies unremarkable and a hepatitis A, B and C panel negative 3 weeks before presentation.

Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: optimization of kinase selectivity and pharmacokinetics.

The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.

Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1.

The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.

A personal journey in advocacy.

Over the past decade, neurology advocacy has caught the attention of neurologists feeling increasingly frustrated about the health care environment in which they practice. We describe our experience in practicing advocacy at the national and local levels. Neurologists can participate in many levels of advocacy to benefit their patients and their profession.

The slowed brain: cortical oscillatory activity in hepatic encephalopathy.

Oscillatory activity of the human brain has received growing interest as a key mechanism of large-scale integration across different brain regions. Besides a crucial role of oscillatory activity in the emergence of other neurological and psychiatric diseases, recent evidence indicates a key role in the pathophysiology of hepatic encephalopathy (HE). This review summarizes the current knowledge on pathological alterations of oscillatory brain activity in association with liver dysfunction and HE in the context of spontaneous brain activity, motor symptoms, sensory processing, and attention.

Regional primary care team to deliver best-practice diabetes care: a needs-driven health workforce model reflecting a biopsychosocial construct of health.

Objective: Best-practice diabetes care can reduce the burden of diabetes and associated health care costs. But this requires access to a multidisciplinary team with the right skill mix. We applied a needs-driven evidence-based health workforce model to describe the primary care team required to support best-practice diabetes care, paying particular attention to diverse clinic populations.