A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo

Background Most medullary thyroid carcinomas (MTC) recur or progress despite optimal surgical resection. Current targeted-therapies show promise but lack durable efficacy and tolerability. The purpose of this study was to build upon previous in vitro work and evaluate Withaferin A (WA), a novel RET inhibitor, in a metastatic murine model of MTC. Methods 5 million DRO-81-1 human MTC-cells injected in the left posterior neck of Nu/Nu mice uniformly generated metastases to the liver, spleen, and/or lungs. Treatment with WA (8mg/kg/day i.p.×21 days) was started for tumors >100 mm3. Endpoints were survival, tumor>1500 mm3, decreased bodyweight, or body score (all measured thrice weekly). Results All controls (saline; n=5) died or deteriorated from metastatic disease by 7 weeks post injection. All treated animals were alive,(WA; n=5), having tumor regression and growth-delay without toxicity or weight-loss at 6 wks post treatment; p<0.01. Tumor cells treated with WA demonstrated inhibition of total and phospho-RET levels by Western-Blot analysis in a dose-dependent manner (almost complete inhibition with 5uM WA treatment) as well as potent inhibition of phospho-ERK and phospho-AKT levels. Conclusions Withaferin A is a novel natural-product RET-inhibitor with efficacy in a metastatic murine model of MTC. Further long-term efficacy/toxicity studies are warranted to evaluate this compound for clinical translation

Acute encephalitis syndrome surveillance, Kushinagar district, Uttar Pradesh, India, 2011-2012

In India, quality surveillance for acute encephalitis syndrome (AES), including laboratory testing, is necessary for understanding the epidemiology and etiology of AES, planning interventions, and developing policy. We reviewed AES surveillance data for January 2011-June 2012 from Kushinagar District, Uttar Pradesh, India. Data were cleaned, incidence was determined, and demographic characteristics of cases and data quality were analyzed. A total of 812 AES case records were identified, of which 23\% had illogical entries. AES incidence was highest among boys<6 years of age, and cases peaked during monsoon season. Records for laboratory results (available for Japanese encephalitis but not AES) and vaccination history were largely incomplete, so inferences about the epidemiology and etiology of AES could not be made. The low-quality AES/Japanese encephalitis surveillance data in this area provide little evidence to support development of prevention and control measures, estimate the effect of interventions, and avoid the waste of public health resources

Hepatocellular carcinoma in Pakistan: where do we stand?

Context: From the 1970s till the mid 1990s, hepatitis B was the most common etiological factor for hepatocellular carcinoma (HCC) in Pakistan. Afterwards, a shift in HCC etiology was observed with a steady rise in hepatitis C virus (HCV) related HCC cases. HCV-3a, which is the most prevalent genotype, is also most frequent in HCV related HCC. There was an increase in the proportion of non-B non-C (NBNC) HCC cases as well, which might be attributed to an increase in non-alcoholic fatty liver disease. Evidence Acquisition: The age-standardized rate for HCC is 7.64/100 000 in males and 2.8/100 000 in females. Male to female ratio is 3.6:1. Usual age of presentation is in the fifth and sixth decade. Most patients present with advanced disease, as they are not in a regular surveillance program. This is more so for patients with NBNC chronic liver disease. As many sonologists in Pakistan are practicing without sufficient training to pick up early lesions, alpha-fetoprotein is still recommended to compliment ultrasound in the surveillance of HCC. Results: Majority of HCC patients present with nonresectable disease. Interventions such as transarterial chemoembolization, radiofrequency ablation, resection and chemotherapy including sorafenib are available in selected centers. Pakistan appears to be in an area of intermediate endemicity for HCC. There is a need for population based epidemiological studies to estimate the exact disease burden. Conclusions: Measures to prevent the spread of hepatitis C and B can slow down the epidemic rise in the incidence of HCC in the coming decades. There is a need to implement a proper surveillance program to identify HCC cases at an early stage

Overview of large area triple-GEM detectors for the CMS forward muon upgrade

In order to cope with the harsh environment expected from the high luminosity LHC, the CMS forward muon system requires an upgrade. The two main challenges expected in this environment are an increase in the trigger rate and increased background radiation leading to a potential degradation of the particle ID performance. Additionally, upgrades to other subdetectors of CMS allow for extended coverage for particle tracking, and adding muon system coverage to this region will further enhance the performance of CMS

A novel application of Fiber Bragg Grating (FBG) sensors in MPGD

We present a novel application of Fiber Bragg Grating (FBG) sensors in the construction and characterisation of Micro Pattern Gaseous Detector (MPGD), with particular attention to the realisation of the largest triple (Gas electron Multiplier) GEM chambers so far operated, the GE1/1 chambers of the CMS experiment at LHC. The GE1/1 CMS project consists of 144 GEM chambers of about 0.5 m2 active area each, employing three GEM foils per chamber, to be installed in the forward region of the CMS endcap during the long shutdown of LHC in 2108-2019. The large active area of each GE1/1 chamber consists of GEM foils that are mechanically stretched in order to secure their flatness and the consequent uniform performance of the GE1/1 chamber across its whole active surface. So far FBGs have been used in high energy physics mainly as high precision positioning and re-positioning sensors and as low cost, easy to mount, low space consuming temperature sensors. FBGs are also commonly used for very precise strain measurements in material studies. In this work we present a novel use of FBGs as flatness and mechanical tensioning sensors applied to the wide GEM foils of the GE1/1 chambers. A network of FBG sensors have been used to determine the optimal mechanical tension applied and to characterise the mechanical tension that should be applied to the foils. We discuss the results of the test done on a full-sized GE1/1 final prototype, the studies done to fully characterise the GEM material, how this information was used to define a standard assembly procedure and possible future developments.Comment: 4 pages, 4 figures, presented by Luigi Benussi at MPGD 2015 (Trieste, Italy). arXiv admin note: text overlap with arXiv:1512.0848

Charged particle detection performance of Gas Electron Multiplier (GEM) detectors for the upgrade of CMS endcap muon system at the CERN LHC

The Compact Muon Solenoid (CMS) detector is one of the two general-purpose detectors at the CERN LHC. LHC will provide exceptional high instantaneous and integrated luminosity after second long shutdown. The forward region |η| ≥ 1:5 of CMS detector will face extremely high particle rates in tens of kHz/cm2 and hence it will affect the momentum resolution, efficiency and longevity of the muon detectors. Here, η is pseudorapidity defined as η = -ln(tan(θ/2)), where θ is the polar angle measured from z-axis. To overcome these issues the CMSGEM collaboration has proposed to install new large size rate capable Triple Gas Electron Multiplier (GEM) detectors in the forward region of CMS muon system. The first set of Triple GEM detectors will be installed in the GE1/1 region (1:6 <; |η| <; 2.2) of the muon endcap during the long shutdown 2 (LS2) of the LHC. Towards this goal, full size CMS Triple GEM detectors have been fabricated and tested at the CERN SPS, H2 and H4 test beam facility. The GEM detectors were operated with two gas mixtures: Ar/CO2 (70/30) and Ar/CO2/CF4 (45/15/40). In 2014, good quality data was collected during test beam campaigns. In this paper, the performance of the detectors is summarized based on their tracking efficiency and time resolution

Design of a constant fraction discriminator for the VFAT3 front-end ASIC of the CMS GEM detector

In this work the design of a constant fraction discriminator (CFD) to be used in the VFAT3 chip for the read-out of the triple-GEM detectors of the CMS experiment, is described. A prototype chip containing 8 CFDs was implemented using 130 nm CMOS technology and test results are shown. © CERN 2016

Quality control for the first large areas of triple-GEM chambers for the CMS endcaps

The CMS Collaboration plans to equip the very forward muon system with triple-GEM detectors that can withstand the environment of the High-Luminosity LHC.This project is at the final stages of R&D and moving to production. A large area of several 100 m 2 are to be instrumented with GEM detectors which will be produced in six different sites around the world. A common construction and quality control procedure is required to ensure the performance of each detector.The quality control steps will include optical inspection,cleaning and baking of all materials and parts used to build the detector,leakage current tests of the GEM foils,high voltage tests,gas leak tests of the chambers and monitoring pressures time,gain calibration to know the optimal operation region of the detector,gain uniformity tests, and studying the efficiency,noise and tracking performance of the detectors in a cosmic stand using scintillator

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Editors’ Introduction: An Overview of the Educational Administration and Leadership Curriculum: Traditions of Islamic Educational Administration and Leadership in Higher Education

This chapter provides an overview of several topics relevant to constructing an approach to teaching educational administration and leadership in Muslim countries. First, it places the topic in the context of the changing nature and critiques of the field that argue for a greater internationalisation to both resist some of the negative aspects of globalisation and to represent countries’ traditions in the professional curriculum. Then, it identifies literature that presents the underlying principles and values of Islamic education that guide curriculum and pedagogy and shape its administration and leadership including the Qur’an and Sunnah and the classical educational literature which focuses on aims, values and goals of education as well as character development upon which a ‘good’ society is built. This is followed by a section on the Islamic administration and leadership traditions that are relevant to education, including the values of educational organisations and how they should be administered, identifying literature on the distinctive Islamic traditions of leadership and administrator education and training as it applies to education from the establishment of Islam and early classical scholars and senior administrators in the medieval period who laid a strong foundation for a highly sophisticated preparation and practice of administration in philosophical writings and the Mirrors of Princes writings, and subsequent authors who have built upon it up to the contemporary period. The final section provides an overview of the chapters in this collection