Nab-paclitaxel/gemcitabine combination is more effective than gemcitabine alone in locally advanced, unresectable pancreatic cancer - A GISCAD phase II randomized trial

The role of combination chemotherapy has not yet been established in unresectable locally advanced pancreatic cancer (LAPC) lacking dedicated randomized trials

The Large-Scale Polarization Explorer (LSPE)

The LSPE is a balloon-borne mission aimed at measuring the polarization of the Cosmic Microwave Background (CMB) at large angular scales, and in particular to constrain the curl component of CMB polarization (B-modes) produced by tensor perturbations generated during cosmic inflation, in the very early universe. Its primary target is to improve the limit on the ratio of tensor to scalar perturbations amplitudes down to r = 0.03, at 99.7% confidence. A second target is to produce wide maps of foreground polarization generated in our Galaxy by synchrotron emission and interstellar dust emission. These will be important to map Galactic magnetic fields and to study the properties of ionized gas and of diffuse interstellar dust in our Galaxy. The mission is optimized for large angular scales, with coarse angular resolution (around 1.5 degrees FWHM), and wide sky coverage (25% of the sky). The payload will fly in a circumpolar long duration balloon mission during the polar night. Using the Earth as a giant solar shield, the instrument will spin in azimuth, observing a large fraction of the northern sky. The payload will host two instruments. An array of coherent polarimeters using cryogenic HEMT amplifiers will survey the sky at 43 and 90 GHz. An array of bolometric polarimeters, using large throughput multi-mode bolometers and rotating Half Wave Plates (HWP), will survey the same sky region in three bands at 95, 145 and 245 GHz. The wide frequency coverage will allow optimal control of the polarized foregrounds, with comparable angular resolution at all frequencies.Comment: In press. Copyright 2012 Society of Photo-Optical Instrumentation Engineers. One print or electronic copy may be made for personal use only. Systematic reproduction and distribution, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper are prohibite

A multicenter randomized phase 4 trial comparing sodium picosulphate plus magnesium citrate vs. polyethylene glycol plus ascorbic acid for bowel preparation before colonoscopy. The PRECOL trial

Background: Adequate bowel preparation before colonoscopy is crucial. Unfortunately, 25% of colonoscopies have inadequate bowel cleansing. From a patient perspective, bowel preparation is the main obstacle to colonoscopy. Several low-volume bowel preparations have been formulated to provide more tolerable purgative solutions without loss of efficacy. Objectives: Investigate efficacy, safety, and tolerability of Sodium Picosulphate plus Magnesium Citrate (SPMC) vs. Polyethylene Glycol plus Ascorbic Acid (PEG-ASC) solutions in patients undergoing diagnostic colonoscopy. Materials and methods: In this phase 4, randomized, multicenter, twoarm trial, adult outpatients received either SPMC or PEG-ASC for bowel preparation before colonoscopy. The primary aims were quality of bowel cleansing (primary endpoint scored according to Boston Bowel Preparation Scale) and patient acceptance (measured with six visual analogue scales). The study was open for treatment assignment and blinded for primary endpoint assessment. This was done independently with videotaped colonoscopies reviewed by two endoscopists unaware of study arms. A sample size of 525 patients was calculated to recognize a difference of 10% in the proportion of successes between the arms with a two-sided alpha error of 0.05 and 90% statistical power. Results: Overall 550 subjects (279 assigned to PEG-ASC and 271 assigned to SPMC) represented the analysis population. There was no statistically significant difference in success rate according to BBPS: 94.4% with PEG-ASC and 95.7% with SPMC (P = 0.49). Acceptance and willing to repeat colonoscopy were significantly better for SPMC with all the scales. Compliance was less than full in 6.6 and 9.9% of cases with PEG-ASC and SPMC, respectively (P = 0.17). Nausea and meteorism were significantly more bothersome with PEG-ASC than SPMC. There were no serious adverse events in either group. Conclusion: SPMC and PEG-ASC are not different in terms of efficacy, but SPMC is better tolerated than PEG-ASC. SPMC could be an alternative to lowvolume PEG based purgative solutions for bowel preparation

The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells

The protein product of the ocular albinism type 1 gene, named OA1, is a pigment cell-specific G protein-coupled receptor exclusively localized to intracellular organelles, namely lysosomes and melanosomes. Loss of OA1 function leads to the formation of macromelanosomes, suggesting that this receptor is implicated in organelle biogenesis, however the mechanism involved in the pathogenesis of the disease remains obscure. We report here the identification of an unexpected abnormality in melanosome distribution both in retinal pigment epithelium (RPE) and skin melanocytes of Oa1-knock-out (KO) mice, consisting in a displacement of the organelles from the central cytoplasm towards the cell periphery. Despite their depletion from the microtubule (MT)-enriched perinuclear region, Oa1-KO melanosomes were able to aggregate at the centrosome upon disruption of the actin cytoskeleton or expression of a dominant-negative construct of myosin Va. Consistently, quantification of organelle transport in living cells revealed that Oa1-KO melanosomes displayed a severe reduction in MT-based motility; however, this defect was rescued to normal following inhibition of actin-dependent capture at the cell periphery. Together, these data point to a defective regulation of organelle transport in the absence of OA1 and imply that the cytoskeleton might represent a downstream effector of this receptor. Furthermore, our results enlighten a novel function for OA1 in pigment cells and suggest that ocular albinism type 1 might result from a different pathogenetic mechanism than previously thought, based on an organelle-autonomous signalling pathway implicated in the regulation of both membrane traffic and transport

Thermal architecture for the QUBIC cryogenic receiver

QUBIC, the QU Bolometric Interferometer for Cosmology, is a novel forthcoming instrument to measure the B-mode polarization anisotropy of the Cosmic Microwave Background. The detection of the B-mode signal will be extremely challenging; QUBIC has been designed to address this with a novel approach, namely bolometric interferometry. The receiver cryostat is exceptionally large and cools complex optical and detector stages to 40 K, 4 K, 1 K and 350 mK using two pulse tube coolers, a novel 4He sorption cooler and a double-stage 3He/4He sorption cooler. We discuss the thermal and mechanical design of the cryostat, modelling and thermal analysis, and laboratory cryogenic testing.Fil: May, A. J.. University of Manchester; Reino UnidoFil: Chapron, C.. Astroparticule et Cosmologie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Coppi, G.. University of Manchester; Reino UnidoFil: D’Alessandro, G.. Università di Roma; ItaliaFil: de Bernardis, P.. Università di Roma; ItaliaFil: Masi, S.. Università di Roma; ItaliaFil: Melhuish, S.. University of Manchester; Reino UnidoFil: Piat, M.. Astroparticule et Cosmologie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Piccirillo, L.. University of Manchester; Reino UnidoFil: Schillaci, A.. Università di Roma; ItaliaFil: Thermeau, J. P.. Astroparticule et Cosmologie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Bonaparte, J.. Comisión Nacional de Energía Atómica; ArgentinaFil: Di Donato, Andrés Leonardo. Comisión Nacional de Energía Atómica; ArgentinaFil: Fasciszewski Zeballos, Alejandro Miguel. Comisión Nacional de Energía Atómica; ArgentinaFil: Gamboa Lerena, Martín Miguel. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Garcia, Beatriz Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Etchegoyen, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Gomez Berisso, Mariano. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: González, M.. Comisión Nacional de Energía Atómica; ArgentinaFil: Harari, Diego Dario. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kristukat, C.. Universidad Nacional de San Martín; ArgentinaFil: Medina, Maria Clementina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Ringegni, P.. Universidad Nacional de la Plata. Facultad de Ingeniería. Uidet Grupo de Ensayos Mecanicos Aplicados.; ArgentinaFil: Romero, Gustavo Esteban. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Suarez, C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Mundo, Luis Mariano. Universidad Nacional de la Plata. Facultad de Ingeniería. Uidet Grupo de Ensayos Mecanicos Aplicados.; ArgentinaFil: Watson, B.. University of Manchester; Reino UnidoFil: Wicek, F.. Laboratoire de l’Accélérateur Linéaire; FranciaFil: Zannoni, M.. Università degli Studi di Milano; ItaliaFil: Zullo, A.. Istituto Nazionale Di Fisica Nucleare; ItaliaMillimeter, Submillimeter, and Far-Infrared Detectors and Instrumentation for Astronomy IXEstados UnidosSociety of Photographic Instrumentation Engineer

Inflammation-Driven Reprogramming of CD4+Foxp3+ Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo

While natural CD4+Foxp3+ regulatory T (nTREG) cells have long been viewed as a stable and distinct lineage that is committed to suppressive functions in vivo, recent evidence supporting this notion remains highly controversial. We sought to determine whether Foxp3 expression and the nTREG cell phenotype are stable in vivo and modulated by the inflammatory microenvironment. Here, we show that Foxp3+ nTREG cells from thymic or peripheral lymphoid organs reveal extensive functional plasticity in vivo. We show that nTREG cells readily lose Foxp3 expression, destabilizing their phenotype, in turn, enabling them to reprogram into Th1 and Th17 effector cells. nTREG cell reprogramming is a characteristic of the entire Foxp3+ nTREG population and the stable Foxp3NEG TREG cell phenotype is associated with a methylated foxp3 promoter. The extent of nTREG cell reprogramming is modulated by the presence of effector T cell-mediated signals, and occurs independently of variation in IL-2 production in vivo. Moreover, the gut microenvironment or parasitic infection favours the reprogramming of Foxp3+ TREG cells into effector T cells and promotes host immunity. IL-17 is predominantly produced by reprogrammed Foxp3+ nTREG cells, and precedes Foxp3 down-regulation, a process accentuated in mesenteric sites. Lastly, mTOR inhibition with the immunosuppressive drug, rapamycin, stabilizes Foxp3 expression in TREG cells and strongly inhibits IL-17 but not RORγt expression in reprogrammed Foxp3− TREG cells. Overall, inflammatory signals modulate mTOR signalling and influence the stability of the Foxp3+ nTREG cell phenotype

CD133, CD15/SSEA-1, CD34 or side populations do not resume tumor-initiating properties of long-term cultured cancer stem cells from human malignant glio-neuronal tumors

<p>Abstract</p> <p>Background</p> <p>Tumor initiating cells (TICs) provide a new paradigm for developing original therapeutic strategies.</p> <p>Methods</p> <p>We screened for TICs in 47 human adult brain malignant tumors. Cells forming floating spheres in culture, and endowed with all of the features expected from tumor cells with stem-like properties were obtained from glioblastomas, medulloblastoma but not oligodendrogliomas.</p> <p>Results</p> <p>A long-term self-renewal capacity was particularly observed for cells of malignant glio-neuronal tumors (MGNTs). Cell sorting, karyotyping and proteomic analysis demonstrated cell stability throughout prolonged passages. Xenografts of fewer than 500 cells in Nude mouse brains induced a progressively growing tumor. CD133, CD15/LeX/Ssea-1, CD34 expressions, or exclusion of Hoechst dye occurred in subsets of cells forming spheres, but was not predictive of their capacity to form secondary spheres or tumors, or to resist high doses of temozolomide.</p> <p>Conclusions</p> <p>Our results further highlight the specificity of a subset of high-grade gliomas, MGNT. TICs derived from these tumors represent a new tool to screen for innovative therapies.</p

Expression of genes for bone morphogenetic proteins BMP-2, BMP-4 and BMP-6 in various parts of the human skeleton

BACKGROUND: Differences in duration of bone healing in various parts of the human skeleton are common experience for orthopaedic surgeons. The reason for these differences is not obvious and not clear.METHODS: In this paper we decided to measure by the use of real-time RT-PCR technique the level of expression of genes for some isoforms of bone morphogenetic proteins (BMPs), whose role is proven in bone formation, bone induction and bone turnover. Seven bone samples recovered from various parts of skeletons from six cadavers of young healthy men who died in traffic accidents were collected. Activity of genes for BMP-2, -4 and -6 was measured by the use of fluorescent SYBR Green I.RESULTS: It was found that expression of m-RNA for BMP-2 and BMP-4 is higher in trabecular bone in epiphyses of long bones, cranial flat bones and corpus mandibulae then in the compact bone of diaphyses of long bones. In all samples examined the expression of m-RNA for BMP-4 was higher than for BMP-2.CONCLUSION: It was shown that m-RNA for BMP-6 is not expressed in the collected samples at all. It is postulated that differences in the level of activation of genes for BMPs is one of the important factors which determine the differences in duration of bone healing of various parts of the human skeleton.Author has checked copyrightDG 16/11/1