High Voltage System for the CMS Electromagnetic Calorimeter

The CMS electromagnetic calorimeter (ECAL) is made of about 75000 lead tungstate crystals. The 61200 crystals of the barrel part are read by avalanche photodiodes (APD) with internal amplification of the signal. Since the gain strongly depends on the bias voltage, the APDs require a very stable power supply system. To preserve the high energy resolution of the calorimeter, a stability of the bias voltage of the order of 10^-4 is required over several months, a typical interval between absolute calibrations of the full read-out chain with physics events. This paper describes the High Voltage power supply system developed for CMS ECAL and its performances as measured in laboratory tests and during test-beam operations of several modules of the calorimeter

Tissue expression of lactate transporters (MCT1 and MCT4) and prognosis of malignant pleural mesothelioma (brief report)

Funder: NIHR Cambridge Biomedical Research CentreFunder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265Abstract: Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the pleura, mainly related to asbestos exposure. As in other solid tumors, malignant cells exhibit high glucose uptake and glycolytic rates with increased lactic acid efflux into the interstitial space. Lactate transport into and out of cells, crucial to maintaining intracellular pH homeostasis and glycolysis, is carried out by monocarboxylate transporters (MCTs) and the chaperone basigin (CD147). We set out to examine the clinical significance of basigin, MCT1 and MCT4 in the context of MPM and to evaluate their expression in relation to the evolution of the disease. Methods: We used immunohistochemistry to measure the expression of basigin, MCT1 and MCT4 in a cohort of 135 individuals with MPM compared to a series of 15 non-MPM pleura specimens. Moreover, by Kaplan–Meier and Cox analyses we evaluated whether an expression over the average of these markers could be associated with the patients’ overall survival (OS). Results: We detected positive staining of basigin, MCT1, and MCT4 in most MPM specimens. In particular, MCT4 was always positive in malignant tissues but undetectable in the 4 normal pleural specimens incorporated within the tissue microarray. This was confirmed in the additional series of 15 normal pleural samples. Moreover, MCT4 expression was significantly associated with reduced OS. Conclusion: In this study, the tissue expression of basigin did not prove to be exploitable as a diagnostic or prognostic marker for MPM patients. The expression of MCT1 was not informative either, being tightly correlated with that of basigin. However, the expression of MCT4 showed promise as a diagnostic/therapeutic and prognostic biomarker

Dose-Dependent Impairment of the Immune Response to the Moderna-1273 mRNA Vaccine by Mycophenolate Mofetil in Patients with Rheumatic and Autoimmune Liver Diseases

The purpose of this study was to evaluate the efficacy and safety of the Moderna-1273 mRNA vaccine for SARS-CoV-2 in patients with immune-mediated diseases under different treatments. Anti-trimeric spike protein antibodies were tested in 287 patients with rheumatic or autoimmune diseases (10% receiving mycophenolate mofetil, 15% low-dose glucocorticoids, 21% methotrexate, and 58% biologic/targeted synthetic drugs) at baseline and in 219 (76%) 4 weeks after the second Moderna-1273 mRNA vaccine dose. Family members or caretakers were enrolled as the controls. The neutralizing serum activity against SARS-CoV-2-G614, alpha, and beta variants in vitro and the cytotoxic T cell response to SARS-CoV-2 peptides were determined in a subgroup of patients and controls. Anti-SARS-CoV-2 antibody development, i.e., seroconversion, was observed in 69% of the mycophenolate-treated patients compared to 100% of both the patients taking other treatments and the controls (p < 0.0001). A dose-dependent impairment of the humoral response was observed in the mycophenolate-treated patients. A daily dose of >1 g at vaccination was a significant risk factor for non-seroconversion (ROC AUC 0.89, 95% CI 0.80-98, p < 0.0001). Moreover, in the seroconverted patients, a daily dose of >1 g of mycophenolate was associated with significantly lower anti-SARS-CoV-2 antibody titers, showing slightly reduced neutralizing serum activity but a comparable cytotoxic response compared to other immunosuppressants. In non-seroconverted patients treated with mycophenolate at a daily dose of >1 g, the cytotoxic activity elicited by viral peptides was also impaired. Mycophenolate treatment affects the Moderna-1273 mRNA vaccine immunogenicity in a dose-dependent manner, independent of rheumatological disease

Intercalibration of the barrel electromagnetic calorimeter of the CMS experiment at start-up

Calibration of the relative response of the individual channels of the barrel electromagnetic calorimeter of the CMS detector was accomplished, before installation, with cosmic ray muons and test beams. One fourth of the calorimeter was exposed to a beam of high energy electrons and the relative calibration of the channels, the intercalibration, was found to be reproducible to a precision of about 0.3%. Additionally, data were collected with cosmic rays for the entire ECAL barrel during the commissioning phase. By comparing the intercalibration constants obtained with the electron beam data with those from the cosmic ray data, it is demonstrated that the latter provide an intercalibration precision of 1.5% over most of the barrel ECAL. The best intercalibration precision is expected to come from the analysis of events collected in situ during the LHC operation. Using data collected with both electrons and pion beams, several aspects of the intercalibration procedures based on electrons or neutral pions were investigated

Il farmaco: ricerca, sviluppo e applicazione in terapia

[Italiano]:Il farmaco: ricerca, sviluppo e applicazione in terapia si propone l’obiettivo di offrire una panoramica sul processo di Ricerca e Sviluppo che un farmaco compie a partire dal momento in cui viene progettato fino alla sua pratica utilizzazione. Quando una molecola è ritenuta potenzialmente adatta per creare un medicinale, si attiva un lungo percorso che ha come traguardo la realizzazione di un nuovo mezzo terapeutico e la sua approvazione per l’immissione in commercio. Un percorso scandito dalla rigorosa osservanza di regolamenti e leggi che si sono evoluti nel tempo di pari passo con il progresso scientifico e tecnologico, ma spesso anche a seguito di reazioni avverse o eventi dannosi irreversibili che hanno innescato processi di revisione delle norme e dei protocolli sperimentali. Questo libro parte con una densa ricognizione sulla storia della farmacologia occidentale, al fine di agevolare la comprensione del coacervo di vicende e circostanze che nel tempo hanno fatto da sfondo a tutte quelle dinamiche attraverso cui il processo di Ricerca e Sviluppo si è gradualmente affermato e consolidato. Notevole attenzione è stata poi dedicata ad alcuni risvolti divenuti oramai cruciali all’interno dell’articolato universo normativo in cui il farmaco è collocato, quali le terapie avanzate e i nuovi approcci per la ricerca clinica. Inoltre, gli autori si sono concentrati sulla prescrizione dei cosiddetti off-label e sulle tematiche di farmacoutilizzazione e farmacovigilanza che, nel giro di pochi decenni, sono assurte a sfere di conoscenza sempre più significative e influenti nelle prospettive presenti e future, non solo delle scienze farmaceutiche ma dell’intera società. Lo sforzo compiuto per redigere questo volume trova la sua ragion d’essere proprio nel voler mettere a disposizione dei lettori uno sguardo d’insieme sul farmaco e sulle complesse sfide che ancora lo attendono./ [English]:“The drug: research, development and application in therapy” is an in-depth study on the Research and Development process that a drug performs from the moment it is designed up to its practical use. When a molecule is considered suitable for a medicine, a long process is activated which has as its goal the creation of a new therapeutic tool and its approval for marketing. A path marked by the strict observance of regulations and laws that have evolved over time in step with scientific and technological progress. A path that however has often been determined also by tragic events following damaging adverse reactions that have triggered processes of revision of the norms and experimental protocols. This book starts with a summary on the history of Western pharmacology, written to allow the reader to understand the circumstances that have been the background to those dynamics through which the Research and Development process has gradually consolidated. An important part of the book is dedicated to some aspects that are crucial in the normative universe in which the drug is placed, such as the advanced therapies and new approaches for clinical research. The authors also focused on the prescriptions of off-label drugs and on the issues of pharmacoutilization and pharmacovigilance, two disciplines that, in a few years, have become increasingly influential in the present and future perspectives, not only of the pharmaceutical sciences but of the entire society

Oxidative addition of organic halides on palladium(0) complexes stabilized by dimethylfumarate and quinoline-based N-P or N-S spectator ligands

We have studied the oxidative addition of some organic halides on palladium(0) dimethylfumarate complexes bearing heteroditopic (N–P or N–S) quinoline-based spectator ligands from the experimental and theoretical point of view. We have measured the half-life of some oxidative addition reactions carried out in two different solvents (CD2Cl2 and CD3CN). The reactions were studied under mild conditions by NMR and the reactivities of different oxidants towards the complexes under study were compared. The rates of reaction were influenced by the nature of the spectator ligands and the solvent. The thioquinoline derivatives display a higher reactivity than that of the phosphoquinoline complexes and in general the reaction rates are higher in CD3CN than in CD2Cl2, although such a behavior is not always observed. We propose a plausible mechanism for the oxidative reaction in different solvents based on the experimental results and an adequate computational approach. Finally, the solid state structures of two reaction products were resolved and reported.We have studied the oxidative addition of some organic halides on palladium(0) dimethylfumarate complexes bearing heteroditopic (N-P or N-S) quinoline-based spectator ligands from the experimental and theoretical point of view. We have measured the half-life of some oxidative addition reactions carried out in two different solvents (CD2Cl2 and CD3CN). The reactions were studied under mild conditions by NMR and the reactivities of different oxidants towards the complexes under study were compared. The rates of reaction were influenced by the nature of the spectator ligands and the solvent. The thioquinoline derivatives display a higher reactivity than that of the phosphoquinoline complexes and in general the reaction rates are higher in CD3CN than in CD2Cl2, although such a behavior is not always observed. We propose a plausible mechanism for the oxidative reaction in different solvents based on the experimental results and an adequate computational approach. Finally, the solid state structures of two reaction products were resolved and reported. (C) 2015 Elsevier Ltd. All rights reserved

Attack of molecular iodine to novel palladacyclopentadienyl complexes bearing isocyanides as spectator ligands. A computational and mechanistic study

We have synthesized some palladacyclopentadienyl complexes bearing 2,6-dimethylbenzo-, 2- tosylaceto- and t-butyl-isocyanides (DIC, TOSMIC and TIC, respectively) as spectator ligands. The oxidative addition of I2 to the DIC derivatives yielded complexes bearing iodine, the butadienyl fragment s-coordinated, and the isocyanides in mutual trans position as final species. On the basis of a kinetic study carried out by means of UVevis and 1H NMR techniques we have proposed a plausible mechanism which is in accord with a computational investigation done by other authors on similar compounds and confirmed by a computational approach we have performed. The proposed mechanism suggests the formation of a Pd(IV) octahedral intermediate complex bearing two iodines in meridional position. The latter yields another intermediate complex bearing iodine, the open butadienyl fragment s-coordinated, and the isocyanides cis to each other which eventually isomerizes to the final trans product. The reaction rates related to the formation of the cis derivatives (k1) and to the isomerization process k'1 were determined as refined parameters of the non linear regression analysis of the monoexponential rela- tionship which is a function of the UVevis spectral changes and time

Synthesis and reactivity toward olefin exchange and oxidative addition of some platinum(0) olefin complexes with thioquinolines as spectator ligands

We have synthesized and fully characterized by NMR, IR and elemental analysis sixteen Pt(0) derivatives stabilized by four different thioquinoline spectator ligands and four different deactivated olefins. Moreover we have studied the reactivity and proposed a mechanism for olefin-olefin, olefin-alkyne exchange and oxidative addition of alkyl halides to this new class of Pt(0) derivatives based on detailed kinetic measurements. The kinetic study was carried out by NMR and UV–Vis techniques and in one case we have determined the activation parameters. Finally, we were able to resolve the solid state structure of a couple of diastereoisomers among the four possible isomers generated by the combination of two stereocenters