Cediranib for alveolar soft part sarcoma: a randomised study in relation to clinical practice.

Summary Background Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS. Methods In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0–1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing. Findings Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27–45). Median follow-up was 34·3 months (IQR 23·7–55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was −8·3% (IQR −26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase. Interpretation Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. Funding Cancer Research UK and AstraZeneca

Merger of compact stars in the two-families scenario

We analyse the phenomenological implications of the two-families scenario on the merger of compact stars. That scenario is based on the coexistence of both hadronic stars and strange quark stars. After discussing the classification of the possible mergers, we turn to detailed numerical simulations of the merger of two hadronic stars, i.e., "first family" stars in which delta resonances and hyperons are present, and we show results for the threshold mass of such binaries, for the mass dynamically ejected and the mass of the disk surrounding the post-merger object. We compare these results with those obtained within the one-family scenario and we conclude that relevant signatures of the two-families scenario can be suggested, in particular: the possibility of a rapid collapse to a black hole for masses even smaller than the ones associated to GW170817; during the first milliseconds, oscillations of the postmerger remnant at frequencies higher than the ones obtained in the one-family scenario; a large value of the mass dynamically ejected and a small mass of the disk, for binaries of low total mass. Finally, based on a population synthesis analysis, we present estimates of the number of mergers for: two hadronic stars; hadronic star - strange quark star; two strange quark stars. We show that for unequal mass systems and intermediate values of the total mass, the merger of a hadronic star and a strange quark star is very likely (GW170817 has a possible interpretation into this category of mergers). On the other hand, mergers of two strange quark stars are strongly suppressed.Comment: 18 pages, 16 figure

Génesis del partido liberal santafesino

La génesis del partido liberal santafesino está estrechamente ligada a la resolución del largo conflicto de dominación sostenido, altiva pero precariamente, por la Confederación urquicista con el Estado secesionista de Buenos Aires. Es preciso conectar la aparición de aquél con  la creciente convicción en una parte del sector dirigente de la provincia de que el precio de la unidad nacional era el reconocimiento del liderazgo porteño; aunque posteriormente se evolucionaría hacia el rechazo de toda pretensión de tutelaje mitrista. En Santa Fe nunca había existido una oposición de peso al partido federal dominante. Si en la etapa rosista hubo figuras que sumaron su concurso a los levantamientos contra el dictador porteño, como Domingo Cullen y Santiago Oroño, la preponderancia de Urquiza luego de Caseros había uniformado el panorama político santafesino y toda la dirigencia provincial militó desde entonces en las filas del Partido Nacional, encabezadas por el caudillo entrerriano, a quien, además, la ligaban intereses comunes derivados de la coparticipación en empresas lucrativas. Por lo tanto, la división política se redujo durante esa etapa a la puja de predominio entre dos círculos, el "cullista" (por José María Cullen), de tendencia más liberal y modernizante, propenso a la inclinación hacia Buenos Aires, y el "lopizta" (por Juan Pablo López), más conservador y apegado a la herencia caudillista, en actitud intransigente y combativa frente a la injerencia porteña.  Pero, en realidad, sólo después de Pavón  se producirá en la provincia un reordenamiento político en el que los sectores adheridos a la nueva situación tratarán de justificar su viraje oportunista sacando a relucir los polvorientos antecedentes "unitarios" de sus ancestros (que en verdad eran federales antirrosistas) y esto les permitirá adueñarse de la conducción de la flamante agrupación liberal de la provincia (el "Club Libertad"), inexistente antes de aquel hecho de armas y, consecuentemente, del gobierno.  Nicasio Oroño, una vez admitido -no sin esfuerzo- en el nuevo régimen, en el que se había introducido utilizando el canal que le facilitaba su integración a la familia-gobierno de los Cullen, delinearía con trazos cada vez más firmes el desdibujado perfil inicial del  liberalismo santafesino, poniendo con ello los cimientos del que, en los años subsiguientes, se converti­ría en un liderazgo innovador y progresista, radical y coherente, contrastando por lo mismo con la ambigua fisonomía que exhibió la conducción nacional que decía responder al mismo ideario.Fil: Pasquali, Patricia Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Genetic Variation in 11β-Hydroxysteroid Dehydrogenase Type 1 Predicts Adrenal Hyperandrogenism among Lean Women with Polycystic Ovary Syndrome

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Production Strategies of TiNx Coatings via Reactive High Power Impulse Magnetron Sputtering for Selective H2 Separation

This scientific work aims to optimize the preparation of titanium nitride coatings for selective H-2 separation using the Reactive High Power Impulse Magnetron Sputtering technology (RHiPIMS). Currently, nitride-based thin films are considered promising membranes for hydrogen. The first series of TiNx/Si test samples were developed while changing the reactive gas percentage (N-2%) during the process. Obtained coatings were extensively characterized in terms of morphology, composition, and microstructure. A 500 nm thick, dense TiNx coating was then deposited on a porous alumina substrate and widely investigated. Moreover, the as-prepared TiNx films were heat-treated in an atmosphere containing hydrogen in order to prove their chemical and structural stability; which revealed to be promising. This study highlighted how the RHiPIMS method permits fine control of the grown layer's stoichiometry and microstructure. Moreover, it pointed out the need for a protective layer to prevent surface oxidation of the nitride membrane by air and the necessity to deepen the study of TiNx/alumina interface in order to improve film/substrate adhesion

Survey on carbapenem-resistant bacteria in pigs at slaughter and comparison with human clinical isolates in Italy

This study is focused on resistance to carbapenems and third-generation cephalosporins in Gram-negative microorganisms isolated from swine, whose transmission to humans via pork consumption cannot be excluded. In addition, the common carriage of carbapenem-resistant (CR) bacteria between humans and pigs was evaluated. Sampling involved 300 faecal samples collected from slaughtered pigs and 300 urine samples collected from 187 hospitalised patients in Parma Province (Italy). In swine, MIC testing confirmed resistance to meropenem for isolates of Pseudomonas aeruginosa and Pseudomonas oryzihabitans and resistance to cefotaxime and ceftazidime for Escherichia coli, Ewingella americana, Enterobacter agglomerans, and Citrobacter freundii. For Acinetobacter lwoffii, Aeromonas hydrofila, Burkolderia cepacia, Corynebacterium indologenes, Flavobacterium odoratum, and Stenotrophomonas maltophilia, no EUCAST MIC breakpoints were available. However, ESBL genes (blaCTXM-1, blaCTX-M-2, blaTEM-1, and blaSHV) and AmpC genes (blaCIT, blaACC, and blaEBC) were found in 38 and 16 isolates, respectively. P. aeruginosa was the only CR species shared by pigs (4/300 pigs; 1.3%) and patients (2/187; 1.1%). P. aeruginosa ST938 carrying blaPAO and blaOXA396 was detected in one pig as well as an 83-year-old patient. Although no direct epidemiological link was demonstrable, SNP calling and cgMLST showed a genetic relationship of the isolates (86 SNPs and 661 allele difference), thus suggesting possible circulation of CR bacteria between swine and humans

Surface Optimization of Commercial Porous Ti Substrates by EPD of Titanium Nitride

In this work, the infiltration of TiN powders by electrophoretic deposition (EPD) in aqueous media was considered as alternative method to reduce the size craters and the roughness of commercial porous Ti substrates. Ti substrates can be used as suitable supports for the deposition of dense hydrogen separation TiNx-based membranes by physical vapor deposition (PVD) techniques. The influence of various EPD deposition parameters on surface morphology and roughness of TiN-infiltrated substrates were investigated in order to optimize their surface properties. The results suggest that a multi-step EPD procedure is an effective technique for reducing substrate surface defects of commercial porous Ti substrates which could then be successfully used as proper supports for the deposition of dense and defect-free TiNx layers, also aligning the thermal mismatch between the active layer and the porous substrate

How Porcine Acellular Dermal Matrix Influences the Development of the Breast Capsule 1 Year after Implantation: A Histopathological Analysis

Background: In prepectoral breast reconstruction (PPBR) the acellular dermal matrix (ADM)'s integration capacity into the tissue is known. The aim of this study was to analyze the effect of the ADM on development and composition of the peri-implant breast capsule in a dynamic setting of breast tissue expansion during two-stage prepectoral breast reconstruction.Methods: This is a prospective single-center study in which 50 patients who underwent mastectomy and breast reconstruction with prepectoral tissue expander and Braxon ADM (group A) and submuscular tissue expander (group B) were enrolled. One-year post implantation hematoxylin & eosin (H&E) staining and immunohistochemistry analyses were done on capsule tissue samples.Results: The analysis conducted on H&E-stained samples showed a significant reduction of cellular density and a decrease of the cellular infiltration in capsules of ADM-covered expanders compared with naked expander capsules (P < 0.05). The immunohistochemical analyses showed that group A capsules presented significantly less M1 CD68+ macrophages (P < 0.05), lower alfa-SMA expression levels, and a lower number of myofibroblasts (P < 0.05) compared with group B capsules. Presence of lymphatic vessels was minimally detected in both groups.Conclusions: The ADM presence around the prepectoral tissue expander influences the development of the peri-implant capsule, causing a significant reduction of the number of cells and inflammatory infiltrate, especially M1 macrophages and myofibroblasts. The ADM Braxon is therefore effective in creating a noninflamed capsule around the implant and in dynamic tissue conditions, and such an environment is maintained in time

Intracerebral administration of Interleukin-12 (IL-12) and IL-18 modifies the course of mouse scrapie

BACKGROUND: Prion diseases are characterised by a neurodegenerative pattern in which the function of immune system remains still elusive. In the present study, we evaluate if an exogenous treatment with Interleukin-12 (IL-12) and IL-18, able to activate microglia, is able to affect scrapie pathogenesis. RESULTS: Cytokines injected intracranially, induced a strong inflammatory response characterised by TNF-α production and microglia activation. Two groups of mice were injected intracerebrally with high dose of ME7 strain of scrapie containing IL-12 and IL-18 or sterile saline. Cytokines-treated mice showed a more pronounced accumulation of PrP(Sc )in brain tissues at 90 days post-inoculation and a shorter mean survival times than untreated mice. CONCLUSION: We can conclude that intracerebral administration of IL-12 and IL-18 can modulate scrapie pathogenesis possibly through a microglia-mediated pattern