Nouvelles observations dans le dépocentre volcano-sédimentaire carbonifère du Massif du Tazekka, Moyen-Atlas, Maroc : implications sur l'évolution géodynamique de la chaîne Hercynienne

A análise integrada das estruturas tectónicas e das fácies do Complexo Vulcano Sedimentar do Maciço de Tazekka sugere que este, à escala da grande bacia carbonífera de ante país da Meseta Oriental marroquina, corresponde a um depocentro ou sub bacia em compressão controlada pela propagação, para NW, de dobras de amortecimento do cavalgamento de Hajra Sbaa el Caid. As sequências tectono sedimentares, detrito conglomeráticas e/ou tufíticas, estão associadas a um magmatismo extrusivo com basaltos, andesitos, dacitos, riodacitos e riólitos homogéneos ou piroclásticos com blocos re sedimentados. Estes vulcanitos correspondem a uma sequência sub alcalina equivalente. As sequências calco alcalinas orogénicas características de ambientes de subducção. Estes resultados, assim como a comparação das idades de contracção regional na Meseta marroquina, permitem integrar o Maciço de Tazekka num contexto de wedge top deepzone dum sistema de bacias de ante país flexural, em compressão comandada pela progressão de duas sequências de cavalgamentos prógrados, de NW, desde o Fameno Tournaisiano ao Viseano sup. Terminal Westfaliano inf., da Meseta Oriental para a Meseta Ocidental, em Marrocos setentrional

Breakdown of Conformal Invariance at Strongly Random Critical Points

We consider the breakdown of conformal and scale invariance in random systems with strongly random critical points. Extending previous results on one-dimensional systems, we provide an example of a three-dimensional system which has a strongly random critical point. The average correlation functions of this system demonstrate a breakdown of conformal invariance, while the typical correlation functions demonstrate a breakdown of scale invariance. The breakdown of conformal invariance is due to the vanishing of the correlation functions at the infinite disorder fixed point, causing the critical correlation functions to be controlled by a dangerously irrelevant operator describing the approach to the fixed point. We relate the computation of average correlation functions to a problem of persistence in the RG flow.Comment: 9 page

Comprehensive evaluation of the Copernicus Atmosphere Monitoring Service (CAMS) reanalysis against independent observations: Reactive gases

The Copernicus Atmosphere Monitoring Service (CAMS) is operationally providing forecast and reanalysis products of air quality and atmospheric composition. In this article, we present an extended evaluation of the CAMS global reanalysis data set of four reactive gases, namely, ozone (O-3), carbon monoxide (CO), nitrogen dioxide (NO2), and formaldehyde (HCHO), using multiple independent observations. Our results show that the CAMS model system mostly provides a stable and accurate representation of the global distribution of reactive gases over time. Our findings highlight the crucial impact of satellite data assimilation and emissions, investigated through comparison with a model run without assimilated data. Stratospheric and tropospheric O-3 are mostly well constrained by the data assimilation, except over Antarctica after 2012/2013 due to changes in the assimilated data. Challenges remain for O-3 in the Tropics and high-latitude regions during winter and spring. At the surface and for short-lived species (NO2), data assimilation is less effective. Total column CO in the CAMS reanalysis is well constrained by the assimilated satellite data. The control run, however, shows large overestimations of total column CO in the Southern Hemisphere and larger year-to-year variability in all regions. Concerning the long-term stability of the CAMS model, we note drifts in the time series of biases for surface O-3 and CO in the Northern midlatitudes and Tropics and for NO2 over East Asia, which point to biased emissions. Compared to the previous Monitoring Atmospheric Composition and Climate reanalysis, changes in the CAMS chemistry module and assimilation system helped to reduce biases and enhance the long-term temporal consistency of model results for the CAMS reanalysis

A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

Altres ajuts: Bayer HealthCare Pharmaceuticals Inc.Purpose: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. Patients and methods: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. Results: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C. Conclusions: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifier: NCT02835924

Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO)

Background: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. Results: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvβ3 and αvβ5 expression was neither a predictive nor a prognostic indicator. Conclusions: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment

A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen

A multicentre phase II trial to determine the efficacy of vinflunine as second-line therapy in patients with advanced transitional cell carcinoma (TCC) of the bladder; secondary objectives were to assess duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients had tumours that failed or progressed after first-line platinum-containing regimens for advanced or metastatic disease, or had progressive disease after platinum-containing chemotherapy given with adjuvant or neoadjuvant intent. Response and adverse events were assessed according to WHO criteria and NCI-CTC (version 2), respectively. Out of 51 patients treated with 320 mg m−2 of vinflunine, nine patients responded to the therapy yielding an overall response rate of 18% (95% CI: 8.4–30.9%), and 67% (95%CI: 52.1–79.3%) achieved disease control (PR+SD). Of note, responses were seen in patients with relatively poor prognostic factors such as a short (<12 months) interval from prior platinum therapy (19%, including an 11% response rate in those progressing <3 months after platinum treatment), prior treatment for metastatic disease (24%), prior treatment with vinca alkaloids (14%) and visceral involvement (20%). The median duration of response was 9.1 months (95% CI: 4.2–15.0) and the median PFS was 3.0 months (95% CI: 2.4–3.8). The median OS was 6.6 months (95% CI: 4.8–7.6). The main haematological toxicity was grade 3–4 neutropenia, observed in 67% of patients (42% of cycles). Febrile neutropenia was observed in five patients (10%) and among them two were fatal. Constipation was frequently observed (but was manageable and noncumulative) and was grade 3–4 in only 8% of patients. The incidence of grade 3 nausea and vomiting was very low (4 and 6% of patients, respectively). Neither grade 3–4 sensory neuropathy nor severe venous irritation was observed. Moreover, and of importance in this particular study population, no grade 3–4 renal function impairment was observed. Vinflunine is an active agent for the treatment of platinum-pretreated bladder cancer, and these results warrant further investigation in phase III trials, either as monotherapy or in combination with other agents as treatment of advanced/metastatic TCC of the bladder

Endogenous TNF alpha orchestrates the trafficking of neutrophils into and within lymphatic vessels during acute inflammation

This work was supported by funds from Arthritis Research UK (19913 to M.-B.V.) and the Wellcome Trust (098291/Z/12/Z to S.N.). S. A. was supported by a QMUL Principal’s Award PhD Studentship

Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m−2 q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed >6 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9–43.2%)). Among the responders, seven patients had relapsed during a period of <3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2–7.2), median progression-free survival was 3.7 months (95% CI: 2.8–4.2) and median overall survival was 14.3 months (95% CI: 9.2–19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease

Neutrophils: the forgotten cell in JIA disease pathogenesis

Juvenile idiopathic arthritis (JIA) has long been assumed to be an autoimmune disease, triggered by aberrant recognition of "self" antigens by T-cells. However, systems biology approaches to this family of diseases have suggested complex interactions between innate and adaptive immunity that underlie JIA. In particular, new data suggest an important role for neutrophils in JIA pathogenesis. In this short review, we will discuss the new data that support a role for neutrophils in JIA, discuss regulatory functions that link neutrophils to adaptive immune responses, and discuss future areas of investigation. Above all else, we invite the reader to re-consider the use of the term "autoimmunity" as applied to the family of illnesses we collectively call JIA