Late-stage tectonic evolution of the Al-Hajar Mountains, Oman: New constraints from Palaeogene sedimentary units and low-temperature thermochronometry

Mountain building in the Al-Hajar Mountains (NE Oman) occurred during two major shortening stages, related to the convergence between Africa-Arabia and Eurasia, separated by nearly 30 Ma of tectonic quiescence. Most of the shortening was accommodated during the Late Cretaceous, when northward subduction of the Neo-Tethys Ocean was followed by the ophiolites obduction on top of the former Mesozoic margin. This shortening event lasted until the latest Santonian - early Campanian. Maastrichtian to Eocene carbonates unconformably overlie the eroded nappes and seal the Cretaceous foredeep. These neo-autochthonous post-nappe sedimentary rocks were deformed, along with the underlying Cretaceous tectonic pile, during the second shortening event, itself including two main exhumation stages. In this study we combine remotely sensed structural data, seismic interpretation, field-based structural investigations and apatite (U-Th)/He (AHe) cooling ages to obtain new insights into the Cenozoic deformation stage. Seismic interpretation indicates the occurrence of a late Eocene flexural basin, later deformed by an Oligocene thrusting event, during which the post-nappe succession and the underlying Cretaceous nappes of the internal foredeep were uplifted. This stage was followed by folding of the post-nappe succession during the Miocene. AHe data from detrital siliciclastic deposits in the frontal area of the mountain chain provide cooling ages spanning from 17.3 to 42 Ma, consistent with available data for the structural culminations of Oman. Our work points out how renewal of flexural subsidence in the foredeep and uplift of the mountain belt were coeval processes, followed by layer-parallel shortening preceding final fold amplification

Ultrasound Effectiveness of Steroid Injection for hand Psoriatic Dactylitis: Results from a Longitudinal Observational Study

Introduction: To assess clinical and ultrasound effectiveness of steroid injection (local treatment, LT) into the digital flexor tendon sheath for the treatment of psoriatic dactylitis compared to systemic treatment (ST) alone. Methods: In this observational, multicentre, prospective study, 88 cases of symptomatic hand dactylitis were evaluated clinically and sonographically by high-frequency ultrasound (US) probe in both greyscale (GS) and power Doppler (PD). The presence of flexor tenosynovitis (FT), soft tissue oedema (STO), peritendon extensor inflammation and synovitis was assessed (including DACtylitis glObal Sonographic—DACTOS—score) before treatment, at 1-month (T1) and 3-months (T3) follow-up. LT was proposed to all patients. Patients refusing LT were treated with oral NSAIDs. Patients continued the same baseline csDMARDs and/or corticosteroid therapy during the whole follow-up period. US response was defined for DACTOS score < 3 and US remission for DACTOS score = 0. Results: At T3 evaluation the ST group showed a significantly higher persistence (grade > 1) of FT and STO (p < 0.001 for all) and MCP synovitis (p = 0.001). US remission was achieved only in the LT group (at T3 31% vs. 0, p < 0.001). The percentage of patients with DACTOS < 3 was significantly greater in the LT group compared with ST group, at both T1 (49% vs. 5%, p < 0.001) and T3 evaluation (76% vs. 7%, p < 0.001). In multiple conditional logistic regression analysis, the only factor associated with US remission was LT (T3 odds ratio = 41.21, p < 0.001). Conclusions: US confirmed the effectiveness of steroid injection for dactylitis by demonstrating that it involves the resolution of extra-articular inflammation, in particular FT and STO

Activation of Fas/FasL pathway and the role of c-FLIP in primary culture of human cholangiocarcinoma cells

Intrahepatic cholangiocarcinoma (iCCA) represents a heterogeneous group of malignancies emerging from the biliary tree, often in the context of chronic bile ducts inflammation. The immunological features of iCCA cells and their capability to control the lymphocytes response have not yet been investigated. The aims of the present study were to evaluate the interaction between iCCA cells and human peripheral blood mononuclear cells (PBMCs) and the role of Fas/FasL in modulating T-cells and NK-cells response after direct co-culture. iCCA cells express high levels of Fas and FasL that increase after co-culture with PBMCs inducing apoptosis in CD4(+), CD8(+) T-cells and in CD56(+) NK-cells. In vitro, c-FLIP is expressed in iCCA cells and the co-culture with PBMCs induces an increase of c-FLIP in both iCCA cells and biliary tree stem cells. This c-FLIP increase does not trigger the caspase cascade, thus hindering apoptotis of iCCA cells which, instead, underwent proliferation. The increased expression of Fas, FasL and c-FLIP is confirmed in situ, in human CCA and in primary sclerosing cholangitis. In conclusion our data indicated that iCCA cells have immune-modulatory properties by which they induce apoptosis of T and NK cells, via Fas/FasL pathway, and escape inflammatory response by up-regulating c-FLIP system

Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells

BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naive cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGF beta/SMAD (transforming growth factor-beta/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naive cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.Fapesp-grant number 2012/04194-1, 2013/05172-4, 2014/24400-0 and 2015/10821-7, CNPq-grant number 150447/2013-2 and 471512/2013-3 and PRODOC-grant no 3193-32/2010. Work in the lab of KS Smalley was supported by the National Institutes of Health grants R01 CA161107, R21 CA198550, and Skin SPORE grant P50 CA168536info:eu-repo/semantics/publishedVersio

Expert consensus document:Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted

SupportingProactive Reuse by Identifying EquivalentRequirements

Though very important in software engineering, linking artifacts of the same type (clone detection) or of different types (traceability recovery) is extremely tedious, error-prone and requires significant effort. Past research focused on supporting analysts with mechanisms based on Natural Language Processing (NLP) to identify candidate links. Because a plethora of NLP techniques exists, and their performances vary among contexts, it is important to characterize them according to the provided level of support. The aim of this paper is to characterize a comprehensive set of NLP techniques according to the provided level of support to the human analyst in detecting equivalent requirements. The characterization consists on a case study, featuring real requirements, in the context in which SELEX Sistemi Integrati is involved, i.e. the defense and aerospace domain. The major result from the case study is that simple NLP are more precise than complex ones

SupportingProactive Reuse by Identifying EquivalentRequirements

Though very important in software engineering, linking artifacts of the same type (clone detection) or of different types (traceability recovery) is extremely tedious, error-prone and requires significant effort. Past research focused on supporting analysts with mechanisms based on Natural Language Processing (NLP) to identify candidate links. Because a plethora of NLP techniques exists, and their performances vary among contexts, it is important to characterize them according to the provided level of support. The aim of this paper is to characterize a comprehensive set of NLP techniques according to the provided level of support to the human analyst in detecting equivalent requirements. The characterization consists on a case study, featuring real requirements, in the context in which SELEX Sistemi Integrati is involved, i.e. the defense and aerospace domain. The major result from the case study is that simple NLP are more precise than complex ones