Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1

Characterization of contaminant phases in foraminifera carbonates by electron microprobe mapping.

The advent of new microanalytical techniques such as electron microprobe mapping (EMP) and laser ablation microsamplers coupled to mass spectrometers (LA-ICP-MS) provides a new array of possibilities to explore in great detail the trace elements distribution in foraminiferal carbonates. Here we apply these techniques to characterize diagenetic phases present in foraminiferal shells from Ocean Drilling Program Site 1240 in the Panama Basin, a region characterized by the presence of manganese-rich minerals in the sediments. The combined application of these techniques allows us to characterize the elemental and spatial distribution on the surface and across the foraminiferal shells. Results illustrate the presence of at least two different Mn-rich contaminant phases in the foraminiferal carbonates: Mn-rich carbonates and ferromanganese oxides. Elemental maps also highlight the relevance of the foraminifera shell texture and porosity in the distribution and formation of these contaminant phases. In the case of Neogloboquadrina dutertrei, Mn phases form a continuous thin layer in the inner part of the chambers, whereas for Globigerinoides ruber, Mn phases have a rather patchy distribution and are usually found within the pores. Significant high magnesium concentrations are always associated with these Mn-rich phases. These new findings support the need of removing these Mn-rich contaminant phases in order to measure accurately the Mg/Ca ratios in the foraminifera shell and therefore obtain reliable Mg/Ca paleotemperature reconstructions

Targeting the transforming growth factor-β signaling pathway in human cancer

The transforming growth factor-β (TGF-β) signaling pathway plays a pivotal role in diverse cellular processes. TGF-β switches its role from tumor suppressor in normal or dysplastic cells to a tumor promoter in advanced cancers. It is widely believed that Smad-dependent pathway is involved in TGF-β tumor suppressive functions, whereas activation of Smad-independent pathways coupled with the loss of tumor suppressor functions of TGF-β is important for its pro-oncogenic functions. TGF-β signaling has been considered as a very suitable therapeutic target. The discovery of oncogenic actions of TGF-β has generated a great deal of enthusiasm for developing TGF-β signaling inhibitors for the treatment of cancer. The challenge is to identify the group of patients where targeted tumors are not only refractory to TGF-β-induced tumor suppressor functions but also responsive to tumor promoting effects of TGF-β. TGF-β pathway inhibitors including small and large molecules have now entered clinical trials. Preclinical studies with these inhibitors have shown promise in a variety of different tumor models. Here we emphasize on the mechanisms of signaling and specific targets of the TGF-β pathway that are critical effectors of tumor progression and invasion. This report also focuses on the therapeutic intervention of TGF-β signaling in human cancers