Spatial and seasonal variations in the stable carbon isotopic composition of methane in stream sediments of eastern Amazonia

The stable carbon isotopic composition of methane (δ13 C-CH4) gas bubbles formed in the sediments of three Amazonian streams was determined over a 5-yr period. The study sites were two ' 'várzea' floodplain (Açu and Maicá) and one 'terra-firme' (Jamaraquá) streams. The δ 13C of sedimentary organic matter (SOM) from the surrounding vegetation and bottom sediments were also determined. The mean δ13C value of SOM was lower in the terra-firme (-29.6‰) than in the várzea stream (-23.8‰) as a result of less C4 plant deposition in the former. The δ 13C-CH4 values varied systematically both seasonally and spatially among the sites during all 5 yr of the study, in association with changes during hydrologic cycle. Overall, the variation in values of δ 13C-CH4 during the high water phase covered a narrower range of values, -63 to -56‰. Contrastively, during the low water phase the δ 13C-CH4 values for várzea and terra-firme streams are different and are in direct opposition. At this phase, the δ13C-CH4 at terra-firme stream is at least 20‰ depleted of 13C compared to várzea streams. Changes in organic matter sources, water levels and associated microbial degradation processes control the observed seasonal and spatial variations in net stable carbon isotopic composition of methane

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting