Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma

Background: Ipilimumab is an approved immunotherapy that has shown an overall survival benefit in patients with cutaneous metastatic melanoma in two phase III trials. As results of registrational trials might not answer all questions regarding safety and efficacy of ipilimumab in patients with advanced melanoma seen in daily clinical practice, the Dermatologic Cooperative Oncology Group conducted a phase II study to assess the efficacy and safety of ipilimumab in patients with different subtypes of metastatic melanoma. Patients and methods: We undertook a multicenter phase II study in melanoma patients irrespective of location of the primary melanoma. Here we present data on patients with pretreated metastatic cutaneous, mucosal and occult melanoma who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs),including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. Results: 103 pretreated patients received at least one dose of ipilimumab, including 83 cutaneous, seven mucosal and 13 occult melanomas. 1-year OS rates for cutaneous, mucosal and occult melanoma were 38 %,14 % and 27 %,respectively. Median OS was 6.8 months (95 % CI 5.3-9.9) for cutaneous, 9.6 months (95 % CI 1.6-11.1) for mucosal, and 9.9 months (lower 95 % CI 2.3, upper 95 % CI non-existent) for occult melanoma. Overall response rates for cutaneous, mucosal and occult melanoma were 16 %,17 % and 11 %,respectively. Eleven patients had partial response (16 %) and ten patients experienced stable disease (14 %),none achieved a complete response. Treatment-related AEs were observed in 71 patients (69 %),including 20 grade 3-4 events (19 %). No new and unexpected safety findings were noted. Conclusions: Ipilimumab is a treatment option for pretreated patients with advanced cutaneous melanoma seen in daily routine. Toxicity was manageable when treated as per protocol-specific guidelines

Overview of BioCreative II gene normalization

Background: The goal of the gene normalization task is to link genes or gene products mentioned in the literature to biological databases. This is a key step in an accurate search of the biological literature. It is a challenging task, even for the human expert; genes are often described rather than referred to by gene symbol and, confusingly, one gene name may refer to different genes (often from different organisms). For BioCreative II, the task was to list the Entrez Gene identifiers for human genes or gene products mentioned in PubMed/MEDLINE abstracts. We selected abstracts associated with articles previously curated for human genes. We provided 281 expert-annotated abstracts containing 684 gene identifiers for training, and a blind test set of 262 documents containing 785 identifiers, with a gold standard created by expert annotators. Inter-annotator agreement was measured at over 90%. Results: Twenty groups submitted one to three runs each, for a total of 54 runs. Three systems achieved F-measures (balanced precision and recall) between 0.80 and 0.81. Combining the system outputs using simple voting schemes and classifiers obtained improved results; the best composite system achieved an F-measure of 0.92 with 10-fold cross-validation. A 'maximum recall' system based on the pooled responses of all participants gave a recall of 0.97 (with precision 0.23), identifying 763 out of 785 identifiers. Conclusion: Major advances for the BioCreative II gene normalization task include broader participation (20 versus 8 teams) and a pooled system performance comparable to human experts, at over 90% agreement. These results show promise as tools to link the literature with biological databases

Developing Transdisciplinary Approaches to Sustainability Challenges: The Need to Model Socio-Environmental Systems in the Longue Durée

Human beings are an active component of every terrestrial ecosystem on Earth. Although our local impact on the evolution of these ecosystems has been undeniable and extensively documented, it remains unclear precisely how our activities are altering them, in part because ecosystems are dynamic systems structured by complex, non-linear feedback processes and cascading effects. We argue that it is only by studying human–environment interactions over timescales that greatly exceed the lifespan of any individual human (i.e., the deep past or longue durée), we can hope to fully understand such processes and their implications. In this article, we identify some of the key challenges faced in integrating long-term datasets with those of other areas of sustainability science, and suggest some useful ways forward. Specifically, we (a) highlight the potential of the historical sciences for sustainability science, (b) stress the need to integrate theoretical frameworks wherein humans are seen as inherently entangled with the environment, and (c) propose formal computational modelling as the ideal platform to overcome the challenges of transdisciplinary work across large, and multiple, geographical and temporal scales. Our goal is to provide a manifesto for an integrated scientific approach to the study of socio-ecological systems over the long term

Developing Transdisciplinary Approaches to Sustainability Challenges: The Need to Model Socio-Environmental Systems in the Longue Durée

Human beings are an active component of every terrestrial ecosystem on Earth. Although our local impact on the evolution of these ecosystems has been undeniable and extensively documented, it remains unclear precisely how our activities are altering them, in part because ecosystems are dynamic systems structured by complex, non-linear feedback processes and cascading effects. We argue that it is only by studying human–environment interactions over timescales that greatly exceed the lifespan of any individual human (i.e., the deep past or longue durée), we can hope to fully understand such processes and their implications. In this article, we identify some of the key challenges faced in integrating long-term datasets with those of other areas of sustainability science, and suggest some useful ways forward. Specifically, we (a) highlight the potential of the historical sciences for sustainability science, (b) stress the need to integrate theoretical frameworks wherein humans are seen as inherently entangled with the environment, and (c) propose formal computational modelling as the ideal platform to overcome the challenges of transdisciplinary work across large, and multiple, geographical and temporal scales. Our goal is to provide a manifesto for an integrated scientific approach to the study of socio-ecological systems over the long term

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Sainte-Marie-aux-Mines, Wegscheid, Sewen (Haut-Rhin). Mines et métallurgie des métaux non-ferreux en Alsace du haut Moyen Âge au xviie s.

Le projet collectif de recherche Mines et métallurgie des métaux non-ferreux en Alsace du haut Moyen Âge au xviie s. regroupe différentes actions (prospections, sondages et fouilles) qui s’inscrivent dans une volonté de comprendre l’évolution des savoir-faire et l’organisation socio-économique de la production d’argent, cuivre et plomb sur une période de neuf siècles. En 2017, les opérations ont été poursuivies sur deux secteurs : au nord des Vosges moldanubiennes, sur le massif de l’Altenber..

Sainte-Marie-aux-Mines, Wegscheid, Sewen (Haut-Rhin). Mines et métallurgie des métaux non-ferreux en Alsace du haut Moyen Âge au xviie s.

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