Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.

Melanoma is a devastating skin cancer characterized by distinct biological subtypes. Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations. Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22). Although the vast majority >90% of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious. Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found. Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo. Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found. Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP). Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs. Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models. Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma

Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism

Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While extracellular adduct formation completely blocked the cytotoxic activity of landomycins, intracellularly it led to massively decreased reduced glutathione levels. Accordingly, landomycin E strongly synergized with glutathione-depleting agents like menadione but exerted reduced activity under hypoxia. Summarizing, landomycins represent natural glutathione-depleting agents and fluorescence probes for intracellular anthraquinone-based angucycline metabolism

CoForTips Congo basin forests: tipping points for biodiversity conservation and resilience. Final Report (La modélisation des changements d’utilisation des terres dans les pays d’Afrique Centrale 2000-2030)

L'utilisation des terres est un facteur crucial pour le développement économique et l'environnement. Ainsi une terre dédiée à l’agriculture permettra une production régulière qui sera bénéfique pour satisfaire les besoins alimentaires des populations alentour et potentiellement, pour l’économie dans son ensemble. Par contre, les terres agricoles ont un contenu carbone bien inférieur à une terre forestière et sont généralement pauvres en biodiversité. Les terres peuvent être utilisées de différentes manières afin de répondre à différents objectifs et il peut être potentiellement difficile de satisfaire tous ces objectifs à la fois, donnant lieu à des choix difficiles lors de la conception des politiques. Les pays membres de la Commission des forêts d'Afrique centrale (COMIFAC) ont identifié l’initiative pour la réduction des émissions issues de la déforestation et de la dégradation forestière et l'amélioration des stocks de carbone (REDD+) comme un enjeu majeur dans la dernière revision du Plan de Convergence pour la Gestion Durable des Forêts, aux côtés de la conservation et de l’utilisation durable de la diversité biologique et de la réduction des impacts du changement climatique. Cette étude a pour objectif d’identifier les zones soumises aux pressions de conversion les plus fortes dans le futur et les conséquences en termes de production agricole, d’émissions de gaz à effet de serre (GES) et de risque de perte de biodiversité, avec pour but d’accompagner les institutions impliquées dans la REDD+ ainsi que dans la planification des Stratégies Nationales et Plans d’Action pour la Biodiversité dans les pays de la COMIFAC

Modelling Land Use Changes in the Republic of Congo 2000-2030 . A report by the REDD-PAC project.

This study is intended to assist institutions involved in REDD+ and the planning of National Strategies and Action plans for Biodiversity in the Republic of Congo by attempting to identify the areas under the greatest conversion pressures in the future and the consequences in terms of agricultural production, greenhouse gas emissions and biodiversity loss.Cette étude essaye d’identifier les zones soumises aux pressions de conversion les plus fortes dans le futur et les conséquences en termes de production agricole, d’émissions de gaz à effet de serre et de risque de perte de biodiversité. L’objectif du projet REDD-PAC est d’accompagner les institutions impliquées dans la REDD+ ainsi que dans la planification de la Stratégie Nationale et du Plan d’Action pour la Biodiversité en République du Congo

Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial

Background: The combination of paclitaxel with cisplatin or carboplatin has significant activity in non-small-cell lung cancer (NSCLC). This phase III study of chemotherapy-naïve advanced NSCLC patients was designed to assess whether response rate in patients receiving a paclitaxel/carboplatin combination was similar to that in patients receiving a paclitaxel/cisplatin combination. Paclitaxel was given at a dose of 200 mg/m2 (3-h intravenous infusion) followed by either carboplatin at an AUC of 6 or cisplatin at a dose of 80 mg/m2, all repeated every 3 weeks. Survival, toxicity and quality of life were also compared. Patients and methods: Patients were randomised to receive one of the two combinations, stratified according to centre, performance status, disease stage and histology. The primary analyses of response rate and survival were carried out on response-evaluable patients. Survival was also analysed for all randomised patients. Toxicity analyses were carried out on all treated patients. Results: A total of 618 patients were randomised. The two treatment arms were well balanced with regard to gender (83% male), age (median 58 years), performance status (83% ECOG 0-1), stage (68% IV, 32% IIIB) and histology (38% squamous cell carcinoma). In the paclitaxel/carboplatin arm, 306 patients received a total of 1311 courses (median four courses, range 1-10 courses) while in the paclitaxel/cisplatin arm, 302 patients received a total of 1321 courses (median four courses, range 1-10 courses). In only 76% of courses, carboplatin was administered as planned at an AUC of 6, while in 96% of courses, cisplatin was given at the planned dose of 80 mg/m2. The response rate was 25% (70 of 279) in the paclitaxel/carboplatin arm and 28% (80 of 284) in the paclitaxel/cisplatin arm (P = 0.45). Responses were reviewed by an independent radiological committee. For all randomised patients, median survival was 8.5 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm [hazard ratio 1.20, 90% confidence interval (CI) 1.03-1.40]; the 1-year survival rates were 33% and 38%, respectively. On the same dataset, a survival update after 22 months of additional follow-up yielded a median survival of 8.2 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm (hazard ratio 1.22, 90% CI 1.06-1.40; P = 0.019); the 2-year survival rates were 9% and 15%, respectively. Excluding neutropenia and thrombocytopenia, which were more frequent in the paclitaxel/carboplatin arm, and nausea/vomiting and nephrotoxicity, which were more frequent in the paclitaxel/cisplatin arm, the rate of severe toxicities was generally low and comparable between the two arms. Overall quality of life (EORTC QLQ-C30 and LC-13) was also similar between the two arms. Conclusions: This is the first trial comparing carboplatin and cisplatin in the treatment of advanced NSCLC. Although paclitaxel/carboplatin yielded a similar response rate, the significantly longer median survival obtained with paclitaxel/cisplatin indicates that cisplatin-based chemotherapy should be the first treatment optio