757 research outputs found
The role of anti-EGFR therapies in EGFR-TKI-resistant advanced non-small cell lung cancer
Anti-EGFR; Biomarcador; Inhibidor de la tirosina quinasaAnti-EGFR; Biomarcador; Inhibidor de la tirosina quinasaAnti-EGFR; Biomarker; Tyrosine kinase inhibitorEpidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the current recommended option for the first-line treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). Resistance to first-generation TKIs led to the development of second- and third-generation TKIs with improved clinical outcomes. However, sequential administration of TKIs has led to the emergence of new EGFR resistance mutations and persistent tumor cell survival. This evidence highlights the potential role of EGFR in transducing growth signals in NSCLC tumor cells. Therefore, dual inhibition of EGFR using combinations of anti-EGFR monoclonal antibodies (mAbs) and EGFR-TKIs may offer a unique treatment strategy to suppress tumor cell growth. Several clinical studies have demonstrated the benefits of dual blockade of EGFR using anti-EGFR mAbs coupled with EGFR-TKIs in overcoming treatment resistance in patients with EGFR-mutated NSCLC. However, a single treatment option may not result in the same clinical benefits in all patients with acquired resistance. Biomarkers, including EGFR overexpression, EGFR gene copy number, EGFR and KRAS mutations, and circulating tumor DNA, have been associated with improved clinical efficacy with anti-EGFR mAbs in patients with NSCLC and acquired resistance. Further investigation of biomarkers may allow patient selection for those who could benefit from anti-EGFR mAbs in combination with EGFR-TKIs. This review summarizes findings of recent studies of anti-EGFR mAbs in combination with EGFR-TKIs for the treatment of patients with EGFR-mutated NSCLC, as well as clinical evidence for potential biomarkers towards personalized targeted medicine
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
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