Suchergebnisse

The recent development of the CRISPR/Cas9 system as an efficient and accessi- ble programmable genome-editing tool has revolutionized basic science research. CRISPR/Cas9 system-based technologies have armed researchers with new power- ful tools to unveil the impact of genetics on disease development by enabling the creation of precise cellular and animal models of human diseases. The therapeutic potential of these technologies is tremendous, particularly in gene therapy, in which a patient-specific mutation is genetically corrected in order to treat human dis- eases that are untreatable with conventional therapies. However, the translation of CRISPR/Cas9 into the clinics will be challenging, since we still need to improve the efficiency, specificity and delivery of this technology. In this review, we focus on several in vitro, in vivo and ex vivo applications of the CRISPR/Cas9 system in human disease-focused research, explore the potential of this technology in translational medicine and discuss some of the major challenges for its future use in patients ; This project has received funding from the 'European Union's Horizon 2020 research and innovation programme under grant agreement No (748585)

Melanoma is the deadliest form of skin cancer being responsible for 80% of skin cancer deaths. Fur- thermore, the incidence of metastatic melanoma has increased over the past three decades with a mortality rate that continues to rise faster than most of all other cancers. The last few years have witnessed an unparalleled change in treatment options for patients with metastatic melanoma by the development of new therapeutic strate- gies like targeted therapies and immunotherapies that highly improved the patient's prognosis. Despite the para- digm-shifting success of these novel treatments, their effectiveness is still limited by intrinsic or acquired resis- tance. The objective of this review is to provide an overview of the new available treatment modalities, criteria to select patients who might benefit from a specific therapy, mechanisms of innate and acquired resistance to these treatments and to discuss strategies to overcome drug resistance. ; 'This project has received funding from the 'European Union's Horizon 2020 research and innovation programme under grant agreement No 748585'

Context Reproduction is a critical component of fitness, and understanding factors that influence temporal and spatial dynamics in reproductive output is important for effective management and conservation. Although several indices of reproductive output for wide-ranging species, such as migratory birds, exist, there has been no theoretical justification for their estimators or associated measures of variance. Aims The aims of our research were to develop statistical justification for an estimator of reproduction and associated variances on the basis of an existing national wing-collection survey and banding data, and to demonstrate the applicability of this estimator to a migratory game bird. Methods We used a Bayesian hierarchical modelling approach to integrate wing-collection data, which provides information on population age ratios, and band-recovery data, which provides information on recovery probabilities of various age classes, for American woodcock (Scolopax minor) to estimate productivity and associated measures of variance. We present two models of relative vulnerability between age classes: one model assumed that adult recovery probabilities were higher, but that annual fluctuations were synchronous between the two age classes (i.e. an additive effect of age and year). The second model assumed that adults, on average, had higher recovery probabilities than did juveniles and that annual fluctuations were asynchronous through time (i.e. an interaction between age and year). Key results Fitting our models within a hierarchical Bayesian framework efficiently incorporates the two data types into a single estimator and derives appropriate variances for the productivity estimator. Further, use of Bayesian methods enabled us to derive credible intervals that avoid the reliance on asymptotic assumptions. When applied to American woodcock data, the additive model resulted in biologically realistic and more precise age-ratio estimates each year and is adequate when the relative vulnerability to sampling only slightly varies or does not vary among components of a population (e.g. age, sex class) among years. Therefore, we recommend using woodcock indices from our analysis based on this model. Conclusions We provide a flexible modelling framework for estimating productivity and associated variances that can incorporate ecological covariates to explore various factors that could drive annual dynamics in productivity. Applying our model to the American woodcock data indicated that assumptions about the variability in relative recovery probabilities could greatly influence the precision of our productivity estimator. Therefore, researchers should carefully consider the assumption of temporally variable relative recovery probabilities (i.e. ratio of juvenile to adults' recovery probability) for different age classes when applying this estimator. Implications Several national and international management strategies for migratory game birds in North America rely on measures of productivity from harvest survey parts collections, without a justification of the estimator or providing estimates of precision. We derive an estimator of productivity with realistic measures of uncertainty that can be directly incorporated into management plans or ecological studies across large spatial scales.

FOXO factors are tumour suppressor proteins commonly inactivated in human tumours by posttranslational modifications. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. Therefore, the pharmacological activation of FOXO proteins is considered as an attractive therapeutic approach to treat cancer and age-related diseases. In order to identify agents capable of activating FOXOs, we tested a collection of small chemical compounds using image-based high content screening technology. Here, we report the discovery of LOM612 (compound 1a), a newly synthesized isothiazolonaphthoquinone as a potent FOXO relocator. Compound 1a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a and FOXO1 in U2OS cells in a dose-dependent manner. This activity does not affect the subcellular localization of other cellular proteins including NFkB or inhibit CRM1-mediated nuclear export. Furthermore, compound 1a shows a potent antiproliferative effect in human cancer cell lines. ; This project has received funding from the 'European Union's Horizon 2020 research and innovation programme under grant agreement No 748585

Poor survival and treatment failure of patients with cancer are mainly due to resistance to therapy. Tribbles homologue 2 (TRIB2) has recently been identified as a protein that promotes resistance to several anti-cancer drugs. In this study, RNA sequencing and bioinformatics analysis were used with the aim of characterizing the impact of TRIB2 on the expression of genes and developing pharmacological strategies to revert these TRIB2-mediated changes, thereby overcoming therapy resistance. We show that two naturally occurring alkaloids, harmine and piperlongumine, inverse the gene expression profile produced by TRIB2 and sensitize cancer cells to anti-cancer drugs. Our data suggest that harmine and piperlongumine or similar compounds might have the potential to overcome TRIB2-mediated therapy resistance in cancer patients. ; This project has received funding from the 'European Union's Horizon 2020 research and innovation programme under grant agreement No 748585