Rational design of cancer gene panels with OncoPaD

Software: Docker 1.12+.A tool aimed at the rational design of cancer gene panels. It estimates the cost-effectiveness of the designed panel on a cohort of tumors and provides reports on the importance of individual mutations for tumorigenesis or therapy

Mutational landscape of RNA-binding proteins in human cancers

RNA Binding Proteins (RBPs) are a class of post-transcriptional regulatory molecules which are increasingly documented to be dysfunctional in cancer genomes. However, our current understanding of these alterations is limited. Here, we delineate the mutational landscape of ∼1300 RBPs in ∼6000 cancer genomes. Our analysis revealed that RBPs have an average of ∼3 mutations per Mb across 26 cancer types. We identified 281 RBPs to be enriched for mutations (GEMs) in at least one cancer type. GEM RBPs were found to undergo frequent frameshift and inframe deletions as well as missense, nonsense and silent mutations when compared to those that are not enriched for mutations. Functional analysis of these RBPs revealed the enrichment of pathways associated with apoptosis, splicing and translation. Using the OncodriveFM framework, we also identified more than 200 candidate driver RBPs that were found to accumulate functionally impactful mutations in at least one cancer. Expression levels of 15% of these driver RBPs exhibited significant difference, when transcriptome groups with and without deleterious mutations were compared. Functional interaction network of the driver RBPs revealed the enrichment of spliceosomal machinery, suggesting a plausible mechanism for tumorogenesis while network analysis of the protein interactions between RBPs unambiguously revealed the higher degree, betweenness and closeness centrality for driver RBPs compared to non-drivers. Analysis to reveal cancer-specific Ribonucleoprotein (RNP) mutational hotspots showed extensive rewiring even among common drivers between cancer types. Knockdown experiments on pan-cancer drivers such as SF3B1 and PRPF8 in breast cancer cell lines, revealed cancer subtype specific functions like selective stem cell features, indicating a plausible means for RBPs to mediate cancer-specific phenotypes. Hence, this study would form a foundation to uncover the contribution of the mutational spectrum of RBPs in dysregulating the post-transcriptional regulatory networks in different cancer types

研究課題

An Excel file containing information on lncRNAs probed for FM bias. The first sheet contains a README file with details on the contents of the other two sheets. The second sheet contains the list of all lncRNAs probed, a summary of their biological function, and the original source from which we extracted them. The third sheet contains the FM bias p value computed for each significantly FM biased lncRNA in each cohort. (ODS 13 kb

Variabilidad genética, diversidad fenotípica e identificación de poblaciones sobresalientes de maíz cacahuacintle

En el año 2001 se hizo un estudio con el objetivo de estimar variabilidad genética, diversidad fenotípica e identificar poblaciones sobresalientes de Cacahuacintle. El material genético, consistente en 34 poblaciones, fue evaluado en un diseño experimental de bloques completos al azar con tres repeticiones por localidad. Los resultados indicaron lo siguiente: 1) Hubo poca variabilidad genética entre Cacahuacintles. 2) Hubo cuatro grupos de variables independientes: a) rendimiento de grano, diámetro de mazorca y alturas de planta y mazorca, b) longitud, peso de olote y de grano por mazorca, c) número de hileras de grano, y d) peso volumétrico del grano. 3) El análisis de conglomerados clasificó a los 34 Cacahuacintles en tres grupos; el grupo 3 estuvo integrado por las poblaciones con rendimientos entre 5.04 y 5.38 t ha-1En el año 2001 se hizo un estudio con el objetivo de estimar variabilidad genética, diversidad fenotípica e identiÀcar poblaciones sobresalientes de Cacahuacintle. El material genético, consistente en 34 poblaciones, fue evaluado en un diseño experimental de bloques completos al azar con tres repeticiones por localidad. Los resultados indicaron lo siguiente: 1) Hubo poca variabilidad genética entre Cacahuacintles. 2) Hubo cuatro grupos de variables independientes: a) rendimiento de grano, diámetro de mazorca y alturas de planta y mazorca, b) longitud, peso de olote y de grano por mazorca, c) número de hileras de grano, y d) peso volumétrico del grano. 3) El análisis de conglomerados clasiÀcó a los 34 Cacahuacintles en tres grupos; el grupo 3 estuvo integrado por las poblaciones con rendimientos entre 5.04 y 5.38 t ha-1

Beyond the standard seesaw: neutrino masses from Kahler operators and broken supersymmetry

We investigate supersymmetric scenarios in which neutrino masses are generated by effective d=6 operators in the Kahler potential, rather than by the standard d=5 superpotential operator. First, we discuss some general features of such effective operators, also including SUSY-breaking insertions, and compute the relevant renormalization group equations. Contributions to neutrino masses arise at low energy both at the tree level and through finite threshold corrections. In the second part we present simple explicit realizations in which those Kahler operators arise by integrating out heavy SU(2)_W triplets, as in the type II seesaw. Distinct scenarios emerge, depending on the mechanism and the scale of SUSY-breaking mediation. In particular, we propose an appealing and economical picture in which the heavy seesaw mediators are also messengers of SUSY breaking. In this case, strong correlations exist among neutrino parameters, sparticle and Higgs masses, as well as lepton flavour violating processes. Hence, this scenario can be tested at high-energy colliders, such as the LHC, and at lower energy experiments that measure neutrino parameters or search for rare lepton decays.Comment: LaTeX, 34 pages; some corrections in Section

Biomarkers of palbociclib response in hormone receptor-positive advanced breast cancer from the PARSIFAL trial

Biomarkers; Hormone receptor-positive; Advanced breast cancerBiomarcadores; Cáncer de mama avanzado; Receptor hormonal positivoBiomarcadors; Càncer de mama avançat; Receptor hormonal positiuCurrently, there are no clinically actionable biomarkers to predict patient to cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) plus endocrine therapy for hormone receptor (HR)[+]/ human epidermal growth factor receptor 2 (HER2)[-] advanced breast cancer (ABC). Herein, we report an exploratory biomarker substudy (transFAL) from a subset of patients included in PARSIFAL, a phase II randomized clinical trial that evaluated first-line palbociclib plus fulvestrant or letrozole for HR[+]/HER2[−] ABC. No definitive biomarkers were discovered, however, worse outcomes were found with CDK6 postivity (p = 0.008), ER negativity (p = 0.008), high Ki67 (p = 0.04), and TP53 mutation (p = 0.04). ctDNA density (p = 0.036) and number of mutations (p = 0.033) at baseline were significantly higher for resistant patients. Our study reveals future directions to explore in the goal to determine biomarkers of response to CDK4/6i

Improving the prediction of the functional impact of cancer mutations by baseline tolerance transformation

High-throughput prioritization of cancer-causing mutations (drivers) is a key challenge of cancer genome projects, due to the number of somatic variants detected in tumors. One important step in this task is to assess the functional impact of tumor somatic mutations. A number of computational methods have been employed for that purpose, although most were originally developed to distinguish disease-related nonsynonymous single nucleotide variants (nsSNVs) from polymorphisms. Our new method, transformed Functional Impact score for Cancer (transFIC), improves the assessment of the functional impact of tumor nsSNVs by taking into account the baseline tolerance of genes to functional variants.We acknowledge funding from the Spanish Ministry of Science and Technology (grant number SAF2009-06954) and the Spanish National Institute of Bioinformatics (INB)

Las simulaciones, una alternativa para el estudio de los protocolos P2P

Resumen: La arquitectura y funcionalidad de las redes P2P hacen que sean atractivas para ser utilizadas en ambientes distribuidos locales y aplicaciones de amplia distribución, el análisis de sus protocolos de ruteo bajo diferentes ataques como son los de negación de existencia y de servicio, así como su análisis estadístico, hacen que las simulaciones cobren gran importancia, y sean una alternativa adecuada para su estudio, pues existen varios protocolosde esta categoría como Pastry o Chord, los cuales son de gran importancia dada su amplia utilización en diferentes aplicaciones para el envío y recuperación satisfactoria de información tanto en la nube como en aplicaciones distribuidas, razón por la cual su análisis es importante, este trabajo se centra en Pastry dado que es utilizado en la versión Azure de Microsoft Windows. Palabras clave: Redes P2P, DoS, simulaciones, cómputo en la nube

Origins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues

López-Bigas, Núri