Cancer gene prioritization by integrative analysis of mRNA expression and DNA copy number data: a comparative review

A variety of genome-wide profiling techniques are available to probe complementary aspects of genome structure and function. Integrative analysis of heterogeneous data sources can reveal higher-level interactions that cannot be detected based on individual observations. A standard integration task in cancer studies is to identify altered genomic regions that induce changes in the expression of the associated genes based on joint analysis of genome-wide gene expression and copy number profiling measurements. In this review, we provide a comparison among various modeling procedures for integrating genome-wide profiling data of gene copy number and transcriptional alterations and highlight common approaches to genomic data integration. A transparent benchmarking procedure is introduced to quantitatively compare the cancer gene prioritization performance of the alternative methods. The benchmarking algorithms and data sets are available at http://intcomp.r-forge.r-project.orgComment: PDF file including supplementary material. 9 pages. Preprin

Impact of Linear-PWM and MPC controllers on the power device losses in a grid-tied two-level inverter

This paper presents a comparative analysis of the estimated power losses and device junction temperatures in a two-level grid-tied converter commanded by a linear current controller with a pulse-with-modulator (PWM) or a finite-control-set (FCS) model predictive controller (MPC). This analysis is performed for two points of operation: (a) converter delivering only active power to the grid, (b) exchanging capacitive-reactive power with the grid (STATCOM). Using an electrothermal model based on the firing signals and measured converter currents, the simulation results show the important role of the operating point and control methodology of the converter losses and device junction temperature excursions. The results show that using the MPC controller improves the converter performance when the converter delivers only active power to the grid. In the case of STATCOM operation the total losses are similar, but there is a relative increase of the losses on the diodes. The use of SiC Schottky diodes has been evaluated, with an improvement of the converter performance for both controllers

Power device losses in two-level converters with direct current controllers for grid connected applications

Direct current controllers have been widely used in grid-tied applications and electric drives. Direct controllers select the switching states of the converter without the intervention of a modulation stage. In comparison with PWM based controllers, direct controllers have a faster dynamic response to reference-tracking and disturbance rejection. The different control strategies can affect the total converter losses and device loss distribution; hence it is important to evaluate them when novel control methodologies are presented and compare them to the conventional PWM current controllers. To this end, fully electrothermal simulations can be paramount. Using a grid connected two-level converter, this paper evaluates the power device losses and the resulting junction temperatures excursions of the power semiconductors chips when a direct current controller is used and compares the results to those obtained with PWM controllers working at the same operating points

Creación de un Laboratorio de Análisis Socio-Político de América Latina (AMELAT -LAB)

El objetivo principal de este proyecto era crear un espacio de colaboración entre estudiantes, investigadores y profesores para el análisis y comprensión de problemáticas y fenómenos sociales y politicos actuales en América Latina

Combined clinical and genomic signatures for the prognosis of early stage non-small cell lung cancer based on gene copy number alterations

BACKGROUND: The development of a more refined prognostic methodology for early non-small cell lung cancer (NSCLC) is an unmet clinical need. An accurate prognostic tool might help to select patients at early stages for adjuvant therapies. RESULTS: A new integrated bioinformatics searching strategy, that combines gene copy number alterations and expression, together with clinical parameters was applied to derive two prognostic genomic signatures. The proposed methodology combines data from patients with and without clinical data with a priori information on the ability of a gene to be a prognostic marker. Two initial candidate sets of 513 and 150 genes for lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), respectively, were generated by identifying genes which have both: a) significant correlation between copy number and gene expression, and b) significant prognostic value at the gene expression level in external databases. From these candidates, two panels of 7 (ADC) and 5 (SCC) genes were further identified via semi-supervised learning. These panels, together with clinical data (stage, age and sex), were used to construct the ADC and SCC hazard scores combining clinical and genomic data. The signatures were validated in two independent datasets (n = 73 for ADC, n = 97 for SCC), confirming that the prognostic value of both clinical-genomic models is robust, statistically significant (P = 0.008 for ADC and P = 0.019 for SCC) and outperforms both the clinical models (P = 0.060 for ADC and P = 0.121 for SCC) and the genomic models applied separately (P = 0.350 for ADC and P = 0.269 for SCC). CONCLUSION: The present work provides a methodology to generate a robust signature using copy number data that can be potentially used to any cancer. Using it, we found new prognostic scores based on tumor DNA that, jointly with clinical information, are able to predict overall survival (OS) in patients with early-stage ADC and SCC

Landscape of somatic allelic imbalances and copy number alterations in HER2-amplified breast cancer

Introduction: Human epidermal growth factor receptor 2 (HER2)-amplified breast cancer represents a clinically well-defined subgroup due to availability of targeted treatment. However, HER2-amplified tumors have been shown to be heterogeneous at the genomic level by genome-wide microarray analyses, pointing towards a need of further investigations for identification of recurrent copy number alterations and delineation of patterns of allelic imbalance. Methods: High-density whole genome array-based comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) array data from 260 HER2-amplified breast tumors or cell lines, and 346 HER2-negative breast cancers with molecular subtype information were assembled from different repositories. Copy number alteration (CNA), loss-of-heterozygosity (LOH), copy number neutral allelic imbalance (CNN-AI), subclonal CNA and patterns of tumor DNA ploidy were analyzed using bioinformatical methods such as genomic identification of significant targets in cancer (GISTIC) and genome alteration print (GAP). The patterns of tumor ploidy were confirmed in 338 unrelated breast cancers analyzed by DNA flow cytometry with concurrent BAC aCGH and gene expression data. Results: A core set of 36 genomic regions commonly affected by copy number gain or loss was identified by integrating results with a previous study, together comprising > 400 HER2-amplified tumors. While CNN-AI frequency appeared evenly distributed over chromosomes in HER2-amplified tumors, not targeting specific regions and often < 20% in frequency, the occurrence of LOH was strongly associated with regions of copy number loss. HER2-amplified and HER2-negative tumors stratified by molecular subtypes displayed different patterns of LOH and CNN-AI, with basal-like tumors showing highest frequencies followed by HER2-amplified and luminal B cases. Tumor aneuploidy was strongly associated with increasing levels of LOH, CNN-AI, CNAs and occurrence of subclonal copy number events, irrespective of subtype. Finally, SNP data from individual tumors indicated that genomic amplification in general appears as monoallelic, that is, it preferentially targets one parental chromosome in HER2-amplified tumors. Conclusions: We have delineated the genomic landscape of CNAs, amplifications, LOH, and CNN-AI in HER2-amplified breast cancer, but also demonstrated a strong association between different types of genomic aberrations and tumor aneuploidy irrespective of molecular subtype

SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair

The research leading to these results is supported by Cancer Research UK (XYG, RAB, EG, PM, PE, SG, C Santos, AJR, NM, PAB, AS and C Swanton), Breast Cancer Research Foundation (C Swanton and NK), Medical Research Council (ID: G0902275 to MG and C Santos; ID: G0701935/2 to AJR and C Swanton), the Danish Cancer Society (AMM, J Bartkova and J Bartek), the Lundbeck Foundation (R93-A8990 to J Bartek), the Ministry of the interior of the Czech Republic (grant VG20102014001 to MM and J Bartek), the National Program of Sustainability (grant LO1304 to MM and J Bartek), the Danish Council for Independent Research (grant DFF-1331-00262 to J Bartek), NIHR RMH/ICR Biomedical Research Centre for Cancer (JL), the EC Framework 7 (PREDICT 259303 to XYG, EG, PM, MG, TJ and C Swanton; DDResponse 259892 to J Bartek and J Bartkova and RESPONSIFY ID:259303 to C Swanton), UCL Overseas Research Scholarship (SG). C Swanton is also supported by the European Research Council, Rosetrees Trust and The Prostate Cancer Foundation. This research is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre

GW190412: Observation of a Binary-Black-Hole Coalescence with Asymmetric Masses

We report the observation of gravitational waves from a binary-black-hole coalescence during the first two weeks of LIGO’s and Virgo’s third observing run. The signal was recorded on April 12, 2019 at 05∶30∶44 UTC with a network signal-to-noise ratio of 19. The binary is different from observations during the first two observing runs most notably due to its asymmetric masses: a ∼30 M_⊙ black hole merged with a ∼8 M_⊙ black hole companion. The more massive black hole rotated with a dimensionless spin magnitude between 0.22 and 0.60 (90% probability). Asymmetric systems are predicted to emit gravitational waves with stronger contributions from higher multipoles, and indeed we find strong evidence for gravitational radiation beyond the leading quadrupolar order in the observed signal. A suite of tests performed on GW190412 indicates consistency with Einstein’s general theory of relativity. While the mass ratio of this system differs from all previous detections, we show that it is consistent with the population model of stellar binary black holes inferred from the first two observing runs