Computational integration of genome-wide observational and functional data in cancer

The emergence of high throughput technologies is enabling the characterization of cancer genomes at unprecedented resolution and scale. However, such data suffer from the typical limitations of observational studies, which are frequently challenged by their inability to differentiate between causality and correlation. Recently, several datasets of genome-wide functional assays performed on tumor cell lines have become available. Given the ability of these assays to interrogate cancer genomes for the function of each individual gene, these data can provide vital cues to identify causal events and, with them, novel drug targets. Unfortunately, current analytical methods have been unable to overcome the challenges posed by these assays, which include poor signal to noise ratio and wide-spread off-target effects. Given the largely orthogonal strengths and weaknesses of descriptive analysis of genetic and genomic observational data from cancer genomes and genome-wide functional screening, I hypothesized that integrating the two data types into unified computational models would significantly increase the power of the biological analysis. In this dissertation I use integrative approaches to tackle two crucial problems in cancer research: the identification of driver genes and the discovery of tumor lethalities. I use the resulting methods to study breast cancer, the second most common form of this disease. The first part of the dissertation focuses on the analysis of regions of copy number alteration for the identification of driver genes. I first describe how a simple integrative method enabled the identification of BIN3, a novel driver of metastasis in breast cancer. I then describe Helios, an unsupervised method for the identification of driver genes in regions of SCNA that integrates different data sources into a single probabilistic score. Applying Helios to breast cancer data identified a set of candidate drivers highly enriched with known drivers (p-value < e-14). In vitro validation of 12 novel candidates predicted by Helios found 10 conferred enhanced anchorage independent growth, demonstrating Helios's exquisite sensitivity and specificity. I further provide an extensive characterization of RSF-1, a driver identified by Helios whose amplification correlates with poor prognosis, which displayed increased tumorigenesis and metastasis in mouse models. The second part of this dissertation addresses the problem of identifying tumor vulnerabilities using genome-wide shRNA screens across tumor cell lines. I approach this endeavor using a novel integrative method that employs different biomarkers of cellular state to facilitate the identification of clusters of hairpins with similar phenotype. When applied to breast cancer data, the method not only recapitulates the main subtypes and lethalities associated to this malignancy, but also identifies several novel putative lethalities. Taken together, this research demonstrates the importance of the computational integration of genome-wide functional and observational data in cancer research, providing novel approaches that yield important insights into the biology of the disease

Diachronism in the late Neoproterozoic–Cambrian arc-rift transition of North Gondwana: a comparison of Morocco and the Iberian Ossa-Morena Zone

In the northwestern border of the West African craton (North Gondwana), a transition from late Neoproterozoic subduction/collision to Cambrian rift processes was recorded in the Anti-Atlas (Morocco) and in the Ossa-Morena Zone (Iberia). Cambrian rifting affected both Pan-African and Cadomian basements in a stepwise and diachronous way. Subsequently, both areas evolved into a syn-rift margin episodically punctuated by uplift and tilting that precluded Furongian sedimentation. A comparison of sedimentary, volcanic and geodynamic evolution is made in the late Neoproterozoic (Pan-African and Cadomian) belts and Cambrian rifts trying to solve the apparent diachronous (SW–NE-trending) propagation of an early Palaeozoic rifting regime that finally led to the opening of the Rheic Ocean

Estudio cinético y mecanismos de reacciones en el proceso de depósito de aleaciones ternarias de Ni-P-Mo

Un depósito de Ni-P-Mo vía química genera un recubrimiento ingenieril empleado por su buena resistencia al desgaste y a la corrosión Los recubrimientos químicos Ni-P-Mo se obtienen por depósito auto catalítica empleando una solución de composición específica, en la que el sustrato cataliza la reacción. El objetivo de este trabajo es determinar la cinética de la reacción de depósito de recubrimientos autocatalíticos Ni-P-Mo de un baño de composición específica, a través de la determinación del consumo en reactivos, el incremento en peso del sustrato recubierto, el espesor y la microdureza del recubrimiento. Se encontró una velocidad media para el depósito de 1.61 mg.min-1cm-2, pero ésta es diferente para cada elemento. Durante la depósito, el factor determinante en la velocidad de depositación es el Mo debido a que (1) su depósito se inhibe por la presencia de fósforo en la solución que se codeposita con el níquel y (2) incrementos en la concentración de molibdato en la solución la hacen inestable. Los resultados obtenidos permiten proponer el mecanismo de codepósito Ni-P-Mo, a través del planteamiento de las reacciones que tienen lugar durante el proceso de depositación

Rift-related volcanism predating the birth of the Rheic Ocean

Two very different periods of magma emplacement in the crust of the Ossa-Morena zone (early and main events) in SW Iberia have been previously interpreted to record a Cambrian/Early Ordovician rifting event that is thought to have culminated in the opening of the Rheic Ocean during the Early Ordovician. New stratigraphic, petrographic, geochemical and Sm–Nd isotope data from Cambrian volcanic rocks included in six key low-grade sections in both Portugal and Spain considerably improve our understanding of these events. These data: (1) confirm the existence of two rift-related magmatic events in the Cambrian of the Ossa-Morena zone, (2) demonstrate that the early rift-related event was associated with migmatite and core-complex formation in the mid-upper crust and is represented by felsic peraluminous rocks, the parent magmas of which were derived mainly from crustal sources, and (3) show the main rift-related event to be represented by a bimodal association of felsic and mafic rocks with minor amounts of intermediate rocks. Some of the mafic rocks show N-MORB affinity, whereas others have OIB or E-MORB affinities, suggesting different heterogeneous mantle sources (depleted and enriched, asthenospheric and lithospheric, plume-like and non-plume-like). The acid and intermediate rocks appear to represent hybrid mixtures of crust and mantle-derived magmas. This new data supports the hypothesis that the onset of rifting was associated with a process of oblique ridgetrench collision. We interpret the significant differences between the early and main events as reflecting the evolution froma wide rift stagewith passive extensionmainly accommodated by lower-crust flowin a high heatflow setting, to a narrow rift stage with active extension characterized by extension rates that outpaced thermal diffusion rates

Changes in body weight, C-reactive protein, and total adiponectin in non-obese women after 12 months of a small-volume, home-based exercise program

OBJECTIVE: Our objective was to evaluate the effects of small-volume, home-based exercise combined with slight caloric restriction on the inflammatory markers C-reactive protein and adiponectin. METHODS: In total, 54 women were randomly assigned to one of two groups for exercise intervention: the control or home-based exercise groups. Weight, waist and hip circumferences, and inflammatory markers were measured at baseline and after 6 and 12 months. Women allocated to the home-based exercise group received a booklet explaining the physical exercises to be practiced at home at least 3 times per week, 40 minutes per session, at low-to-moderate intensity. All participants received dietary counseling aimed at reducing caloric intake by 100-300 calories per day, with a normal distribution of macro-nutrients (26-28% of energy as fat). Clinicaltrials.gov: NCT01206413 RESULTS: The home-based exercise group showed a significantly greater reduction in weight and body mass index at six months, but no difference between groups was observed thereafter. With regard to the inflammatory markers, a greater but non-statistically significant reduction was found for C-reactive protein in the home-based exercise group at six months; however, this difference disappeared after adjusting for weight change. No differences in adiponectin were found at the 6- or 12-month follow-up. CONCLUSION: Small-volume, home-based exercise did not promote changes in inflammatory markers independent of weight change

Enfermedad de Hirschsprung, a propósito de un caso

Introduction: Hirschsprung's disease (HD) is within theclinical context one of Pediatric diseases that lowerIncidencehas, representing barely 2.7% of all of them, according todata from the American College of Pediatrics (ACP). However, its pathophysiologyand clinical behavior governed by the age of the patient are&nbsp;the main variablesthat complicate the diagnosis and give errors of up to 35%(ACP). The mortality of patients can amount up to 65% whenthe EH is complicated with a picture of Necrotizingenterocolitis, in a patient who has notbeen theeliminationof meconium within the first 12 hours of life must suspecteh, always takinginto account the patient's age and recallingthat preterm the same delay can be considered normal, while in the case oflarger aged patients the incidence of thedisease is lower, however the diagnostic probability should not be disregarded. Sepsis in abdominal origin andnecrotising enterocolitis are two of the major complicationsof which the physician should be prevented, even when, asreported in the present case, even patients who are opposedto the main factors of risk described in literature, such asage, can develop a HD box and a latent risk of complicationlikethe rest of patients that if shared these risk factors. Objective: To describe a case of Hirschsprung's disease. Material and methods: a descriptive, retrospective studyabout Hirschsprung's disease clinical case presenta-tion. Results: Describes a case of Hirschsprung's disease inpediatric patient with complications and resolution satisfactory quirurgica. Conclusions: The proper implementation of the clinicalmethod allows an accurate diagnosis and timely treatmentof Hirschsprung's disease.Introducción: La Enfermedad deHirschsprung (EH) es dentro del contexto clínico-quirúrgico una de las patologías pediátricas que menor incidencia posee, representando a penas el 2,7% de todas ellas según datos del Colegio Americano de Pediatría (ACP). Sin embargo, su fisiopatología y su comportamiento clínico regido por la edad del paciente son las principales variables que complican el diagnóstico y dan errores de hasta un 35% (ACP). La mortalidad de los pacientes puede ascender hasta un 65% cuando la EHse complica con un cuadro de enterocolitis necrotizante, en un paciente que no se ha conseguido la eliminación de meconio dentro de las 12 primeras horas de vida deberá sospecharse de EH, siempre tomando en cuenta la edad del pacientey recordando que en pretérminos el retraso del mismopuede considerarse normal, mientras que en el caso de pacientes más grandes de edadla incidencia de la patología es menor, sin embargo la probabilidad diagnóstica no debe de ser menospreciada. La sepsis de origen abdominal y enterocolitis necrotizante son dos de las grandes complicaciones de las cuales el médico debe estar prevenido, más aún, cuando, como se relata en el presente caso clínico, incluso pacientes que se contraponen a los principales factores de riesgo descritos por la literatura, como la edad, pueden desarrollar un cuadro de EH y tener un riesgo latente de complicación al igual que el resto de pacientes que si comparten dichos factores de riesgos. Objetivo: Describir un caso clínico de Enfermedad de Hirschsprung. Material y métodos: Se realizó un estudio descriptivo, retrospectivo, presentación de caso clínico sobre Enfermedad de Hirschsprung. Resultados: Se describe un caso de Enfermedad de Hirschsprung en paciente pediátrico con complicaciones y resolución quirpurgica satisfactoria. Conclusiones: La adecuada aplicación del método clínico permite un diagnóstico preciso y tratamiento oportuno de la Enfermedad de Hirschsprung

Enfermedad de Hirschsprung, a propósito de un caso

Introduction: Hirschsprung's disease (HD) is within theclinical context one of Pediatric diseases that lowerIncidencehas, representing barely 2.7% of all of them, according todata from the American College of Pediatrics (ACP). However, its pathophysiologyand clinical behavior governed by the age of the patient are&nbsp;the main variablesthat complicate the diagnosis and give errors of up to 35%(ACP). The mortality of patients can amount up to 65% whenthe EH is complicated with a picture of Necrotizingenterocolitis, in a patient who has notbeen theeliminationof meconium within the first 12 hours of life must suspecteh, always takinginto account the patient's age and recallingthat preterm the same delay can be considered normal, while in the case oflarger aged patients the incidence of thedisease is lower, however the diagnostic probability should not be disregarded. Sepsis in abdominal origin andnecrotising enterocolitis are two of the major complicationsof which the physician should be prevented, even when, asreported in the present case, even patients who are opposedto the main factors of risk described in literature, such asage, can develop a HD box and a latent risk of complicationlikethe rest of patients that if shared these risk factors. Objective: To describe a case of Hirschsprung's disease. Material and methods: a descriptive, retrospective studyabout Hirschsprung's disease clinical case presenta-tion. Results: Describes a case of Hirschsprung's disease inpediatric patient with complications and resolution satisfactory quirurgica. Conclusions: The proper implementation of the clinicalmethod allows an accurate diagnosis and timely treatmentof Hirschsprung's disease.Introducción: La Enfermedad deHirschsprung (EH) es dentro del contexto clínico-quirúrgico una de las patologías pediátricas que menor incidencia posee, representando a penas el 2,7% de todas ellas según datos del Colegio Americano de Pediatría (ACP). Sin embargo, su fisiopatología y su comportamiento clínico regido por la edad del paciente son las principales variables que complican el diagnóstico y dan errores de hasta un 35% (ACP). La mortalidad de los pacientes puede ascender hasta un 65% cuando la EHse complica con un cuadro de enterocolitis necrotizante, en un paciente que no se ha conseguido la eliminación de meconio dentro de las 12 primeras horas de vida deberá sospecharse de EH, siempre tomando en cuenta la edad del pacientey recordando que en pretérminos el retraso del mismopuede considerarse normal, mientras que en el caso de pacientes más grandes de edadla incidencia de la patología es menor, sin embargo la probabilidad diagnóstica no debe de ser menospreciada. La sepsis de origen abdominal y enterocolitis necrotizante son dos de las grandes complicaciones de las cuales el médico debe estar prevenido, más aún, cuando, como se relata en el presente caso clínico, incluso pacientes que se contraponen a los principales factores de riesgo descritos por la literatura, como la edad, pueden desarrollar un cuadro de EH y tener un riesgo latente de complicación al igual que el resto de pacientes que si comparten dichos factores de riesgos. Objetivo: Describir un caso clínico de Enfermedad de Hirschsprung. Material y métodos: Se realizó un estudio descriptivo, retrospectivo, presentación de caso clínico sobre Enfermedad de Hirschsprung. Resultados: Se describe un caso de Enfermedad de Hirschsprung en paciente pediátrico con complicaciones y resolución quirpurgica satisfactoria. Conclusiones: La adecuada aplicación del método clínico permite un diagnóstico preciso y tratamiento oportuno de la Enfermedad de Hirschsprung

A new order, Entrophosporales, and three new Entrophospora species in Glomeromycota

As a result of phylogenomic, phylogenetic, and morphological analyses of members of the genus Claroideoglomus, four potential new glomoid spore-producing species and Entrophospora infrequens, a new order, Entrophosporales, with one family, Entrophosporaceae (=Claroideoglomeraceae), was erected in the phylum Glomeromycota. The phylogenomic analyses recovered the Entrophosporales as sister to a clade formed by Diversisporales and Glomeraceae. The strongly conserved entrophosporoid morph of E. infrequens, provided with a newly designated epitype, was shown to represent a group of cryptic species with the potential to produce different glomoid morphs. Of the four potential new species, three enriched the Entrophosporales as new Entrophospora species, E. argentinensis, E. glacialis, and E. furrazolae, which originated from Argentina, Sweden, Oman, and Poland. The fourth fungus appeared to be a glomoid morph of the E. infrequens epitype. The physical association of the E. infrequens entrophosporoid and glomoid morphs was reported and illustrated here for the first time. The phylogenetic analyses, using nuc rDNA and rpb1 concatenated sequences, confirmed the previous conclusion that the genus Albahypha in the family Entrophosporaceae sensu Oehl et al. is an unsupported taxon. Finally, the descriptions of the Glomerales, Entrophosporaceae, and Entrophospora were emended and new nomenclatural combinations were introduced

ERS/EAACI statement on adherence to international adult asthma guidelines

Clinical practice guidelines based on the best available evidence, aim to standardize and optimize asthma diagnosis and management. Nevertheless, there are concerns that particularly between different groups of healthcare professionals (HCPs), adherence to guidelines is suboptimal. Further to these concerns, the aims of this ERS/EAACI Statement were (1) via an international online survey, to evaluate and compare the understanding of and adherence to international asthma guidelines by HCPs of different specialties, (2) via systematic reviews of the literature, to assess effectiveness of strategies focused at improving implementation of guideline-recommended interventions, and compare process and clinical outcomes in patients managed by Specialists (respiratory physicians or allergists) or Generalists (internists or general practitioners). The online survey identified discrepancies between HCPs of different specialties which may be due to poor dissemination or lack of knowledge of the guidelines but also a reflection of the adaptations HCPs working in different clinical settings make, based on their resources. The systematic reviews demonstrated that multifaceted quality improvement initiatives addressing multiple challenges to guidelines adherence, or the input from additional specialized HCPs are most effective in improving guidelines adherence. More data are needed to evaluate differences in process and clinical outcomes among patients managed by Generalists or Specialists. Our results reveal a need for guidelines to consider the heterogeneity of real-life settings for asthma management and tailor their recommendations accordingly. Continuous, multifaceted quality improvement processes are required to optimize and maintain guidelines adherence. Validated referral pathways for uncontrolled asthma or for uncertain diagnosis are needed