A Regularized Method for Selecting Nested Groups of Relevant Genes from Microarray Data

Gene expression analysis aims at identifying the genes able to accurately predict biological parameters like, for example, disease subtyping or progression. While accurate prediction can be achieved by means of many different techniques, gene identification, due to gene correlation and the limited number of available samples, is a much more elusive problem. Small changes in the expression values often produce different gene lists, and solutions which are both sparse and stable are difficult to obtain. We propose a two-stage regularization method able to learn linear models characterized by a high prediction performance. By varying a suitable parameter these linear models allow to trade sparsity for the inclusion of correlated genes and to produce gene lists which are almost perfectly nested. Experimental results on synthetic and microarray data confirm the interesting properties of the proposed method and its potential as a starting point for further biological investigationsComment: 17 pages, 8 Post-script figure

Iterative Projection Methods for Structured Sparsity Regularization

In this paper we propose a general framework to characterize and solve the optimization problems underlying a large class of sparsity based regularization algorithms. More precisely, we study the minimization of learning functionals that are sums of a differentiable data term and a convex non differentiable penalty. These latter penalties have recently become popular in machine learning since they allow to enforce various kinds of sparsity properties in the solution. Leveraging on the theory of Fenchel duality and subdifferential calculus, we derive explicit optimality conditions for the regularized solution and propose a general iterative projection algorithm whose convergence to the optimal solution can be proved. The generality of the framework is illustrated, considering several examples of regularization schemes, including l1 regularization (and several variants), multiple kernel learning and multi-task learning. Finally, some features of the proposed framework are empirically studied

Nonparametric Sparsity and Regularization

In this work we are interested in the problems of supervised learning and variable selection when the input-output dependence is described by a nonlinear function depending on a few variables. Our goal is to consider a sparse nonparametric model, hence avoiding linear or additive models. The key idea is to measure the importance of each variable in the model by making use of partial derivatives. Based on this intuition we propose and study a new regularizer and a corresponding least squares regularization scheme. Using concepts and results from the theory of reproducing kernel Hilbert spaces and proximal methods, we show that the proposed learning algorithm corresponds to a minimization problem which can be provably solved by an iterative procedure. The consistency properties of the obtained estimator are studied both in terms of prediction and selection performance. An extensive empirical analysis shows that the proposed method performs favorably with respect to the state-of-the-art

Interleukin-4 Causes Susceptibility to Invasive Pulmonary Aspergillosis through Suppression of Protective Type I Responses

Aspergillus fumigatus, an opportunistic fungal pathogen, causes multiple allergic and non-allergic airway diseases. Invasive pulmonary aspergillosis (IPA) is a nonallergic, life-threatening disease of immunocompromised patients. In a murine model of IPA, interleukin (IL)—4-deficient (IL-4−/−) BALB/c mice were used to examine the role of IL-4 in lung pathology and immune responses. IL-4−/− mice were more resistant than wild-type mice to infection caused by multiple intranasal injections of viable A. fumigatus conidia. Resistance was associated with decreased lung inflammatory pathology, impaired T helper (Th)—2 responses (including lung eosinophilia), and an IL-12—dependent Th1 response. In contrast, development of host-detrimental antifungal Th2 cells occurred in IL-12−/− and interferon-γ−/− mice and in IL-4−/− mice when subjected to IL-12 neutralization. These results demonstrate that IL-4 renders mice susceptible to infection with A. fumigatus by inhibition of protective Th1 responses. IL-4 appears to have a distinct role in the pathogenesis of allergic and nonallergic lung diseases caused by the fungu

Large-scale Nonlinear Variable Selection via Kernel Random Features

We propose a new method for input variable selection in nonlinear regression. The method is embedded into a kernel regression machine that can model general nonlinear functions, not being a priori limited to additive models. This is the first kernel-based variable selection method applicable to large datasets. It sidesteps the typical poor scaling properties of kernel methods by mapping the inputs into a relatively low-dimensional space of random features. The algorithm discovers the variables relevant for the regression task together with learning the prediction model through learning the appropriate nonlinear random feature maps. We demonstrate the outstanding performance of our method on a set of large-scale synthetic and real datasets.Comment: Final version for proceedings of ECML/PKDD 201

A biology-driven approach identifies the hypoxia gene signature as a predictor of the outcome of neuroblastoma patients

Background Hypoxia is a condition of low oxygen tension occurring in the tumor microenvironment and it is related to poor prognosis in human cancer. To examine the relationship between hypoxia and neuroblastoma, we generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome. Results We obtained the gene expression profile of 11 hypoxic neuroblastoma cell lines and we derived a robust 62 probesets signature (NB-hypo) taking advantage of the strong discriminating power of the l1-l2 feature selection technique combined with the analysis of differential gene expression. We profiled gene expression of the tumors of 88 neuroblastoma patients and divided them according to the NB-hypo expression values by K-means clustering. The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups. Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene. NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification. Conclusions Our results demonstrate that the NB-hypo is a novel and independent prognostic factor for neuroblastoma and support the view that hypoxia is negatively correlated with tumors' outcome. We show the power of the biology-driven approach in defining hypoxia as a critical molecular program in neuroblastoma and the potential for improvement in the current criteria for risk stratification.Foundation KiKaChildren's Neuroblastoma Cancer FoundationSKK FoundationDutch Cancer Societ

Metodi di valutazione delle proprietà naftogeniche originarie di una roccia madre.

The knowledge of the original potential is of primary importance in order to obtain a good geochemical model for the petroleum system modeling. For mature source rocks it is possible to measure in laboratory only the residual features: petroleum potential – PPR, total organic carbon content – TOCR, hydrogen index – HIR. In case of extremely mature rocks only the TOC value remains as a proof of an early naphthogenic appeal. Historically, there were at least three different methods to evaluate the original petroleum potential. After a bibliographical review on the subject, the different evaluation hypotheses introduced by Claypool (in Hunt, 1995), Scotti (1998, Agip internal report) and Jarvie (2012) have been verified and compared. The common base is the utilization of the residual features, which can be measured in laboratory, and the analysis of the original quality of the organic matter, or more precisely of the kerogen, its diagenetic product, in terms of one more plausible value of the hydrogen index - HI. Once the reliability of the results in different theoretical conditions has been tested, we have verified the different approaches on real sample of source rocks, considering the samples from the Hils Syncline in the Posidonia Shale (Germany). The intrusion of the laccolitic body in this region allowed different conditions of maturity within the same formation, making possible the measurement of the naphthogenic residual features, through the decrease of the HI in samples that can be considered similar. The more recently proposed method (Jarvie, 2012) is also the most accurate, even if of complex application. Claypool (1995) proposed a formula that is even more complex and of difficult application, since it needs many parameters sometimes indefinable; moreover, in particular situations, it can lead to poor quality results. Scotti's method (1998) offers results that are identical to those obtained with Jarvie's formula (2012) only in case of overmature source rocks; if the maturity of the source rocks is intermediate and the kerogen is of excellent quality, we can observe a gap in comparison to Jarvie's method (2012). Using a simpler version of this formula, the calculation often converge towards the more precise formula proposed by Jarvie (2012). This seems to be of easier use, since it does not consider a really critical parameter that is the quantity of free hydrocarbon present in the sample, which can be sometimes hard to identify due to the presence of migrated hydrocarbons, in addition to indigenous ones. The study allowed to define the limits and the peculiarities of each proposed method and to establish which is the more correct work flow in order to evaluate the original potential of a source rock.ope

Camparison of estimated glomerular filtration rate with serum creatinie and 51Cr-EDTA method in head and neck cancer patients treated with cisplatin

Orientador: Celso Dario RamosDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Objetivos: A avaliação da função renal, em particular da taxa de filtração glomerular (TFG), é extremamente importante em pacientes submetidos à quimioterapia com cisplatina, um fármaco nefrotóxico. Os objetivos deste trabalho foram comparar a estimativa da TFG pela fórmula Crockcroft-Gault (TFGe), que se baseia na creatinina sérica, com a TFG medida pelo método do EDTA-51Cr (TFG-EDTA), considerado "padrão-ouro", em pacientes com diagnóstico de carcinoma de cabeça e pescoço (CCP) antes e 30 dias após quimioterapia com cisplatina e acompanhar a evolução da função renal desses pacientes após 6 meses. Pacientes e Métodos: Foram avaliados 69 pacientes com diagnóstico de CCP submetidos à quimioterapia com cisplatina, sendo 6 mulheres e 63 homens. Esses pacientes foram submetidos ao exame com EDTA-51Cr e coleta de sangue para cálculo da TFGe antes e 30 dias após a quimioterapia. A função renal de 40 destes pacientes também foi analisada através da TFG-EDTA 6 meses após a quimioterapia. Resultados: A média da TFGe e TFG-EDTA pré-quimioterapia foi de 91,21 ml/min/1.73m2 e 84,33 ml/min/1.73m2, respectivamente. Trinta dias após a quimioterapia com cisplatina esta média foi de 78,79 ml/min/1.73m2 para a TFGe e 64,97 ml/min/1.73 m2 para a TFG-EDTA. A diferença entre os valores encontrados tanto pré-quimioterapia quanto pós-quimioterapia foi estatisticamente significante (p<0,0001). Nos 40 pacientes que tiveram a TFG acompanhada com EDTA-51Cr, foi encontrada média de 79,3, 60,9 e 64,9 ml/min/1.73m2, antes, 30 dias e 6 meses, respectivamente, após o tratamento com cisplatina. Conclusão: A medida da TFGe apresenta baixa acurácia para a avaliação da função renal em pacientes com CCP, tanto antes como imediatamente após o tratamento com cisplatina, e não pode ser recomendada como substituta do método com EDTA-51Cr. Há queda significativa da função renal após quimioterapia com cisplatina nestes pacientes e não ocorre recuperação completa da função renal 6 meses após o tratamento na maioria dos casosAbstract: Purpose: Renal function analysis, primarily glomerular filtration rate (GFR), is extremely important in patients undergoing chemotherapy with cisplatin, a nephrotoxic drug. The aim of this current study was to compare estimated TGF using the Crockcroft-Gault formula (eGFR) and the 51Cr-EDTA method EDTA-GFR), which is consider the "gold standard", in head and neck cancer (HNC) patients before and 30 days after chemotherapy with cisplatin. EDTA-GFR was also analysed 6 months after chemotheraphy. Materials and Methods: We evaluated 69 HNC patients who underwent chemotherapy with cisplatin (6 women and 63 men). These patients were submitted to 51Cr-EDTA plasma clearance and blood collection for eGFR calculation before and 30 days after chemotherapy. Forty of these patients had GFR examined by 51Cr-EDTA 6 months after chemotherapy. Results: The mean of eGFR and EDTA-GFR pre-chemotherapy was 91.21ml/min/1.73m2 and 84.33ml/min/1.73m2, respectively. Thirty days after chemotherapy with cisplatin the mean was 78.79ml/min/1.73 m2 for eGFR and 64.97ml/min/1.73m2 for EDTA-GFR. The difference between the values found pre and post-chemotherapy are statistically significant (p <0.0001). In the 40 patients who had GFR followed by 51Cr-EDTA, it was found a mean of 79.3, 60.9 and 64.9 mL/min/1.73m2, before, 30 days and 6 months after treatment with cisplatin, respectively. Conclusions: eGFR showed low accuracy in the assessment of renal function in patients with HNC, both before and immediately after cisplatin treatment, and cannot be recommended as a substitute to the method 51Cr-EDTA. There was a significant decrease in renal function after cisplatin chemotherapy in these patients and in the majority of the cases no recovery of renal function was observed 6 months after treatmentMestradoClinica MedicaMestra em Clínica Médic

Comportamento e desempenho do reforço à flexão de vigas de concreto armado, solicitado a baixa idade e executado inclusive sob carga

In this work, an experimental study of the behaviour and performance ofreinforced concrete beams under bending is presented. The strengthening was performed through the increase of the steel and concrete sections at the tensioned region of the beams, and loaded at early age. The influence of the number of stirrups crossing the interface of the old and new concrete was verified, as well as the contact area of these two regions and the loading condition at the time of thestrengthening. The improvement in performance was evaluated. The behaviour of monolithic and strengthened beams were described. Experimental and theoretical results were compared, as well as the applicability of the criteria in NBR-6118 for the design of strengthenings. The results indicated the effectiveness of the strengthening method which improved considerably the performance of the members. The bond area between the two concretes was sufficient to assure the joint behaviour under loading. The strengthening under loading did not affect the load bearing capacity of the beams, which presented performance in service compatible with the initial displacement and strain. Strengthened and monolithic beams had equivalent behaviour and performance, which were correctly evaluated by the theoretical calculation. The guidelines in NBR-6118 demonstrated to be safe in the prediction of the behaviour and performance of the strengthened beams.Este trabalho apresenta um estudo experimental do comportamento edesempenho de reforço à flexão de vigas de concreto armado. O reforço foi executado através do aumento das seções de concreto e aço da zona tracionada das vigas, e solicitado a baixa idade. Pesquisou-se a influência do número de estribos que atravessava a interface concreto velho - concreto novo, bem como da área de contato entre esses concretos e da condição de solicitação da peça no momento do reforço. A melhoria de desempenho conseguida com o reforço foi avaliada. Foi desenvolvida também comparação entre vigas reforçadas emonolíticas. Resultados experimentais e teóricos foram comparados, assim como verificada a aplicabilidade dos critérios da NBR-6118 em projetos de reforço. Os resultados indicaram que o método de reforço foi bastante eficiente, melhorando consideravelmente o desempenho das peças reforçadas. A área de aderência existente entre os dois concretos foi suficiente para garantir o funcionamento conjunto deles. O reforço sob carga não alterou a capacidade resistente das vigas, que ainda apresentaram desempenho em serviço compatível com os níveisiniciais de deformação e deslocamento. Vigas reforçadas e monolíticas tiveram comportamento e desempenho equivalentes, que foram bem avaliados pelo cálculo teórico. Os critérios de cálculo da NBR-6118 foram seguros na previsão do comportamento e desempenho imediatos das vigas reforçadas