Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Convergence analysis of a new self organizing map based optimization (SOMO) algorithm

The self-organizing map (SOM) approach has been used to perform cognitive and biologically inspired computing in a growing range of cross-disciplinary fields. Recently, the SOM based neural network framework was adapted to solve continuous derivative-free optimization problems through the development of a novel algorithm, termed SOM-based optimization (SOMO). However, formal convergence questions remained unanswered which we now aim to address in this paper. Specifically, convergence proofs are developed for the SOMO algorithm using a specific distance measure. Numerical simulation examples are provided using two benchmark test functions to support our theoretical findings, which illustrate that the distance between neurons decreases at each iteration and finally converges to zero. We also prove that the function value of the winner in the network decreases after each iteration. The convergence performance of SOMO has been benchmarked against the conventional particle swarm optimization algorithm, with preliminary results showing that SOMO can provide a more accurate solution for the case of large population sizes

Comparative Transcriptome Analysis of Listeria monocytogenes Strains of the Two Major Lineages Reveals Differences in Virulence, Cell Wall, and Stress Response▿ †

Listeria monocytogenes is a food-borne, opportunistic, bacterial pathogen causing a wide spectrum of diseases, including meningitis, septicemia, abortion, and gastroenteritis, in humans and animals. Among the 13 L. monocytogenes serovars described, human listeriosis is mostly associated with strains of serovars 4b, 1/2b, and 1/2a. Within the species L. monocytogenes, three phylogenetic lineages are described. Serovar 1/2a belongs to phylogenetic lineage I, while serovars 4b and 1/2b group in phylogenetic lineage II. To explore the role of gene expression in the adaptation of L. monocytogenes strains of these two major lineages to different environments, as well as in virulence, we performed whole-genome expression profiling of six L. monocytogenes isolates of serovars 4b, 1/2b, and 1/2a of distinct origins, using a newly constructed Listeria multigenome DNA array. Comparison of the global gene expression profiles revealed differences among strains. The expression profiles of two strains having distinct 50% lethal doses, as assessed in the mouse model, were further analyzed. Gene ontology term enrichment analysis of the differentially expressed genes identified differences in protein-, nucleic acid-, carbon metabolism-, and virulence-related gene expression. Comparison of the expression profiles of the core genomes of all strains revealed differences between the two lineages with respect to cell wall synthesis, the stress-related sigma B regulon and virulence-related genes. These findings suggest different patterns of interaction with host cells and the environment, key factors for host colonization and survival in the environment

Profili attuali della soggezione del giudice alla \u201clegge\u201d e della vincolativit\ue0 del precedente

In una fase di rilevante difficolt\ue0 per il paradigma tradizionale del principio di legalit\ue0, si \ue8 discusso ampiamente del ruolo dell\u2019interpretazione in relazione all\u2019equilibrio di poteri definito dalla Costituzione. Vero \ue8 che il giudice \ue8 soggetto soltanto alla legge. Tuttavia, \ue8 divenuto impossibile prevedere la effettiva qualificazione giuridica di un fatto se non avendo a mente l\u2019orientamento ermeneutico seguito dalla giurisprudenza di legittimit\ue0. Occorre, perci\uf2, indagare l\u2019assetto attuale della funzione nomofilattica giacch\ue9 solo la sinergia tra legislatore e giudice promette di scongiurare gravi violazioni delle garanzie sovranazionali. Al riguardo, la \u201ccultura del precedente\u201d offre indicazioni di metodo che potrebbero rivelarsi utili, persino in un modello di civil law, quale chiave di lettura delle recenti riforme legislative.While the traditional idea of legality faces a significant crisis, the debate upon interconnections among judicial interpretation and balance of constitutional powers acquires relevance. On one hand, the judge is subject to the law. On the other hand, judicial interpretation became essential in order to assess criminal liability. Thus, it is necessary to deeper examine the function exerted by the Italian Supreme Court: the equilibrium between legislator and judge is the one able to ensure supranational guarantees. In this frame, the \u2018stare decisis doctrine\u2019 could provide the civil law paradigm with useful indications to understand recent legislative reforms.En un periodo de creciente dificultad para el paradigma tradicional del principio de legalidad, se ha discutido ampliamente sobre el rol de la interpretaci\uf3n judicial en relaci\uf3n al equilibrio de poderes definido por la Constituci\uf3n. Por una parte, es cierto que el juez se encuentra sujeto solamente a la ley. Sin embargo, la praxis demuestra que es casi imposible prever la efectiva calificaci\uf3n jur\ueddica de un hecho si no se tiene en consideraci\uf3n el orientamiento hermen\ue9utico seguido por la jurisprudencia. Por lo tanto, es necesario investigar con mayor profundidad la estructura actual de la funci\uf3n nomofil\ue1ctica, toda vez que solo la sinergia entre el legislador y el juez puede asegurar el cumplimiento de las garant\uedas supranacionales. Al respecto, la \u201ccultura del precedente\u201d podr\ueda proveer, al sistema de civil law, \ufatiles indicaciones para entender las recientes reformas legislativas

Insights on PRAME and osteosarcoma by means of gene expression profiling

Osteosarcoma (OS) is the most frequent bone tumor in children and adolescents. Tumor antigens are encoded by genes that are expressed in many types of solid tumors but are silent in normal tissues, with the exception of placenta and male germ-line cells. It has been proposed that antigen tumors are potential tumor markers.The premise of this study is that the identification of novel OS-associated transcripts will lead to a better understanding of the events involved in OS pathogenesis and biology.We analyzed the expression of a panel of seven tumor antigens in OS samples to identify possible tumor markers. After selecting the tumor antigen expressed in most samples of the panel, gene expression profiling was used to identify osteosarcoma-associated molecular alterations. A microarray was employed because of its ability to accurately produce comprehensive expression profiles.PRAME was identified as the tumor antigen expressed in most OS samples; it was detected in 68% of the cases. Microarray results showed differences in expression for genes functioning in cell signaling and adhesion as well as extracellular matrix-related genes, implying that such tumors could indeed differ in regard to distinct patterns of tumorigenesis.The hypothesis inferred in this study was gathered mostly from available data concerning other kinds of tumors. There is circumstantial evidence that PRAME expression might be related to distinct patterns of tumorigenesis. Further investigation is needed to validate the differential expression of genes belonging to tumorigenesis-related pathways in PRAME-positive and PRAME-negative tumors.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)GRAACC (Grupo de Apoio ao Adolescente e Crianca com Cancer)Universidade Federal de São Paulo, UNIFESP, Pediat Oncol Inst GRAACC, Dept Pediat,Genet Lab, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, BR-04023062 São Paulo, BrazilUniv São Paulo, Dept Clin Med, BR-14049 Ribeirao Preto, SP, BrazilUniv São Paulo, Fac Med Ribeirao Preto, Ctr Cellbased Therapy, BR-14049 Ribeirao Preto, SP, BrazilUniv São Paulo, Dept Genet & Evolutionary Biol, BR-14049 Ribeirao Preto, SP, BrazilAlbert Einstein Res & Educ Inst, São Paulo, BrazilUniv São Paulo, Dept Genet, BR-14049 Ribeirao Preto, SP, BrazilUniv São Paulo, Dept Pediat, BR-14049 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Dept Pathol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthoped Surg & Traumatol, BR-04023062 São Paulo, BrazilLudwig Inst, New York, NY USAUniversidade Federal de São Paulo, UNIFESP, Pediat Oncol Inst GRAACC, Dept Pediat,Genet Lab, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthoped Surg & Traumatol, BR-04023062 São Paulo, BrazilFAPESP: 04/12150-8FAPESP: 07/53869-3Web of Scienc

Insights on PRAME and osteosarcoma by means of gene expression profiling

Osteosarcoma (OS) is the most frequent bone tumor in children and adolescents. Tumor antigens are encoded by genes that are expressed in many types of solid tumors but are silent in normal tissues, with the exception of placenta and male germ-line cells. It has been proposed that antigen tumors are potential tumor markers. The premise of this study is that the identification of novel OS-associated transcripts will lead to a better understanding of the events involved in OS pathogenesis and biology. We analyzed the expression of a panel of seven tumor antigens in OS samples to identify possible tumor markers. After selecting the tumor antigen expressed in most samples of the panel, gene expression profiling was used to identify osteosarcoma-associated molecular alterations. A microarray was employed because of its ability to accurately produce comprehensive expression profiles. PRAME was identified as the tumor antigen expressed in most OS samples; it was detected in 68% of the cases. Microarray results showed differences in expression for genes functioning in cell signaling and adhesion as well as extracellular matrix-related genes, implying that such tumors could indeed differ in regard to distinct patterns of tumorigenesis. The hypothesis inferred in this study was gathered mostly from available data concerning other kinds of tumors. There is circumstantial evidence that PRAME expression might be related to distinct patterns of tumorigenesis. Further investigation is needed to validate the differential expression of genes belonging to tumorigenesis-related pathways in PRAME-positive and PRAME-negative tumors.FAPESP (The State of Sao Paulo Research Foundation)[04/12150-8]FAPESP (The State of Sao Paulo Research Foundation)[07/53869-3]GRAACC (Grupo de Apoio ao Adolescente e Crianca com Cancer

An expanded evaluation of protein function prediction methods shows an improvement in accuracy

Background: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent

An expanded evaluation of protein function prediction methods shows an improvement in accuracy

Background: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent.Medicine, Faculty ofScience, Faculty ofOther UBCNon UBCPsychiatry, Department ofReviewedFacult

Additional file 1 of An expanded evaluation of protein function prediction methods shows an improvement in accuracy

A document containing a subset of CAFA2 analyses that are equivalent to those provided about the CAFA1 experiment in the CAFA1 supplement. (PDF 11100 kb