Pathway analysis for identification of potential biomarkers in severe cutaneous drug hypersensitivity reactions

Purpose: To construct a cluster model or a gene signature for Stevens-Johnson syndrome (SJS) using pathways analysis in order to identify some potential biomarkers that may be used for early detection of SJS and epidermal necrolysis (TEN) manifestations. Methods: Gene expression profiles of GSE12829 were downloaded from Gene Expression Omnibus database. A total of 193 differentially expressed genes (DEGs) were obtained. We applied these genes to geneMANIA database, to remove ambiguous and duplicated genes, and after that, characterized the gene expression profiles using geneMANIA, DAVID, REACTOME, STRING and GENECODIS which are online software and databases. Results: Out of 193 genes, only 91 were used (after removing the ambiguous and duplicated genes) for topological analysis. It was found by geneMANIA database search that majority of these genes were coexpressed yielding 84.63 % co-expression. It was found that ten genes were in Physical interactions comprising almost 14.33 %. There were < 1 % pathway and genetic interactions with values of 0.97 and 0.06 %, respectively. Final analyses revealed that there are two clusters of gene interactions and 13 genes were shown to be in evident relationship of interaction with regards to hypersensitivity. Conclusion: Analysis of differential gene expressions by topological and database approaches in the current study reveals 2 gene network clusters. These genes are CD3G, CD3E, CD3D, TK1, TOP2A, CDK1, CDKN3, CCNB1, and CCNF. There are 9 key protein interactions in hypersensitivity reactions and may serve as biomarkers for SJS and TEN. Pathways related gene clusters has been identified and a genetic model to predict SJS and TEN early incidence using these biomarker genes has been developed.

Is the adiposity rebound a rebound in adiposity?

OBJECTIVE: Early adiposity rebound ([AR], when body mass index [BMI] rises after reaching a nadir) strongly predicts later obesity. We investigated whether the upswing in BMI at AR is accompanied by an increase in body fat. DESIGN: Community-based cohort study. SUBJECTS: A total of 299 first-born children (49% male). Measurements. Six-monthly anthropometry and bioelectrical impedance, 4-6.5 years; lean and fat mass index (kg/m(2)) for direct comparison with BMI. Supplementary (0-2 years) weight and length measures (needed for growth curve modelling) were drawn from subjects' child health records. METHODS: AR was estimated from individually modelled BMI curves from birth to 6.5 years. Two main analyses were performed: 1) cross-sectional comparisons of BMI, fat mass index (FMI), lean mass index (LMI) and percent body fat in children with early (<5 years) and later (>5 years) rebound; and 2) investigation of linear trends in BMI, FMI, LMI and percent body fat before and after AR. Results. The 81 children (27%) experiencing early AR had higher BMI, FMI, LMI and percent fat at 6.5 years. Overall, FMI decreased steeply pre-AR, at -0.56 (0.02) kg/m(2) per year (mean [Standard Error]), then flattened post-AR to 0.07 (0.05) kg/m(2) per year. In contrast, LMI increased pre-AR (0.34 [0.01]) and steepened post-AR (0.47 [0.03] kg/m(2) per year). CONCLUSION: The 'adiposity rebound' is characterised by increasing lean mass index, coupled with cessation of the decline in fat mass index. Understanding what controls the dynamics of childhood body composition and mechanisms that delay AR could help prevent obesity.

Anchoring countercyclical capital buffer in Basel III

This thesis proposes two top-down approch frameworks to assess the Basel III countercyclical capital buffer. The empirical results demonstrate that sovereign sector distance-to-default and market illiquidity are more suitable indicator for guiding the decision of the buffer during both build-up and release phase than the official indicator, credit-to-GDP ratio. The findings in this thesis are important to help safeguard the globe financial system.

Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells

SAHA is a class I HDAC/HDAC6 co-inhibitor and an autophagy inducer currently undergoing clinical investigations in breast cancer patients. However, the molecular mechanism of action of SAHA in breast cancer cells remains unclear. In this study, we found that SAHA is equally effective in targeting cells of different breast cancer subtypes and tamoxifen sensitivity. Importantly, we found that down-regulation of survivin plays an important role in SAHA-induced autophagy and cell viability reduction in human breast cancer cells. SAHA decreased survivin and XIAP gene transcription, induced survivin protein acetylation and early nuclear translocation in MCF7 and MDA-MB-231 breast cancer cells. It also reduced survivin and XIAP protein stability in part through modulating the expression and activation of the 26S proteasome and heat-shock protein 90. Interestingly, targeting HDAC3 and HDAC6, but not other HDAC isoforms, by siRNA/pharmacological inhibitors mimicked the effects of SAHA in modulating the acetylation, expression, and nuclear translocation of survivin and induced autophagy in MCF7 and MDA-MB-231 cancer cells. Targeting HDAC3 also mimicked the effect of SAHA in up-regulating the expression and activity of proteasome, which might lead to the reduced protein stability of survivin in breast cancer cells. In conclusion, this study provides new insights into SAHA's molecular mechanism of actions in breast cancer cells. Our findings emphasize the complexity of the regulatory roles in different HDAC isoforms and potentially assist in predicting the mechanism of novel HDAC inhibitors in targeted or combinational therapies in the future.

A comparative analysis of accounting-based valuation models

We empirically compare the reliability of the dividend (DIV) model, the residual income valuation (CT, GLS) model, and the abnormal earnings growth (OJ) model. We find that valuation estimates from the OJ model are generally more reliable than those from the other three models, because the residual income valuation model anchored by book value gets off to a poor start when compared with the OJ model led by capitalized next-year earnings. We adopt a 34-year sample covering from 1985 to 2013 to compare the reliability of valuation estimates via their means of absolute pricing errors (MAPE) and corresponding t statistics. We further use the switching regression of Barrios and Blanco to show that the average probability of OJ valuation estimates is greater in explaining stock prices than the DIV, CT, and GLS models. In addition, our finding that the OJ model yields more reliable estimates is robust to analysts-based and model-based earnings measures.

Liquidity creation, regulatory capital, and bank profitability

We examine the interrelationships among liquidity creation, regulatory capital, and bank profitability of US banks. We find that regulatory capital and liquidity creation affect each other positively after controlling for bank profitability. However, this relationship is largely driven by small banks and primarily during non-crisis periods. It is also sensitive to the level of banks' regulatory capital and how it is measured. Furthermore, we find that banks which create more liquidity and exhibit higher illiquidity risk have lower profitability. Finally, the relationship between regulatory capital and bank performance is not linear and depends on the level of capitalization. Regulatory capital is negatively related to bank profitability for higher capitalized banks but positively related to profitability for lower capitalized banks. Therefore, a change in regulatory capital has differential impacts on bank performance. Our findings have various implications for policymakers and bank regulators.

Resolución 040 del 18 de abril de 2013: Por la cual se acepta un desistimiento

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Les mouvances réglementaires entourant la profession comptable au lendemain de crises financières : propagation du discours néolibéral, production de mythes et gouvernance en silo

C’est en réponse aux plus récentes crises financières que plusieurs processus réglementaires – dont certains constituent les objets d’étude de cette thèse – ont été déployés pour concevoir et implanter diverses réformes « d’amélioration » au sein de la pratique professionnelle des auditeurs financiers. Tant la crise du début des années 2000 que celle de 2007-2008 auraient attiré de vives critiques à l’égard du travail des auditeurs et de leur contribution (prétendument défaillante) au sein du fonctionnement des marchés des capitaux. Considérant leur fonction de « chien de garde » qui est censée assurer, avant tout, la protection du public au sein de ces marchés, il semblait inévitable que leur travail soit, dans une certaine mesure, remis en doute à travers les processus de révision réglementaire mis en place. C’est ainsi que chacun des trois articles qui composent cette thèse offre une analyse de différents aspects – tels que la mise en place, le déroulement, la nature et la substance des discours et des résultats – liés à ces processus de révision réglementaire qui entourent la pratique professionnelle des auditeurs au lendemain des crises financières. En somme, en plus d’indiquer comment ces processus ne sont point à l’abri de controverses, les conclusions de cette thèse inciteront à ce qu’une attention sérieuse soit portée à leur égard afin de préserver le bienfondé de la profession des comptables et des auditeurs. Alors que, dans le premier article, il sera question d’illustrer l’infiltration (critiquable) d’un discours néolibéral au sein des débats qui entourent les processus de révision réglementaire dont il est question, dans le deuxième article, il sera question d’exposer, au sein de ces processus, un mécanisme de production de mythes prônant un certain statu quo. Par ailleurs, dans le dernier article, en plus de mettre en évidence le fait que les approches de gouvernance déployées à travers ces processus de révision réglementaire ne sont pas suffisamment englobantes, on pourra aussi prendre conscience de l’inféodation de l’expertise de l’audit face à son environnement (et plus précisément, face aux expertises de la normalisation comptable et de la financiarisation de l’économie). Sous un regard critique, et à travers des analyses qualitatives, chacun des articles de cette thèse permettra de remettre en question certaines facettes des processus réglementaires et institutionnels qui entourent le champ de la comptabilité et de l’audit.