CDK4/6-Inhibitors Versus Chemotherapy in Advanced HR+/HER2-Negative Breast Cancer: Results and Correlative Biomarker Analyses of the KENDO Randomized Phase II Trial

Background: The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET. Materials and methods: We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples. Results: Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm. Conclusions: The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices

Contributions of chaperone/usher systems to cell binding, biofilm formation and Yersinia pestis virulence

Yersinia pestis genome sequencing projects have revealed six intact uncharacterized chaperone/ usher systems with the potential to play roles in plague pathogenesis. We cloned each locus and expressed them in the Deltafim Escherichia coli strain AAEC185 to test the assembled Y. pestis surface structures for various activities. Expression of each chaperone/usher locus gave rise to specific novel fibrillar structures on the surface of E. coli. One locus, y0561-0563, was able to mediate attachment to human epithelial cells (HEp-2) and human macrophages (THP-1) but not mouse macrophages (RAW264.7), while several loci were able to facilitate E. coli biofilm formation. When each chaperone/usher locus was deleted in Y. pestis, only deletion of the previously described pH 6 antigen (Psa) chaperone/usher system resulted in decreased adhesion and biofilm formation. Quantitative RT-PCR (qRT-PCR) revealed low expression levels for each novel chaperone/usher system in vitro as well as in mouse tissues following intravenous infection. However, a Y. pestis mutant in the chaperone/usher locus y1858-1862 was attenuated for virulence in mice via the intravenous route of infection, suggesting that expression of this locus is, at some stage, sufficient to affect the outcome of a plague infection. qRT-PCR experiments also indicated that expression of the chaperone/usher-dependent capsule locus, caf1, was influenced by oxygen availability and that the well-described chaperone/usher-dependent pilus, Psa, was strongly induced in minimal medium even at 28 degrees C rather than 37 degrees C, a temperature previously believed to be required for Psa expression. These data indicate several potential roles for the novel chaperone/usher systems of Y. pestis in pathogenesis and infection-related functions such as cell adhesion and biofilm formation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91950/1/2011 Microbiology - Contributions of chaperone usher systems to cell binding biofilm formation and Yersinia pestis virulence.pd

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Persistance des inégalités de genre sur le marché du travail : le rôle des normes d'identité et de la structure occupationnelle

Cette thèse contribue à la littérature qui vise à comprendre les causes des inégalités hommes-femmes qui subsistent sur le marché du travail. Les deux premiers chapitres examinent le rôle des normes sociales. Le premier chapitre montre que dans le contexte d'un pays à revenu intermédiaire, l'Uruguay, la norme du soutien de famille masculin affecte non seulement l'offre de main-d'œuvre, mais aussi la qualité des emplois dans lesquels les femmes sont employées, alors que celle-ci conduit les hommes à s'auto-sélectionner dans des emplois formels mieux rémunérés. Le deuxième chapitre utilise des données de panel pour les couples américains et examine comment l'offre de travail à la naissance du premier enfant est conditionné par des gains relatifs au sein du couple. Nous constatons que les normes sociales associées au rôle de la mère influencent fortement les décisions relatives au marché du travail. Même les femmes qui étaient la principale source de revenue au sein du ménage avant leur premier enfant, réduisent considérablement leurs heures de travail et probabilité d'emploi, assumant plus que les hommes le garde d'enfants. Le troisième chapitre étudie l'effet du changement technologique sur l'écart salarial. En utilisant des données administratives pour l'Allemagne, on montre que les femmes ont été moins exposées à l'automatisation du travail et ont augmenté leur emploi dans des professions cognitives non routinières. Cependant, les gains salariaux des hommes ont été plus importants que ceux des femmes au sein des groupes cognitifs, ce qui explique pourquoi les changements technologiques n'ont pas entraîné de réductions plus importantes de l'écart salarial entre les sexes.This dissertation contributes to the literature that aims to understand the underlying causes of the persistent gender inequalities in the labor market. The two first chapters investigate the role of social norms in shaping the observed gender outcomes. The first chapter finds that in the context of a middle-income country like Uruguay, the male breadwinner norm affects not only the labor supply but also the quality of jobs in which women are employed, while they lead men to self-select into better-paid formal jobs. The second chapter uses panel data for US couples and investigates how labor supply responses to the birth of the first child are conditioned by relative earnings within the couple. We find that social norms associated to mother's role strongly shape labor market decisions. Even those women who were the main breadwinners in the household before having their first child, reduce their hours and employment probability dramatically, shouldering the childcare responsibilities more than men, which points towards a misallocation of resources. The third chapter studies the effect of technological change on the wage gap dynamics. Using administrative data for West Germany, I show that gender segregation across occupations has mostly benefited female workers, contributing to narrow the gender gap. This is explained because women have been less exposed to the automation of work and increased their employment in non-routine cognitive occupations. However, the wage gains for male workers have been larger than those for females within the cognitive groups, which explains why, technological change did not lead to greater reductions in the gender wage gap

Sistema informático de bienes para la gestión de almacén en la micro y pequeña empresa del sector textil, Huancayo

La presente investigación titulada “SISTEMA INFORMÁTICO DE BIENES PARA LA GESTIÓN DE ALMACÉN EN LA MICRO Y PEQUEÑA EMPRESA DEL SECTOR TEXTIL, HUANCAYO.”; debe responder al siguiente PROBLEMA GENERAL: ¿De qué manera el sistema informático de bienes, influye en la gestión de almacén en la Empresa de Confecciones Sebastián EIRL? Distrito de Chilca - Huancayo. 2019?. Y teniendo como Objetivo General: Determinar cómo influye el sistema informático de bienes en la gestión de almacén en la Empresa de Confecciones Sebastián EIRL. Distrito de Chilca - Huancayo. 2019 y con su Hipótesis General: El sistema informático de bienes influye de manera directa y significativa en la gestión de almacén en la Empresa de Confecciones Sebastián EIRL. Distrito de Chilca - Huancayo. 2019. El propósito de la investigación se basó en los resultados adquiridos, se propone brindar indicadores, para optimizar la problemática ubicada en la entidad analizada. Se escogió aleatoriamente una población de 60 individuos especialistas y una pequeña muestra no probabilística intencional conformada por 36 encuestados con especialidad. El método empleado en lo investigado es el METODO CIENTIFICO, con un nivel de investigación APLICADA y con un diseño de investigación: CORRELACIONAL, con la aplicación de los instrumentos a los especialistas – Ingenieros de Sistemas, del Distrito de Chilca. Provincia de Huancayo. Las principales conclusiones apriori son: El sistema informático de bienes influye de manera directa y significativa en un 51% en la “Gestión de Almacén” en la Empresa de Confecciones Sebastián EIRL. Distrito de Chilca - Huancayo. 2019. De esta forma se llegó a ACEPTAR el resultado positivamente y comprobar la hipótesis, planteada al inicio de la investigación.Tesi

Frescos de Goya en la Iglesia de San Antonio de la Florida

W Ra. Dir. 08 ; A 302/225 ; A 064/094 (Formato especial

El regidor Alonso Galvan, en el pleyto, que contra el trata doña Ysabel de Alcazar Caruajal, viuda de Francisco de Estrada, como madre legitima, y tutora de don Diego de Estrada : sobre que se de por nulla la uenta que don Melchor de Valdes Caruajal hizo

A 111/103(09

La comisión organizadora del beneficio de la Srta. María Galván ... se verificará el viernes 30 del corriente, en el Teatro Principal, le participa que cuenta también con su eficacísimo apoyo para esta buena obra...

Tít. tomado de principio de textoTexto fechado en Granada el 28 de noviembre de 1894Prospecto anunciadorDigitalización Fondo Granadin

A Story of Three Levels of Sophistication in SCF/KS-DFT Orbital Optimization Procedures

In this work, three versions of self-consistent field/Kohn–Sham density functional theory (SCF/KS-DFT) orbital optimization are described and benchmarked. The methods are a modified version of the geometry version of the direct inversion in the iterative subspace approach (which we call r-GDIIS), the modified restricted step rational function optimization method (RS-RFO), and the novel subspace gradient-enhanced Kriging method combined with restricted variance optimization (S-GEK/RVO). The modifications introduced are aimed at improving the robustness and computational scaling of the procedures. In particular, the subspace approach in S-GEK/RVO allows the application to SCF/KS-DFT optimization of a machine learning technique that has proven to be successful in geometry optimizations. The performance of the three methods is benchmarked for a large number of small- to medium-sized organic molecules, at equilibrium structures and close to a transition state, and a second set of molecules containing closed- and open-shell transition metals. The results indicate the importance of the resetting technique in boosting the performance of the r-GDIIS procedure. Moreover, it is demonstrated that already at the inception of the subspace version of GEK to optimize SCF wave functions, it displays superior and robust convergence properties as compared to those of the standard state-of-the-art SCF/KS-DFT optimization methods