Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1.

Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth. Using murine and human metastatic models, we demonstrated that tumours with PRB > PRA (PRB-H) have a higher proliferation index but less metastatic ability than those with PRA > PRB (PRA-H). Antiprogestins and progestins inhibited metastatic burden in PRA-H and PRB-H models, respectively. In breast cancer samples, LNM retained the same PRA/PRB ratio as their matched primary tumours. Moreover, PRA-H LNM expressed higher total PR levels than the primary tumours. The expression of NDRG1, a metastasis suppressor protein, was higher in PRB-H compared to PRA-H tumours and was inversely regulated by antiprogestins/progestins. The binding of the corepressor SMRT at the progesterone responsive elements of the NDRG1 regulatory sequences, together with PRA, impeded its expression in PRA-H cells. Antiprogestins modulate the interplay between SMRT and AIB1 recruitment in PRA-H or PRB-H contexts regulating NDRG1 expression and thus, metastasis. In conclusion, we provide a mechanistic interpretation to explain the differential role of PR isoforms in metastatic growth and highlight the therapeutic benefit of using antiprogestins in PRA-H tumours. The therapeutic effect of progestins in PRB-H tumours is suggested.

Nuclear action of FGF members in endocrine-related tissues and cancer: Interplay with steroid receptor pathways.

Dysregulation of the fibroblast growth factors/fibroblast growth factor receptor (FGF/FGFR) pathway has been implicated in a wide range of human disorders and several members have been localized in the nuclear compartment. Hormone-activated steroid receptors or ligand independent activated receptors form nuclear complexes that activate gene transcription. This review aims to highlight the interplay between the steroid receptor and the FGF/FGFR pathways and focuses on the current knowledge on nuclear action of FGF members in endocrine-related tissues and cancer. The nuclear trafficking and targets of FGF/FGFR members and the available evidence on the interplay with steroid hormones and receptors is described. Finally, the data on aberrant FGF/FGFR signaling is summarized and the nuclear action of FGF members on endocrine resistant breast cancer is highlighted. Identifying the mechanisms underlying FGF-induced endocrine resistance will be important to understand how to efficiently target endocrine-related diseases and even enhance or restore endocrine sensitivity in hormone receptor positive tumors.

Mutations in the anti-sigma H factor RshA confer resistance to econazole and clotrimazole in Mycobacterium smegmatis.

Azole drugs such as econazole, are active on Mycobacterium tuberculosis and Mycobacterium smegmatis ; however, the identification of their target(s) is still pending. It has been reported that mutations in the non-essential system mmpL5-mmpS5 conferred resistance to econazole in M. tuberculosis . We herein report that an azole-resistant mutant screen in M. smegmatis rendered mutations in rshA, encoding a non-essential anti-sigma H protein.

Increased High Molecular Weight FGF2 in Endocrine-Resistant Breast Cancer.

Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.

Desproporción prótesis-paciente luego de reemplazo de válvula aórtica y seguimiento a 6 años / Patient-prosthesis mismatch in aortic valve replacement: a 6 year follow up

Resumen: Introducción: La desproporción prótesis-paciente (DPP) tras cirugía valvular ocurre cuando el área efectiva de orificio protésico (AEO) es fisiológicamente demasiado pequeño en relación con el tamaño del paciente, lo que resulta en gradientes postoperatorios elevados. Material y métodos: Se realizó un estudio observacional retrospectivo. Se analizaron pacientes con estenosis aórtica sometidos a reemplazo de válvula aórtica durante el año 2010. Se calculó AEO/ASC postoperatorio, si AEO/ASC fue menor de 0,85 cm2/ m2 el paciente fue clasificado como desproporción prótesis-paciente. Los eventos clínicos analizados fueron: mortalidad por cualquier causa, recambio valvular, internación por insuficiencia cardiaca y la capacidad funcional al momento de la encuesta. Se realizaron estadísticas descriptivas para analizar las características de la población. Las variables categóricas se expresaron en porcentaje y las variables continuas en promedio y desviación estándar. El análisis estadístico se realizó con el software IBM® SPSS® 19. Resultados: Se analizaron 26 pacientes sometidos a reemplazo de válvula aórtica con un seguimiento a 6 años, 13 de ellos presentaron DPP y mayor porcentaje de disnea, internación por insuficiencia cardiaca y muerte por cualquier causa. La combinación de eventos clínicos en este grupo de pacientes fue del 53,9%. Conclusión: Se observó un mayor número de eventos cardiovasculares en aquellos pacientes que con des- proporción prótesis-paciente.

Abstract: Background: Prosthesis-patient mismatch (PPM) after aortic valve replacement is related to inferior long-term outcomes. The study aim was to describe the rate of cardiovascular events in patients with or without PPM. Methods: The study was based on a retrospective analysis of information obtained from the electronic medical record. All patients undergoing aortic valve replacement, with or without revascularization surgery during 2010 were included. The effective orifice area (EOA) of the prothesis was obtained based on prosthetic valve data from echocardiography recommendations, was related to body surface area (BSA). PPM was diagnosed when EOA / BSA was < 0.85 cm2/m2. Clinical results were evaluated in January 2017 through our electronic medical record data base and a telephone interview. Helsinki criteria for clinical research were respected. Results: 26 patients were analyzed (20 males) with mean age 64 (SD 11.5) years old. A mechanical prosthesis was implanted in 10 patients and a biological one in the remaining subjects. 13 patients had DPP (EOA/BSA 0.77 ± 0.06). At a mean follow up period of 2190 days 44% were in functional class (NYHA) II-III, 31% had been re-hospitalized for heart failure and 8% had died from cardiac causes (overall death rate 31%). The combined outcome rate (overall death, hospitalization for heart failure or re-replacement of the valve) was 54%. Among the 13 patients without PPM, 31% were in functional class II-III, there were no hospitalizations for heart failure and only 4 patients had died from cardiac causes. Combined outcome rate was 23%. Conclusions: PPM was a marker of poorer clinical results on a long term follow up of patients undergoing aortic valve replacement. Inferential statistical analysis was not performed due to the relatively low number of patients included.

Distinct type I and type II toxin-antitoxin modules control Salmonella lifestyle inside eukaryotic cells.

Toxin-antitoxin (TA) modules contribute to the generation of non-growing cells in response to stress. These modules abound in bacterial pathogens although the bases for this profusion remain largely unknown. Using the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as a model, here we show that a selected group of TA modules impact bacterial fitness inside eukaryotic cells. We characterized in this pathogen twenty-seven TA modules, including type I and type II TA modules encoding antisense RNA and proteinaceous antitoxins, respectively. Proteomic and gene expression analyses revealed that the pathogen produces numerous toxins of TA modules inside eukaryotic cells. Among these, the toxins HokST, LdrAST, and TisBST, encoded by type I TA modules and T4ST and VapC2ST, encoded by type II TA modules, promote bacterial survival inside fibroblasts. In contrast, only VapC2ST shows that positive effect in bacterial fitness when the pathogen infects epithelial cells. These results illustrate how S. Typhimurium uses distinct type I and type II TA modules to regulate its intracellular lifestyle in varied host cell types. This function specialization might explain why the number of TA modules increased in intracellular bacterial pathogens.

Seguridad Social y género / Social security and gender

Este artículo intenta aportar algunos elementos básicos relacionados con el concepto de género para el conocimiento y manejo de esta perspectiva aplicada a la Seguridad Social. El empleo de la categoría de género no es privativo de los estudios relacionados con la mujer, sino que plantea un verdadero desafío de análisis sobre variedad de campos, entre ellos la Seguridad Social.

Evolución de la expectativa de vida de la población de 60 años y mas y la seguridad social / Evolution of the expectative of life of the population of 60 years and the social security

En la esfera de los sistemas de pensiones, y en el marco de los principios filosóficos de la Seguridad Social, adquieren trascendencia los comportamientos de determinadas variables demográficas, por cuanto ellas inciden en aspectos sustantivos de los esquemas de protección. El comportamiento de la mortalidad representa una de las variables de mauyor significación; de ahí que el interés de este artículo es presentar una visión retrospectiva acerca del comportamiento que ha tenido la expectativa de vida de la población costarricense de 60 años y más, en el período que va desde 1900 a 1990, y, además, pone énfasis en la importancia que tiene la tendencia de este indicador de la mortalidad en los sistemas de pensiones de la Seguridad Social.

Transformaciones estructurales en la población económicamente activa de Costa Rica : 1950-1990 / Structural transformation in the active economic population of Costa Rica: 1950-1990

El propósito de la autora es estudiar el comportamiento de la población económicamente activa costarricense en las tres últimas décadas poniendo énfasis en los cambios estructurales experimentados en la economía y la dinámica demográfica y su impacto en la distribución de la fuerza de trabajo por sexo, edad y grandes sectores económicos. Los resultados de este estudio, constituyen un punto de partida para disponer de un panorama de evolución histórica que permita formular hipótesis acerca del comportamiento futuro de la población económicamente activa y sus consecuencias en el desarrollo institucional y teniendo como norte que la población es el sujeto y el objeto de todo proceso de desarrollo