Epigenetic control of SOX9 gene by the histone acetyltransferase P300 in human Sertoli cells.

Background: The transcription factor SOX9 is a key regulator of male sexual development and Sertoli cell differentiation. Altered SOX9 expression has been implicated in the pathogenesis of disorders of sexual development (DSD) in mammals. However, limited information exists regarding the epigenetic mechanisms governing its transcriptional control during sexual development. Methods: This study employed real-time PCR (qPCR), immunofluorescence (IIF), and chromatin immunoprecipitation (ChIP) assays to investigate the epigenetic mechanisms associated with SOX9 gene transcriptional control in human and mouse Sertoli cell lines. To identify the specific epigenetic enzymes involved in SOX9 epigenetic control, functional assays using siRNAs for P300, GCN5, and WDR5 were performed. Results: The transcriptional activation of SOX9 was associated with selective deposition of active histone modifications, such as H3K4me3 and H3K27ac, at its enhancer and promoter regions. Importantly, the histone acetyltransferase P300 was found to be significantly enriched at the SOX9 enhancers, co-localizing with the H3K27ac and the SOX9 transcription factor. Silencing of P300 led to decreased SOX9 expression and reduced H3K27ac levels at the eSR-A and e-ALDI enhancers, demonstrating the crucial role of P300-mediated histone acetylation in SOX9 transcriptional activation. Interestingly, another histone lysine acetyltransferases like GNC5 and methyltransferases as the Trithorax/COMPASS-like may also have a relevant role in male sexual differentiation. Conclusions: Histone acetylation by P300 at SOX9 enhancers, is a key mechanism governing the transcriptional control of this essential regulator of male sexual development. These findings provide important insights into the epigenetic basis of sexual differentiation and the potential pathogenesis of DSDs.

Long Noncoding RNA TALAM1 Is a Transcriptional Target of the RUNX2 Transcription Factor in Lung Adenocarcinoma.

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide. It has been reported that genetic and epigenetic factors play a crucial role in the onset and evolution of lung cancer. Previous reports have shown that essential transcription factors in embryonic development contribute to this pathology. Runt-related transcription factor (RUNX) proteins belong to a family of master regulators of embryonic developmental programs. Specifically, RUNX2 is the master transcription factor (TF) of osteoblastic differentiation, and it can be involved in pathological conditions such as prostate, thyroid, and lung cancer by regulating apoptosis and mesenchymal-epithelial transition processes. In this paper, we identified TALAM1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) as a genetic target of the RUNX2 TF in lung cancer and then performed functional validation of the main findings. METHODS: We performed ChIP-seq analysis of tumor samples from a patient diagnosed with lung adenocarcinoma to evaluate the target genes of the RUNX2 TF. In addition, we performed shRNA-mediated knockdown of RUNX2 in this lung adenocarcinoma cell line to confirm the regulatory role of RUNX2 in TALAM1 expression. RESULTS: We observed RUNX2 overexpression in cell lines and primary cultured lung cancer cells. Interestingly, we found that lncRNA TALAM1 was a target of RUNX2 and that RUNX2 exerted a negative regulatory effect on TALAM1 transcription.

Regulatory Role of the RUNX2 Transcription Factor in Lung Cancer Apoptosis.

Lung cancer is the leading cause of cancer death globally. Numerous factors intervene in the onset and progression of lung tumors, among which the participation of lineage-specific transcription factors stands out. Several transcription factors important in embryonic development are abnormally expressed in adult tissues and thus participate in the activation of signaling pathways related to the acquisition of the tumor phenotype. RUNX2 is the transcription factor responsible for osteogenic differentiation in mammals. Current studies have confirmed that RUNX2 is closely related to the proliferation, invasion, and bone metastasis of multiple cancer types, such as osteosarcoma, breast cancer (BC), prostate cancer, gastric cancer, colorectal cancer, and lung cancer. Thus, the present study is aimed at evaluating the role of the RUNX2 transcription factor in inhibiting the apoptosis process. Loss-of-function assays using sh-RNA from lentiviral particles and coupled with Annexin/propidium iodide (PI) assays (flow cytometry), immunofluorescence, and quantitative PCR analysis of genes related to cell apoptosis (BAD, BAX, BCL2, BCL-XL, and MCL1) were performed. Silencing assays and Annexin/PI assays demonstrated that when RUNX2 was absent, the percentage of dead cells increased, and the expression levels of the BCL2, BCL-XL, and MCL1 genes were downregulated. Furthermore, to confirm whether the regulatory role of RUNX2 in the expression of these genes is related to its binding to the promoter region, we performed chromatin immunoprecipitation (ChIP) assays. Here, we report that overexpression of the RUNX2 gene in lung cancer may be related to the inhibition of the intrinsic apoptosis pathway, specifically, through direct transcriptional regulation of the antiapoptotic gene BCL2 and indirect regulation of BCL-XL and MCL1.

Transcriptional regulation of CDKN2A/p16 by sirtuin 7 in senescence.

Cell senescence is a state of limited cell proliferation during a stress response or as part of a programmed process. When a senescent cell stops dividing, maintaining metabolic activity contributes to cellular homeostasis maintenance. In this process, the cell cycle is arrested at the G0/G1 phase. p16INK4A protein is a key regulator of this process via its cyclin­dependent kinase inhibitor (CDKI) function. CDKI 2A (CDKN2A)/p16 gene expression is regulated by DNA methylation and histone acetylation. Sirtuins (SIRTs) are nicotinamide dinucleotide (NAD+)­dependent deacetylases that have properties which prevent diseases and reverse certain aspects of aging (such as immune, metabolic and cardiovascular diseases). By performing quantitative PCR, Western blot, ChIP, and siRNAs assays, in this study it was demonstrated that CDKN2A/p16 gene transcriptional activation and repression were accompanied by selective deposition and elimination of histone acetylation during the senescence of MRC5 cells. Specifically, significant H3K9Ac and H3K18Ac enrichment in cells with a senescent phenotype concomitant with CDKN2A/p16 gene overexpression was demonstrated compared with the non­senescent phenotype. Furthermore, the presence of H3K18Ac in deacetyl­transferase SIRT7 knockdown MRC5 cells allowed CDKN2A/p16 promoter activation. These results suggested that SIRT7 served as a critical component of an epigenetic mechanism involved in senescence mediated by the CDKN2A/p16 gene.

[Mental Health Care of Health Workers During Covid-19: Recommendations Based on Evidence and Expert Consensus]. / Cuidado de la salud mental del personal de salud durante COVID-19: recomendaciones basadas en evidencia y consenso de expertos.

INTRODUCTION: The crisis situation generated by COVID-19 and the measures adopted have generated social changes in the normal dynamics of the general population and especially for health workers, who find themselves caring for patients with suspected or confirmed infection. Recent studies have detected in them depression and anxiety symptoms and burnout syndrome, with personal and social conditions impacting their response capacity during the health emergency. Our aim was to generate recommendations for the promotion and protection of the mental health of health workers and teams in the first line of care in the health emergency due to COVID-19. METHODS: A rapid literature search was carried out in PubMed and Google Scholar, and an iterative expert consensus and through electronic consultation, with 13 participants from the areas of psychology, psychiatry and medicine; the grading of its strength and directionality was carried out according to the international standards of the Joanna Briggs Institute. RESULTS: Thirty-one recommendations were generated on self-care of health workers, community care among health teams, screening for alarm signs in mental health and for health institutions. CONCLUSIONS: The promotion and protection activities in mental health to face the health emergency generated by COVID-19 worldwide can include coordinated actions between workers, health teams and health institutions as part of a comprehensive, community care, co-responsible and sustained over time.

Cuidado de la salud mental del personal de salud durante COVID-19: recomendaciones basadas en evidencia y consenso de expertos / Mental Health Care of Health Workers During Covid-19: Recommendations Based on Evidence and Expert Consensus

RESUMEN Introducción: La situación de crisis generada por la COVID-19 y las medidas adoptadas han generado cambios sociales en las dinámicas normales de la población general y en especial para los trabajadores de la salud, que se encuentran en atención del paciente con infección sospechada o confirmada. Estudios recientes han detectado en ellos síntomas depresivos y ansiosos y síndrome de burnout, afecciones personales y sociales que alteran su capacidad de respuesta durante la emergencia sanitaria. El objetivo es generar recomendaciones de promoción y protección de la salud mental de los trabajadores y equipos de salud dispuestos como primera línea de atención en la emergencia sanitaria por COVID-19. Métodos: Se realizó una búsqueda rápida de literatura en PubMed y Google Scholar, y un consenso de expertos iterativo y mediante consulta electrónica, con 13 participantes de las áreas de psicología, psiquiatría y medicina; la gradación de su fuerza y direccionalidad se realizó según las normas internacionales del Joanna Briggs Institute. Resultados: Se generaron 31 recomendaciones sobre el autocuidado del trabajador de la salud, el cuidado comunitario entre los equipos de salud, el cribado de signos de alarma en salud mental y para las instituciones sanitarias. Conclusiones: Las actividades de promoción y protección en salud mental para el afrontamiento de la emergencia sanitaria generada por la COVID-19 en todo el mundo pueden abarcar acciones articuladas entre el trabajador, los equipos de salud y las instituciones sanitarias como parte de un cuidado integral, comunitario, corresponsable y sostenidas en el tiempo.

ABSTRACT Introduction: The crisis situation generated by COVID-19 and the measures adopted have generated social changes in the normal dynamics of the general population and especially for health workers, who find themselves caring for patients with suspected or confirmed infection. Recent studies have detected in them depression and anxiety symptoms and burnout syndrome, with personal and social conditions impacting their response capacity during the health emergency. Our aim was to generate recommendations for the promotion and protection of the mental health of health workers and teams in the first line of care in the health emergency due to COVID-19. Methods: A rapid literature search was carried out in PubMed and Google Scholar, and an iterative expert consensus and through electronic consultation, with 13 participants from the areas of psychology, psychiatry and medicine; the grading of its strength and directionality was carried out according to the international standards of the Joanna Briggs Institute. Results:Thirty-one recommendations were generated on self-care of health workers, community care among health teams, screening for alarm signs in mental health and for health institutions. Conclusions: The promotion and protection activities in mental health to face the health emergency generated by COVID-19 worldwide can include coordinated actions between workers, health teams and health institutions as part of a comprehensive, community care, co-responsible and sustained over time.

Recomendaciones para el uso racional de la prueba 25-hidroxivitamina D Resumen de política

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The exponential increase in the request for laboratory tests of 25-Hydroxyvitamin D or [25 (OH) D has ignited the alarms and generated a strong call for attention, since it may reflect deficiencies in the standardization of clinical practice and in the use non-systematic scientific evidence for decision-making in real life, which allows to analyze the indications of the test, its frequency, interpretation and even to assess the impact for health systems, especially when contrasted with the minimum or almost. No effects of the strategy of screening or supplying indiscriminately to the general population, without considering a comprehensive clinical assessment of risks and needs of people. From a purely public health impact point of view, the consequence of massive and unspecified requests is affecting most of the health systems and institutions at the global level. The primary studies that determined average population intake values have been widely used in the formulation of recommendations in Clinical Practice Guidelines, but unfortunately misinterpreted as cut points to diagnose disease and allow the exaggerated prescription of nutritional substitution. The coefficient of variation in routine tests to measure blood levels of 25 (OH) D is high (28%), decreasing the overall accuracy of the test and simultaneously, increasing both the falsely high and falsely low values. The most recent scientific evidence analyzes and seriously questions the usefulness and the real effect of the massive and indiscriminate practice of prescribing vitamin D without an exhaustive risk analysis. The available evidence is insufficient to recommend a general substitution of vitamin D to prevent fractures, falls, changes in bone mineral density, incidence of cardiovascular diseases, cerebrovascular disease, neoplasms and also to modify the growth curve of mothers' children. They received vitamin D as a substitute during pregnancy. The recommendations presented in the document are based on the critical analysis of current evidence and the principles of good clinical practice and invite to consider a rational use of 25 (OH) D tests in the context of a clinical practice focused on people and a comprehensive assessment of needs and risks. The principles of good practice suggest that clinicians may be able to justify that the results of the 25 (OH) D test strongly influence and define clinical practice and modify the outcomes that interest people and impact their health and wellness. Currently there is no clarity on how to interpret the results, and the relationship between symptoms and 25 (OH) D levels, which may not be consistent with the high prevalence of vitamin D deficiency reported. For this reason, it is suggested to review the rationale of the request for tests for systematic monitoring of levels of 25 (OH) D or in all cases where substitution is performed. Consider the use of 25 (OH) D tests within the comprehensive evaluation of people with suspicion or confirmation of the following conditions: rickets, osteomalacia, osteoporosis, hyper or hypoparathyroidism, malabsorption syndromes, sarcopenia, metabolic bone disease.

Introducing care management to Brazil's alcohol and substance use disorder population

Brazil has a sizable alcohol and substance use disorder (ASUD) population, yet there are considerable gaps in treatment access and retention. ASUD, a chronic medical condition, is highly comorbid with medical and behavioral health disorders. This indicates a need for more targeted interventions in order to achieve health care integration (a major goal of Brazil's health care system). Care management - that is, the organization of patient care by an institution - is a viable strategy to engage individuals with ASUD who might benefit from treatment but are not aware of or do not use the available resources, as well as to help maintain patients in treatment. Care management is considered an essential supplement to the treatment of chronic disease. The objective of this article is to discuss the applicability of care management for the treatment of ASUD within the public health care system in Brazil. We describe models of care management that have been adopted internationally and identify the feasibility and advantages for its adoption in Brazil.

Introducing care management to Brazil's alcohol and substance use disorder population.

Brazil has a sizable alcohol and substance use disorder (ASUD) population, yet there are considerable gaps in treatment access and retention. ASUD, a chronic medical condition, is highly comorbid with medical and behavioral health disorders. This indicates a need for more targeted interventions in order to achieve health care integration (a major goal of Brazil's health care system). Care management - that is, the organization of patient care by an institution - is a viable strategy to engage individuals with ASUD who might benefit from treatment but are not aware of or do not use the available resources, as well as to help maintain patients in treatment. Care management is considered an essential supplement to the treatment of chronic disease. The objective of this article is to discuss the applicability of care management for the treatment of ASUD within the public health care system in Brazil. We describe models of care management that have been adopted internationally and identify the feasibility and advantages for its adoption in Brazil.