Investigating Genomic Regulatory Elements in Adipocytes via Computational Analysis

Obesity prevalence has more than doubled since the 1980s. One possible consequence of obesity is insulin resistance (IR), a condition underlying type 2 diabetes mellitus (T2DM). So far, genome wide association studies (GWAS) have attributed 18% of heritable risk for T2DM to genetic variants, but one shortcoming of GWAS is knowing which genes are affected by identified variants. This study aimed to confront this weakness and investigate how epigenetic regulation affects metabolic phenotype. Three histone marks (H3K27ac, H3K4me1, H3K4me3) were targeted by chromatin immunoprecipitation for in vivo samples collected from human subcutaneous adipocytes and metabolically-relevant tissue samples curated from the ENCODE database. We developed the Extremity analysis method to identify enhancers and promoters enriched in histone ChIP-Seq data. Additionally, a full suite of well-established bioinformatics methods were employed, including differential enrichment analysis (DEA) and motif enrichment analysis (MEA), and existing obesity related GWAS were incorporated. Close correlation was found between Extremity and DEA, MEA provided enriched motifs that bind known adipogenic TFs, and the GWAS showed variants in T2DM and WHRadjBMI overlapping H3K4me3 have less heritability in adipocytes than the other two marks. This study provides a new method and potential targets for further understanding epigenetic variation and its effect on metabolic phenotype

Gestión pedagógica e interculturalidad en docentes de una institución educativa pública del distrito de Villa El Salvador, 2021

pedagógica e interculturalidad en docentes de una institución educativa pública del distrito de Villa el Salvador-2021. La metodología de la investigación se enmarca dentro del enfoque cuantitativo, con diseño no experimental, transversal, correlacional . Para recoger los datos se utilizó la técnica de la encuesta por la cual se elaboraron dos cuestionarios para aplicarlos de forma virtual debido a la pandemia, para medir la variable gestión pedagógica con 28 preguntas y para medir la variable interculturalidad 29 preguntas. La muestra poblacional fue no probabilística de tipo intencional por conveniencia estaba compuesta de 75 docentes del Centro educativo Nacional 6069 de Villa el Salvador. Se concluye que existe una relación positiva y significativa entre la gestión pedagógica e interculturalidad en docentes de secundaria, con un p valor de r= 0.740

Centro integral de atención al Adulto Mayor, distrito de San Juan de Miraflores, provincia y departamento de Lima

El tema propuesto es un proyecto arquitectónico de Centro Integral de Atención al Adulto Mayor (CIAM) ubicado en el Sector Ollantay del distrito de San Juan de Miraflores, como un centro satélite del ya existente que ayude a cubrir la alta demanda de población adulta mayor no atendida en este distrito. La línea de investigación de la presente tesis está circunscrita en el campo arquitectónico de carácter social, orientado a la Geronto Arquitectura y la Neuro arquitectura, que brinde talleres de capacitación, atención médica básica y promueva actividades de recreación a los adultos mayores del distrito, con el fin de ayudar a la socialización y reintegración de estos usuarios a la sociedad. Así como también, promover la inclusión de familias que tienen como responsabilidad a una persona adulta mayor

SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

Cancer therapyTeràpia del càncerTerapia del cáncerDespite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients

Plan de negocios para implementar ?Cuid@r-T? empresa de servicios de cuidados paliativos para pacientes con enfermedades cr?nicas avanzadas y/o terminales en Lima

El presente trabajo tiene por objetivo un Plan de Negocios para Implementar un Servicio de Cuidados Paliativos para Pacientes con Enfermedades Cr?nicas Avanzadas y/o terminales en la ciudad de Lima, que oferte servicios de salud especializados a domicilio y por teleconsulta. La empresa se ubicar? en la ciudad de Lima, donde se proyecta una demanda potencial en uso del servicio de 6,384 hogares. Los servicios a desarrollarse teleconsultas, servicios de enfermer?a a domicilio, administraci?n de medicamentos, terapias complementarias a la atenci?n m?dica y alquiler de equipos. Se ha calculado una inversi?n de S/. 542,686. A partir del an?lisis de costos, se determin? el estado de p?rdidas y ganancias por a?o con rendimiento m?nimo del 20% manej?ndose esta tasa como el costo de los fondos obteni?ndose un VAN de S/ 27,591. Los riesgos asumidos en el contexto macroentorno o riesgo pa?s definimos el escenario probable de participaci?n de mercado en el primer a?o del 2.3%, siendo los escenarios extremos (optimista y pesimista de 2.4% y 1.8% respectivamente). Se concluye que una empresa dedicada a brindar servicios de cuidados paliativos y de fin de vida es viable en t?rminos de mercado y financiero atractivas en t?rminos de inversi?n interna

MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer

Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-y (IFNy), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNy in a subset of LCs as a result of JAK2 or IFNGR1 inactivation. A submaximal response affects another subset that shows constitutive low levels of IFNy-stimulated genes (IySGs) coupled with decreased H3K27ac (histone 3 acetylation at lysine 27) depo-sition and promoter hypermethylation and reduced IFN regulatory factor 1 (IRF1) recruitment to the DNA on IFNy stimulation. Most of these are neuroendocrine small cell LCs (SCLCs) with oncogenic MYC/MYCL1/ MYCN. The oncogenic activation of MYC in SCLC cells downregulates JAK2 and impairs IySGs stimulation by IFNy. MYC amplification tends to associate with a worse response to anti-PD1/L1 therapies. Hence alterations affecting the JAK/STAT pathway and MYC activation prevent stimulation by IFNy and may predict anti-PD1/L1 efficacy in LC

SF3B1-mutant MDS as a distinct disease subtype:a proposal from the International Working Group for the Prognosis of MDS

The 2016 revision of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues is characterized by a closer integration of morphology and molecular genetics. Notwithstanding, the myelodysplastic syndrome (MDS) with isolated del(5q) remains so far the only MDS subtype defined by a genetic abnormality. Approximately half of MDS patients carry somatic mutations in spliceosome genes, with SF3B1 being the most commonly mutated one. SF3B1 mutation identifies a condition characterized by ring sideroblasts (RS), ineffective erythropoiesis, and indolent clinical course. A large body of evidence supports recognition of SF3B1-mutant MDSas a distinct nosologic entity. To further validate this notion, we interrogated the data set of the International Working Group for the Prognosis of MDS (IWG-PM). Based on the findings of our analyses, we propose the following diagnostic criteria for SF3B1-mutant MDS: (1) cytopenia as defined by standard hematologic values, (2) somatic SF3B1 mutation, (3) morphologic dysplasia (with or without RS), and (4) bone marrow blasts <5% and peripheral blood blasts <1%. Selected concomitant genetic lesions represent exclusion criteria for the proposed entity. In patients with clonal cytopenia of undetermined significance, SF3B1 mutation is almost invariably associated with subsequent development of overtMDS with RS, suggesting that this genetic lesion might provide presumptive evidence of MDS in the setting of persistent unexplained cytopenia. Diagnosis of SF3B1-mutant MDS has considerable clinical implications in terms of risk stratification and therapeutic decision making. In fact, this condition has a relatively good prognosis and may respond to luspatercept with abolishment of the transfusion requirement. (Blood. 2020;136(2):157-170)

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups

Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p 10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features