CPA\u27s basic guide to mergers & acquisitions

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Análisis de la sensibilidad barorefleja arterial mediante la aplicación de fenilefrina y nitroprusiato sódico en pacientes con trastorno depresivo mayor

La depresión mayor se ha asociado fuertemente con un riesgo aumentado de desarrollar enfermedades cardiovasculares (ECV) y con una tasa de mortalidad de dos a cuatro veces mayor después de un infarto agudo del miocardio. A pesar de la gran evidencia epidemiológica que soporta la relación entre la depresión y las ECV, los mecanismos fisiopatológicos de esta conexión permanecen poco conocidos. Las alteraciones en la función del sistema nervioso autónomo se han postulado como una de las causas probables del riesgo cardiovascular aumentado en pacientes con depresión. Diversos autores han mostrado que los síntomas depresivos están asociados con aberraciones en la regulación autonómica cardíaca, caracterizadas por una actividad simpática aumentada y un tono parasimpático disminuido, que aumentan el riesgo de isquemia miocárdica, taquicardia ventricular, fibrilación ventricular y muerte cardíaca súbita. Los barorreceptores arteriales son mecanorreceptores localizados en el arco aórtico y en el seno carotídeo, que sirven para regular la presión arterial mediante cambios rápidos en la frecuencia y contracción cardíacas y en la capacitancia venosa. El barorreflejo cardíaco muestra un equilibrio entre la actividad simpática y vagal para el mantenimiento de una presión arterial adecuada. Las alteraciones en la sensibilidad barorefleja se han asociado a un mayor riesgo de presentar arritmias ventriculares y muerte cardíaca súbita en sujetos con ECV. Recientemente, diversos estudios han mostrado que la sensibilidad de los barorreceptores arteriales está disminuida en sujetos con trastorno depresivo mayor (TDM) y ECV asociadas. Sin embargo, existen dudas razonables acerca de que estas alteraciones están mas relacionadas con la presencia de las ECV o con efectos secundarios de medicamentos antidepresivos que con el TDM mismo. Por lo tanto, el objetivo del presente estudio fue analizar la sensibilidad barorefleja arterial mediante la aplicación de fenilefrina y nitroprusiato de sódio en pacientes con TDM de novo sin ECV asociada y antes de la instauración de tratamiento antidepresivo. Salud UIS 2008; 40: 160-16

Análisis de la sensibilidad barorefleja arterial mediante la aplicación de fenilefrina y nitroprusiato sódico en pacientes con trastorno depresivo mayor

La depresión mayor se ha asociado fuertemente con un riesgo aumentado de desarrollar enfermedades cardiovasculares (ECV) y con una tasa de mortalidad de dos a cuatro veces mayor después de un infarto agudo del miocardio. A pesar de la gran evidencia epidemiológica que soporta la relación entre la depresión y las ECV, los mecanismos fisiopatológicos de esta conexión permanecen poco conocidos. Las alteraciones en la función del sistema nervioso autónomo se han postulado como una de las causas probables del riesgo cardiovascular aumentado en pacientes con depresión. Diversos autores han mostrado que los síntomas depresivos están asociados con aberraciones en la regulación autonómica cardíaca, caracterizadas por una actividad simpática aumentada y un tono parasimpático disminuido, que aumentan el riesgo de isquemia miocárdica, taquicardia ventricular, fibrilación ventricular y muerte cardíaca súbita. Los barorreceptores arteriales son mecanorreceptores localizados en el arco aórtico y en el seno carotídeo, que sirven para regular la presión arterial mediante cambios rápidos en la frecuencia y contracción cardíacas y en la capacitancia venosa. El barorreflejo cardíaco muestra un equilibrio entre la actividad simpática y vagal para el mantenimiento de una presión arterial adecuada. Las alteraciones en la sensibilidad barorefleja se han asociado a un mayor riesgo de presentar arritmias ventriculares y muerte cardíaca súbita en sujetos con ECV. Recientemente, diversos estudios han mostrado que la sensibilidad de los barorreceptores arteriales está disminuida en sujetos con trastorno depresivo mayor (TDM) y ECV asociadas. Sin embargo, existen dudas razonables acerca de que estas alteraciones están mas relacionadas con la presencia de las ECV o con efectos secundarios de medicamentos antidepresivos que con el TDM mismo. Por lo tanto, el objetivo del presente estudio fue analizar la sensibilidad barorefleja arterial mediante la aplicación de fenilefrina y nitroprusiato de sódio en pacientes con TDM de novo sin ECV asociada y antes de la instauración de tratamiento antidepresivo. Salud UIS 2008; 40: 160-16

PI3Kγ/δ and NOTCH1 Cross-Regulate Pathways That Define the T-cell Acute Lymphoblastic Leukemia Disease Signature

PI3K/AKT and NOTCH1 signaling pathways are frequently dysregulated in T-cell acute lymphoblastic leukemias (T-ALL). Although we have shown that the combined activities of the class I PI3K isoforms p110γ and p110δ play a major role in the development and progression of PTEN-null T-ALL, it has yet to be determined whether their contribution to leukemogenic programing is unique from that associated with NOTCH1 activation. Using an Lmo2-driven mouse model of T-ALL in which both the PI3K/AKT and NOTCH1 pathways are aberrantly upregulated, we now demonstrate that the combined activities of PI3Kγ/δ have both overlapping and distinct roles from NOTCH1 in generating T-ALL disease signature and in promoting tumor cell growth. Treatment of diseased animals with either a dual PI3Kγ/δ or a γ-secretase inhibitor reduced tumor burden, prolonged survival, and induced proapoptotic pathways. Consistent with their similar biological effects, both inhibitors downregulated genes involved in cMYC-dependent metabolism in gene set enrichment analyses. Furthermore, overexpression of cMYC in mice or T-ALL cell lines conferred resistance to both inhibitors, suggesting a point of pathway convergence. Of note, interrogation of transcriptional regulators and analysis of mitochondrial function showed that PI3Kγ/δ activity played a greater role in supporting the disease signature and critical bioenergetic pathways. Results provide insight into the interrelationship between T-ALL oncogenic networks and the therapeutic efficacy of dual PI3Kγ/δ inhibition in the context of NOTCH1 and cMYC signaling

Maternal and neonatal outcomes by labor onset type and gestational age.

OBJECTIVE: We sought to determine maternal and neonatal outcomes by labor onset type and gestational age. STUDY DESIGN: We used electronic medical records data from 10 US institutions in the Consortium on Safe Labor on 115,528 deliveries from 2002 through 2008. Deliveries were divided by labor onset type (spontaneous, elective induction, indicated induction, unlabored cesarean). Neonatal and maternal outcomes were calculated by labor onset type and gestational age. RESULTS: Neonatal intensive care unit admissions and sepsis improved with each week of gestational age until 39 weeks (P \u3c .001). After adjusting for complications, elective induction of labor was associated with a lower risk of ventilator use (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.28-0.53), sepsis (OR, 0.36; 95% CI, 0.26-0.49), and neonatal intensive care unit admissions (OR, 0.52; 95% CI, 0.48-0.57) compared to spontaneous labor. The relative risk of hysterectomy at term was 3.21 (95% CI, 1.08-9.54) with elective induction, 1.16 (95% CI, 0.24-5.58) with indicated induction, and 6.57 (95% CI, 1.78-24.30) with cesarean without labor compared to spontaneous labor. CONCLUSION: Some neonatal outcomes improved until 39 weeks. Babies born with elective induction are associated with better neonatal outcomes compared to spontaneous labor. Elective induction may be associated with an increased hysterectomy risk

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment