Genetic ancestry of participants in the National Children's Study.

BackgroundThe National Children's Study (NCS) is a prospective epidemiological study in the USA tasked with identifying a nationally representative sample of 100,000 children, and following them from their gestation until they are 21 years of age. The objective of the study is to measure environmental and genetic influences on growth, development, and health. Determination of the ancestry of these NCS participants is important for assessing the diversity of study participants and for examining the effect of ancestry on various health outcomes.ResultsWe estimated the genetic ancestry of a convenience sample of 641 parents enrolled at the 7 original NCS Vanguard sites, by analyzing 30,000 markers on exome arrays, using the 1000 Genomes Project superpopulations as reference populations, and compared this with the measures of self-reported ethnicity and race. For 99% of the individuals, self-reported ethnicity and race agreed with the predicted superpopulation. NCS individuals self-reporting as Asian had genetic ancestry of either South Asian or East Asian groups, while those reporting as either Hispanic White or Hispanic Other had similar genetic ancestry. Of the 33 individuals who self-reported as Multiracial or Non-Hispanic Other, 33% matched the South Asian or East Asian groups, while these groups represented only 4.4% of the other reported categories.ConclusionsOur data suggest that self-reported ethnicity and race have some limitations in accurately capturing Hispanic and South Asian populations. Overall, however, our data indicate that despite the complexity of the US population, individuals know their ancestral origins, and that self-reported ethnicity and race is a reliable indicator of genetic ancestry

Regression/eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide.

Malignant gliomas have poor prognosis and urgently require new therapies. Activating Transcription Factor 5 (ATF5) is highly expressed in gliomas, and interference with its expression/function precipitates targeted glioma cell apoptosis in vitro and in vivo. We designed a novel deliverable truncated-dominant-negative (d/n) form of ATF5 fused to a cell-penetrating domain (Pen-d/n-ATF5-RP) that can be intraperitoneally/subcutaneously administered to mice harboring malignant gliomas generated; (1) by PDGF-B/sh-p53 retroviral transformation of endogenous neural progenitor cells; and (2) by human U87-MG xenografts. In vitro Pen-d/n-ATF5-RP entered into glioma cells and triggered massive apoptosis. In vivo, subcutaneously-administered Pen-d/n-ATF5-RP passed the blood brain barrier, entered normal brain and tumor cells, and then caused rapid selective tumor cell death. MRI verified elimination of retrovirus-induced gliomas within 8-21 days. Histopathology revealed growth-suppression of intracerebral human U87-MG cells xenografts. For endogenous PDGF-B gliomas, there was no recurrence or mortality at 6-12 months versus 66% mortality in controls at 6 months. Necropsy and liver-kidney blood enzyme analysis revealed no adverse effects on brain or other tissues. Our findings thus identify Pen-d/n-ATF5-RP as a potential therapy for malignant gliomas

High-Throughput and Cost-Effective Characterization of Induced Pluripotent Stem Cells.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) offers the possibility of studying the molecular mechanisms underlying human diseases in cell types difficult to extract from living patients, such as neurons and cardiomyocytes. To date, studies have been published that use small panels of iPSC-derived cell lines to study monogenic diseases. However, to study complex diseases, where the genetic variation underlying the disorder is unknown, a sizable number of patient-specific iPSC lines and controls need to be generated. Currently the methods for deriving and characterizing iPSCs are time consuming, expensive, and, in some cases, descriptive but not quantitative. Here we set out to develop a set of simple methods that reduce cost and increase throughput in the characterization of iPSC lines. Specifically, we outline methods for high-throughput quantification of surface markers, gene expression analysis of in vitro differentiation potential, and evaluation of karyotype with markedly reduced cost

Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma

CYP2D6; Anal squamous cell carcinoma; Cell cycleCYP2D6; Carcinoma de células escamosas anales; Ciclo celularCYP2D6; Carcinoma anal de cèl·lules escamoses; Cicle cel·lularBackground: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. Methods: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. Results: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p < .0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p = .02, HR = 3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. Conclusions: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. Plain language summary: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy

PAHA study (Psychological active and healthy ageing): Psychological wellbeing, proactive attitude and happiness effects of whole-body vibration versus multi-component training in aged women: study protocol for a randomized controlled trial

Background Evidence demonstrates that physical exercise and psychological wellbeing are closely interlinked, particularly in older-aged women. However, research investigating how different forms of exercise influence mental health in older-aged women is underdeveloped. Methods/Design A randomized controlled trial (N = 300) will assess the relative effectiveness of two different exercise programs (whole-body vibration and Multicomponent Training) for improving psychological wellbeing in older-aged women. The following outcomes will be assessed at three time points (that is, pre, post, and follow-up): psychological wellbeing, proactive attitude, quality of life, and happiness. Discussion Results will have important implications for preventing psychological and physiological disease in older-aged women and for managing health-related costs for this population group.Actividad Física y Deport

Animación japonesa y su influencia en el estilo de vida de jóvenes,caso de un centro comercial, Lima, 2022

El presente proyecto de investigación se centra en el análisis de los elementos que componen a la animación japonesa como producto audiovisual y cómo estos influyen en el estilo de vida de jóvenes que asisten al Centro Comercial Arenales. De tal modo, se describe la relación de su mensaje, examina la relación de la narrativa audiovisual e identifica la relación del uso de plataformas digitales, esto tomando en cuenta la problemática mencionada. Asimismo, se hizo uso de la metodología de enfoque cuantitativo, siendo una investigación de tipo aplicada, con un diseño no experimental de corte transversal. Por otro lado, se utilizó un cuestionario como instrumento de recopilación de datos, teniendo una muestra conformada por 93 individuos pertenecientes a un grupo de 124 jóvenes que asisten con regularidad al mencionado centro comercial

Evaluación del desplazamiento de un polímero de alto peso molecular para maximizar el factor de recobro del pozo SSF_122DTI del campo Shushufindi.

El campo Shushufidi resulta ser uno de los más grandes e importantes para el país, tomando en cuenta cada una de las consideraciones y factores que envuelven este yacimiento petrolífero. Se planteó como objetivo de estudio incrementar la producción de petróleo del campo Shushufindi por medio de la inyección de un polímero de alto peso molecular para aumentar el factor de recobro en el mismo. Para esto se evaluaron las condiciones necesarias y óptimas para incrementar la viscosidad del agua en el yacimiento y mediante este proceso, lograr mejorar la razón de movilidad del petróleo. Los resultados arrogados posterior a los procesos de simulación, indican una mejora de hasta el 12% más del valor de factor de recobro inicial. Se logró comprobar la eficiencia que tiene la Poliacrilamida (PAM), para poder realizar un estudio con la posibilidad de alargar la vida de un yacimiento que aún tenga reservas probadas. Así mismo, se prueba que con las características del campo es posible aplicar técnicas de recuperación mejorada a otros pozos condiciones similare

Synergistic effect of antimetabolic and chemotherapy drugs in triple-negative breast cancer

The triple-negative breast cancer (TNBC) subtype comprises approximately 15% of all breast cancers and is associated with poor long-term outcomes. Classical chemotherapy remains the standard of treatment, with toxicity and resistance being major limitations. TNBC is a high metabolic group, and antimetabolic drugs are effective in inhibiting TNBC cell growth. We analyzed the combined effect of chemotherapy and antimetabolic drug combinations in MDA-MB-231, MDA-MB-468 and HCC1143 human TNBC cell lines. Cells were treated with each drug or with drug combinations at a range of concentrations to establish the half-maximal inhibitory concentrations (IC50). The dose-effects of each drug or drug combination were calculated, and the synergistic or antagonistic effects of drug combinations were defined. Chemotherapy and antimetabolic drugs exhibited growth inhibitory effects on TNBC cell lines. Antimetabolic drugs targeting the glycolysis pathway had a synergistic effect with chemotherapy drugs, and antiglycolysis drug combinations also had a synergistic effect. The use of these drug combinations could lead to new therapeutic strategies that reduce chemotherapy drug doses, decreasing their toxic effect, or that maintain the doses but enhance their efficacy by their synergistic effect with other drugsMaría I. Lumbreras-Herrera and Andrea Zapater-Moros are supported by Consejería de Educación e Investigación de la Comunidad de Madrid (IND2018/BMD-9262). Elena López-Camacho is supported by the Spanish Economy and Competitiveness Ministry (PTQ2018–009760). This work is supported by an unrestricted grant from Roch