TP53 Mutations and HBX Status Analysis in Hepatocellular Carcinomas from Iran: Evidence for Lack of Association between HBV Genotype D and TP53 R249S Mutations

High incidence of HCC is mostly due to the combination of two major risk factors, chronic infection with hepatitis B (HBV) and/or C (HCV) viruses and exposure to the mycotoxin aflatoxin B1, which induces a particular mutation at codon 249 in TP53 (R249S). Eight genotypes of HBV are diversely found in high and low incidence areas. Regardless of documented strong associations between TP53 R249S mutation and HBV genotypes B, C, A or E, there is no report of such association for genotype D despite of the presence of aflatoxin in areas with high prevalence of HBV genotype D. In Iran, 3% of the population is chronically infected with HBV, predominantly genotype D. Twenty-one histologically confirmed HCC cases from Iran were analyzed for TP53 R249S and HBV double mutations 1762T/1764A, hallmarks of more pathogenic forms of HBV. We did not detect any of these mutations. In addition, we report the only case identified so far carrying both R249S mutation and chronic HBV genotype D, a patient from The Gambia in West Africa. This paper suggests that association between HBV genotype D and aflatoxin-induced TP53 mutation is uncommon, explaining the relatively lower incidence of HCC in areas where genotype D is highly prevalent

Testing Diagnostics of Nuclear Activity and Star Formation in Galaxies at z>1

We present some of the first science data with the new Keck/MOSFIRE instrument to test the effectiveness of different AGN/SF diagnostics at z~1.5. MOSFIRE spectra were obtained in three H-band multi-slit masks in the GOODS-S field, resulting in two hour exposures of 36 emission-line galaxies. We compare X-ray data with the traditional emission-line ratio diagnostics and the alternative mass-excitation and color-excitation diagrams, combining new MOSFIRE infrared data with previous HST/WFC3 infrared spectra (from the 3D-HST survey) and multiwavelength photometry. We demonstrate that a high [OIII]/Hb ratio is insufficient as an AGN indicator at z>1. For the four X-ray detected galaxies, the classic diagnostics ([OIII]/Hb vs. [NII]/Ha and [SII]/Ha) remain consistent with X-ray AGN/SF classification. The X-ray data also suggest that "composite" galaxies (with intermediate AGN/SF classification) host bona-fide AGNs. Nearly 2/3 of the z~1.5 emission-line galaxies have nuclear activity detected by either X-rays or the classic diagnostics. Compared to the X-ray and line ratio classifications, the mass-excitation method remains effective at z>1, but we show that the color-excitation method requires a new calibration to successfully identify AGNs at these redshifts.Comment: 7 pages, 4 figures. Accepted to ApJ Letter

Themes addressed in educational groups of sexual and reproductive health: an integrative review

Objective: to identify and analyze national scientific publications on sexual and reproductive health from the perspective of the educational group, according to the national guidelines that guide the practice. Method: this was an integrative review of scientific literature in the national data base of the Virtual Health Library in the period from July to August 2014, based on articles that focused on educational groups contraception. Results: among the 33 articles identified as inclusion and exclusion criteria, 10 were selected. The themes were diverse, as well as the population, however, few studies have focused on abortion, types of violence and gender, and other restricted to contraceptive methods and sexually transmitted diseases. Conclusion: there was a gap in the literature regarding the issues surrounding the topics covered in the educational practices of sexual and reproductive health and which is recommended by the directives, since such approaches disregard the needs of participants

Differences in white blood cell proportions between schizophrenia cases and controls are influenced by medication and variations in time of day

Cases with schizophrenia (SCZ) and healthy controls show differences in white blood cell (WBC) counts and blood inflammation markers. Here, we investigate whether time of blood draw and treatment with psychiatric medications are related to differences in estimated WBC proportions between SCZ cases and controls. DNA methylation data from whole blood was used to estimate proportions of six subtypes of WBCs in SCZ patients (n = 333) and healthy controls (n = 396). We tested the association of case-control status with estimated cell-type proportions and the neutrophil-to-lymphocyte ratio (NLR) in 4 models: with/without adjusting for time of blood draw, and then compared results from blood samples drawn during a 12-h (07:00–19:00) or 7-h (07:00-14:00) period. We also investigated WBC proportions in a subgroup of medication-free patients (n = 51). Neutrophil proportions were significantly higher in SCZ cases (mean=54.1%) vs. controls (mean=51.1%; p = <0.001), and CD8+T lymphocyte proportions were lower in SCZ cases (mean=12.1%) vs. controls (mean=13.2%; p = 0.001). The effect sizes in the 12-h sample (07:00–19:00) showed a significant difference between SCZ vs. controls for neutrophils, CD4+T, CD8+T, and B-cells, which remained significant after adjusting for time of blood draw. In the samples matched for time of blood draw during 07.00–14.00, we also observed an association with neutrophils, CD4+T, CD8+T, and B-cells that was unaffected by further adjustment for time of blood draw. In the medication-free patients, we observed differences that remained significant in neutrophils (p = 0.01) and CD4+T (p = 0.01) after adjusting for time of day. The association of SCZ with NLR was significant in all models (range: p < 0.001 to p = 0.03) in both medicated and unmedicated patients. In conclusion, controlling for pharmacological treatment and circadian cycling of WBC is necessary for unbiased estimates in case-control studies. Nevertheless, the association of WBC with SCZ remains, even after adjusting for the time of day.publishedVersio

Temas abordados nos grupos educativos de saúde sexual e reprodutiva: uma revisão integrativa Themes addressed in educational groups of sexual and reproductive health: an integrative review

Objetivos: Identificar e analisar as publicações científicas nacionais sobre saúde sexual e reprodutiva na perspectiva do grupo educativo, segundo as diretrizes nacionais que orientam tal prática. Métodos: Realizou-se uma revisão integrativa da literatura científica nacional na base de dado da Biblioteca Virtual de Saúde no período de Julho a Agosto de 2014, tendo como base artigos que versavam sobre grupos educativos de contracepção. Resultados: Dentre os 33 artigos identificados, conforme critérios de inclusão e exclusão, foram selecionados 10. Os temas eram diversificados, assim como a população, porém, alguns estudos enfocaram aborto, tipos de violência e gênero, sendo que outros restringiram-se a métodos contraceptivos e doenças sexualmente transmissíveis. Conclusões: Verificou-se lacunas na literatura no que tange às questões que envolvem os temas abordados nas práticas educativas de saúde sexual e reprodutiva e o que é preconizado pelas diretrizes, uma vez que tais abordagens desconsideram as necessidades dos participantes

Temas abordados nos grupos educativos de saúde sexual e reprodutiva: uma revisão integrativa Themes addressed in educational groups of sexual and reproductive health: an integrative review

Objetivos: Identificar e analisar as publicações científicas nacionais sobre saúde sexual e reprodutiva na perspectiva do grupo educativo, segundo as diretrizes nacionais que orientam tal prática. Métodos: Realizou-se uma revisão integrativa da literatura científica nacional na base de dado da Biblioteca Virtual de Saúde no período de Julho a Agosto de 2014, tendo como base artigos que versavam sobre grupos educativos de contracepção. Resultados: Dentre os 33 artigos identificados, conforme critérios de inclusão e exclusão, foram selecionados 10. Os temas eram diversificados, assim como a população, porém, alguns estudos enfocaram aborto, tipos de violência e gênero, sendo que outros restringiram-se a métodos contraceptivos e doenças sexualmente transmissíveis. Conclusões: Verificou-se lacunas na literatura no que tange às questões que envolvem os temas abordados nas práticas educativas de saúde sexual e reprodutiva e o que é preconizado pelas diretrizes, uma vez que tais abordagens desconsideram as necessidades dos participantes

Aflatoxin-Induced TP53 R249S Mutation in HepatoCellular Carcinoma in Thailand: Association with Tumors Developing in the Absence of Liver Cirrhosis

Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3rd among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G→T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (≥67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA ≥150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA ≥150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen–free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function

Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure

Recurrent upper tract urothelial carcinomas (UTUCs) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). Here we delineated the molecular programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe. We applied an integrative multiomics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative microRNA (miRNA) and messenger ribonucleic acid (mRNA) expression profiling, immunohistochemical analysis by tissue microarrays and exome and transcriptome sequencing were performed in UTUC and nontumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor resection. Ribonucleic acid (RNA) and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1,862 target mRNAs, involving deregulation of cell cycle, deoxyribonucleic acid (DNA) damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA-specific mutational signature SBS22, with 68% to 76% AA-specific, deleterious mutations propagated at the transcript level, a possible basis for neoantigen formation and immunotherapy targeting. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients' urine prior to tumor resection, thereby defining biomarkers of tumor presence. The complex gene regulation programs of AAN-associated UTUC tumors involve regulatory miRNAs prospectively applicable to noninvasive urine-based screening of AAN patients for cancer presence and recurrence

Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8(+) T cell response.

Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8(+) T cell populations specific for variants of the nonstructural protein epitope NS3133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3133-DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2(+) TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2(+) TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs