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

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.Additional co-authors: Emily K. Osterweil, Andrew S. MacDonald, Chris J. Schofield, Saverio Tardito, Josephine Bunch, Gillian Douce, Julia M. Edgar, RuAngelie Edrada-Ebel, Richard J. A. Goodwin, Richard Burchmore, Daniel M. Wal

Extremely High Tp53 Mutation Load in Esophageal Squamous Cell Carcinoma in Golestan Province, Iran

Background: Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC. Methodology/Principal Findings: Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 "hotspots" but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40 at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence. Conclusion/Significance: ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis