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1.
Artigo em Inglês | MEDLINE | ID: mdl-34267309

RESUMO

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is diagnosed in ~7% of school-aged children. The role of endocrine-disrupting chemicals (EDC) and oxidative stress in ADHD etiology are not clear. OBJECTIVE: Assessment of the associations between simultaneous exposure to multiple compounds and ADHD in children. METHODS: The case-control study included 76 clinically diagnosed ADHD cases and 98 controls, aged 4-15 years old. Concentrations quartiles of urinary metabolites of acrylamide, acrolein, nonylphenol, phthalates, and organophosphate pesticides and biomarkers of oxidative stress were used to fit logistic regressions for each compound and weighted quantiles sum (WQS) regression for the mixture. RESULTS: Positive dose-response relationships with ADHD were observed for 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) (odds ratio(OR)Q4 = 3.73, 95%CI [1.32, 11.04], ptrend = 0.003), dimethyl phosphate (DMP) (ORQ4 = 4.04, 95%CI [1.34, 12.94], ptrend = 0.014) and diethyl phosphate (ORQ4 = 2.61, 95%CI = [0.93, 7.66], ptrend = 0.030), and for the mixture of compounds (ORWQS = 3.82, 95%CI = [1.78, 8.19]) with the main contributions from HNE-MA (28.9%) and DMP (18.4%). CONCLUSIONS: The dose-response relationship suggests enhanced susceptibility to EDC burden in children even at lower levels, whereas the main risk is likely from organophosphate pesticides. HNE-MA is recommended as a sensitive biomarker of lipid peroxidation in the further elucidation of the oxidative stress role in ADHD etiology.

2.
Sci Total Environ ; 773: 145604, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33592467

RESUMO

This study will help to clarify the relationship between organophosphate pesticides (OPs) and attention deficit/hyperactivity disorder (ADHD) related to oxidative stress and paraoxonases (PON) polymorphisms to further characterize the gene-environment interaction. This case-control study enrolled 85 children with ADHD and 96 control subjects. Urinary OP levels were analyzed by using gas chromatography-mass spectrometry (GC-MS). Oxidative stress biomarkers, such as 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2-Gua), 8-iso-prostaglandin F2α (8-iso-PGF2α), and 4-hydroxy-2-nonenoic acid-mercapturic acid (HNE-MA), were analyzed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S) were calculated to evaluate the additive interactions between OP exposure and PON genetic polymorphism on ADHD. A causal mediation analysis was conducted to clarify the mediation effects of oxidative stress due to OP exposure on ADHD. Children with ADHD had significantly higher DMP (238.95 nmol/g cre. vs. 164.83 nmol/g cre., p value = 0.01) and HNE-MA (30.75 µg/g cre. vs. 18.41 µg/g cre., p value<0.01) concentrations than control children. Children who carried the PON1 GG genotype (rs705379) had low urinary DMP levels, and the level increased with increasing numbers of allele variants. The risk for developing ADHD reached 2.06-fold (OR = 2.06, 95% CI:1.23-3.44) and 1.43-fold (OR = 1.45, 95% CI:1.04-2.03) when the DMP and HNE-MA levels increased by 1 natural log of the concentration, respectively. The estimated AP value was 0.66 (95% CI: 0.17-1.15), indicating that 66% of ADHD cases in DMP-exposed children with the PON1 CT/TT (rs705381) genotype were due to gene-environment interactions. No significant mediation of HNE-MA was observed between DMP exposure and the risk of ADHD. The estimated proportion mediated was only 7.0% (95% CI: -0.08-0.46). This research suggests the role of OP exposure in the occurrence of ADHD after adjusting for covariates.


Assuntos
Arildialquilfosfatase , Transtorno do Deficit de Atenção com Hiperatividade , Arildialquilfosfatase/genética , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estudos de Casos e Controles , Criança , Cromatografia Líquida , Humanos , Organofosfatos/efeitos adversos , Estresse Oxidativo , Polimorfismo Genético , Espectrometria de Massas em Tandem
3.
Gynecol Oncol ; 160(2): 568-578, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33328126

RESUMO

OBJECTIVE: The development of effective cancer treatments depends on the availability of cell lines that faithfully recapitulate the cancer in question. This study definitively re-assigns the histologic identities of two ovarian cancer cell lines, COV434 (originally described as a granulosa cell tumour) and TOV-112D (originally described as grade 3 endometrioid carcinoma), both of which were recently suggested to represent small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), based on their shared gene expression profiles and sensitivity to EZH2 inhibitors. METHODS: For COV434 and TOV-112D, we re-reviewed the original pathology slides and obtained clinical follow-up on the patients, when available, and performed immunohistochemistry for SMARCA4, SMARCA2 and additional diagnostic markers on the original formalin-fixed, paraffin-embedded (FFPE) clinical material, when available. For COV434, we further performed whole exome sequencing and validated SMARCA4 mutations by Sanger sequencing. We studied the growth of the cell lines at baseline and upon re-expression of SMARCA4 in vitro for both cell lines and evaluated the serum calcium levels in vivo upon injection into immunodeficient mice for COV434 cells. RESULTS: The available morphological, immunohistochemical, genetic, and clinical features indicate COV434 is derived from SCCOHT, and TOV-112D is a dedifferentiated carcinoma. Transplantation of COV434 into mice leads to increased serum calcium level. Re-expression of SMARCA4 in either COV434 and TOV-112D cells suppressed their growth dramatically. CONCLUSIONS: COV434 represents a bona fide SCCOHT cell line. TOV-112D is a dedifferentiated ovarian carcinoma cell line.


Assuntos
Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma de Células Pequenas/diagnóstico , Linhagem Celular Tumoral/patologia , Neoplasias Ovarianas/diagnóstico , Animais , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Desdiferenciação Celular/genética , Linhagem Celular Tumoral/efeitos dos fármacos , DNA Helicases/análise , DNA Helicases/deficiência , DNA Helicases/genética , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Proteínas Nucleares/análise , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fatores de Transcrição/análise , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Int J Hyg Environ Health ; 222(6): 955-964, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31248753

RESUMO

Parabens are a group of esters of parahydroxybenzoic acid and are utilized as antimicrobial preservatives in the majority of personal care products (PCPs). Epidemiological studies regarding the adverse effects of parabens on fetuses are still limited. The aim of this study was to determine the association between maternal paraben exposure and birth outcomes. One hundred and ninety-nine pregnant women were enrolled, and maternal urine was collected in the third trimester. The urine concentrations of four parabens (methyl (MP), ethyl (EP), propyl (PP), and butyl (BP)) were determined by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Generalized additive model-penalized regression splines and a multivariable regression model were employed to determine the association between paraben exposure levels and birth outcomes. A causal mediation analysis was conducted to determine the mediation effect of oxidative stress on birth outcomes. The geometric means of urinary MP, EP, PP, and BP were 51.79, 1.26, 4.21, and 1.25 µg/g cre., respectively. In the penalized regression splines, sex-specific associations between maternal MP levels and birth outcomes were observed; a downward curvature was observed between the MP level and birth weight, length, head circumference, and thoracic circumference among female newborns. Pregnant women in the group with MP levels above the third quartile had neonates with significantly lower body weight (ß = -215.98 g, p value = 0.02) compared to those in the group with MP levels lower than the third quartile. No significant mediation of oxidative stress was observed between maternal MP exposure and female birth weight. The estimated proportion mediated ranged from -6% to 15%. The negative association between maternal paraben exposure and female birth outcomes in relation to child development should be carefully considered.


Assuntos
Anti-Infecciosos/urina , Tamanho Corporal , Poluentes Ambientais/urina , Exposição Materna , Parabenos/análise , Adulto , Monitoramento Biológico , Feminino , Humanos , Masculino , Troca Materno-Fetal , Estresse Oxidativo , Gravidez , Caracteres Sexuais , Taiwan
5.
Chemosphere ; 226: 290-297, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30933738

RESUMO

This study determined whether maternal bisphenol A (BPA) exposure influences birth outcomes through oxidative stress and estimated the daily intake of BPA through breast milk for infants. One hundred and eighty-six pregnant women without pregnancy complications were enrolled and maternal urine was collected in the third trimester. Postnatal breast milk was collected in the first and third months after delivery. Concentrations of BPA were determined through ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Generalized additive model-penalized regression splines and a multivariable regression model were employed to determine the effects of BPA exposure and oxidative stress levels on birth outcomes. A causal mediation analysis was conducted to clarify the mediation effects of oxidative stress due to maternal BPA exposure on birth outcomes. The daily intake of BPA in breast milk was calculated using probabilistic risk assessment methods. The geometric means (geometric standard deviation) of BPA levels for maternal urine and first- and third-month breast milk were 2.19 (2.88) µg/g creatinine., 1.35 (3.53) ng/g, and 3.17 (2.97) ng/g, respectively. No significant mediation existed among maternal BPA exposure, oxidative stress level, and neonatal head circumference. Three percent of 1-monthold babies and 1% of 3-month-old babies exceeded the BPA tolerable daily intake of 4 µg/kg-bw/day proposed by the European Food Safety Authority. This study revealed the BPA exposure profile for pregnant women and infants in northern Taiwan. The marginally significant correlation between maternal BPA exposure and neonatal head circumference should be considered.


Assuntos
Compostos Benzidrílicos/análise , Exposição Materna/efeitos adversos , Leite Humano/química , Estresse Oxidativo/efeitos dos fármacos , Fenóis/análise , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Pesos e Medidas Corporais , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Feminino , Humanos , Lactente , Saúde do Lactente , Recém-Nascido , Espectrometria de Massas , Gravidez , Análise de Regressão , Medição de Risco , Taiwan
6.
Am J Surg Pathol ; 43(5): 628-638, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30986800

RESUMO

Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1 mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1 and FOXL2 somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12%) were well differentiated, 31 (74%) moderately differentiated, and 6 (14%) poorly differentiated. Eight (19%) had heterologous elements, and 2 (5%) showed retiform differentiation; all 10 were moderately differentiated. DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2 c.402C>G (p.C134W) mutation was identified in 8/42 (19%) tumors (5 moderately, 3 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1 mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2 mutation (median, 79.5 y; range, 51 to 90 y) (P<0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1 and FOXL2 (15/42, 37%) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2 mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).


Assuntos
Biomarcadores Tumorais/genética , RNA Helicases DEAD-box/genética , Proteína Forkhead Box L2/genética , Mutação , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Tumor de Células de Sertoli-Leydig/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/patologia , Fenótipo , Tumor de Células de Sertoli-Leydig/classificação , Tumor de Células de Sertoli-Leydig/patologia , Adulto Jovem
7.
Gynecol Oncol ; 153(3): 487-495, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30922603

RESUMO

OBJECTIVE: Approximately 15% of endometrial carcinomas (ECs) arise in young women who may wish to avoid surgical menopause and/or preserve fertility. Our aim was to evaluate the prognostic significance of Proactive Molecular risk classifier for Endometrial Carcinoma (ProMisE) in young (<50 yo) women with EC. METHODS: ProMisE was applied to a retrospective cohort of women with ECs <50 yo at diagnosis, and associations between the four ProMisE molecular subtypes (MMR deficient (MMRd), POLE mutated (POLE), p53 wild type (p53wt), and p53 abnormal (p53abn)) and clinicopathological parameters, including outcomes, were assessed. RESULTS: Of 257 ECs, there were 48 (19%) MMRd, 34 (13%) POLE, 164 (64%) p53wt and 11 (4%) p53abn. ProMisE subtypes were associated with differences in all measured clinicopathological parameters except for presence of synchronous ovarian tumours and fertility. Age at diagnosis was youngest and BMI highest in women with p53wt ECs. MMRd and p53abn tumours were more likely to be advanced stage (III/IV), high-risk (ESMO), and receive chemotherapy. ProMisE subtypes were strongly associated with outcomes (overall, disease-specific, and progression-free survival (p < 0.0001 for all)). Advanced stage, grade, LVSI, myometrial invasion and ESMO risk groups showed associations with some but not all survival parameters. ProMisE maintained a strong association with OS and DSS on multivariable analysis. CONCLUSIONS: ProMisE molecular classification is prognostic in young women with EC, enabling early stratification and risk assignment to direct care. Further studies can assess response to therapy, fertility, and cancer-related outcomes within the framework of molecular subtype.


Assuntos
Carcinoma/classificação , DNA Polimerase II/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/classificação , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteína Supressora de Tumor p53/metabolismo , Adulto , Fatores Etários , Índice de Massa Corporal , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/secundário , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida
8.
Mod Pathol ; 32(4): 593, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29968850

RESUMO

The original version of this Article omitted the author Hannah van Meurs from the Department of Gynecology, Center for Gynecologic Oncology Amsterdam, Academic Medical Center, 1100 DD Amsterdam, The Netherlands. This has been corrected in both the PDF and HTML versions of the article.

9.
Environ Res ; 167: 567-574, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30165327

RESUMO

Nonylphenol (NP) and/or bisphenol A (BPA) may have reproductive effects. Although the mechanisms of action remain unclear, steroid hormones biosynthesis, hypothalamus pituitary adrenal axis activity, oxidative stress, and crosstalk interaction of NP and BPA mixture and its pathways may play a contributory role. This cross-sectional study examined whether the interactive effects of NP/BPA and oxidative stress biomarkers played a role in reproductive indices (penis length and anogenital distance (AGD)) in 244 mother-fetus pairs. Four biomarkers of oxidative stress, (8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2Gua), 8-iso-prostaglandin F2α (8-isoPF2α), and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)) were simultaneously analyzed using the high-performance liquid chromatography-electrospray ionization tandem mass spectrometry method. No significant associations were found between reproductive indices and NP/BPA or oxidative stress biomarkers. Maternal exposure to a mixture of NP and BPA may enhance 8-OHdG. Interactive effects were found in the high 8-isoPF2α group, and prenatal NP exposure was inversely associated with penis length (ß = -3.68 mm; p = 0.01). Similar results were noted among boys who were born to mothers in the high 8-isoPF2α group, in which BPA was inversely associated with penis length (ß = -4.43 mm; p = 0.005). Our findings suggest important implications for prenatal exposure to oxidative stress, as evidenced by the 8-isoPF2α level. Thus, NP and BPA may interact to shape fetal reproductive tract development, particularly in boys. The interactive effects of NP/BPA, oxidative stress, and reproductive indices should be considered.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Genitália Masculina/anatomia & histologia , Estresse Oxidativo , Fenóis/efeitos adversos , Estudos Transversais , Feminino , Feto/anatomia & histologia , Humanos , Masculino , Gravidez
10.
Cell ; 173(7): 1755-1769.e22, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29754820

RESUMO

High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Antígenos CD8/metabolismo , Análise por Conglomerados , Feminino , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Perda de Heterozigosidade , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Sequenciamento Completo do Genoma , Adulto Jovem
11.
Mod Pathol ; 31(7): 1107-1115, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29449679

RESUMO

The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERT to maintain telomere length and telomerase activity, which is a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified as gain-of-function mutations that promote transcriptional activation of TERT in multiple cancers, such as melanoma and glioblastoma. A recent study investigating TERT promoter mutations in ovarian carcinomas found C228T and C250T mutations in 15.9% of clear cell carcinomas. However, it is unknown whether these mutations are frequent in other ovarian cancer subtypes, in particular, sex cord-stromal tumors including adult granulosa cell tumors. We performed whole-genome sequencing on ten adult granulosa cell tumors with matched normal blood and identified a TERT C228T promoter mutation in 50% of tumors. We found that adult granulosa cell tumors with mutated TERT promoter have increased expression of TERT mRNA and exhibited significantly longer telomeres compared to those with wild-type TERT promoter. Extension cohort analysis using allelic discrimination revealed the TERT C228T mutation in 51 of 229 primary adult granulosa cell tumors (22%), 24 of 58 recurrent adult granulosa cell tumors (41%), and 1 of 22 other sex cord-stromal tumors (5%). There was a significant difference in overall survival between patients with TERT C228T promoter mutation in the primary tumors and those without it (p = 0.00253, log-rank test). In seven adult granulosa cell tumors, we found the TERT C228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggest that TERT C228T promoter mutations may have an important role in progression of adult granulosa cell tumors.


Assuntos
Tumor de Células da Granulosa/genética , Telomerase/genética , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Tumor de Células da Granulosa/mortalidade , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Prognóstico , Regiões Promotoras Genéticas/genética
12.
Environ Res ; 160: 339-346, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29054088

RESUMO

OBJECTIVE: The aim of this study was to clarify the association between organophosphate pesticides (OPs) and attention-deficit/hyperactivity disorder (ADHD) related to oxidative stress and genetic polymorphisms. METHODS: This case-control study enrolled 93 children with ADHD and 112 control children in north Taiwan. Six dialkyl phosphate (DAP) metabolites of OPs and oxidative stress biomarkers were analyzed. Polymorphisms of the dopamine receptor D4 gene (DRD4) were identified. RESULTS: Children with ADHD had significantly higher dimethylphosphate (DMP, 236.69nmol/g cre. vs. 186.84nmol/g cre., p value = 0.01) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA, 28.95µg/g cre. vs. 16.55µg/g cre., p value<0.01) concentrations than control children. Children who carried DRD4 GA/AA genotypes (rs752306) were less likely than those who carried the DRD4 GG genotype to have ADHD (odds ratio [OR]: 0.45, 95% CI: 0.24-0.84). The estimated value of the AP (attributable proportion due to interaction) was 0.59 (95% CI: 0.13-1.05), indicating that 59% of ADHD cases in DMP-exposed children with the DRD4 GG genotype were due to the gene-environment interaction. After adjustment for other covariates, children who carried the DRD4 GG genotype, had been exposed to high DMP levels (more than the median), and had high HNE-MA levels had a significantly increased risk for developing ADHD (OR = 11.74, 95% CI: 2.12-65.04). CONCLUSION: This study indicated a gene-environment interaction in the risk of ADHD in children. The association between DMP and ADHD in children might relate to the mechanism of lipid peroxidation. Dose-response relationships and the combined effects of OPs, oxidative stress, and genetic polymorphism on ADHD should not be neglected.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Organofosfatos/toxicidade , Estresse Oxidativo , Praguicidas/toxicidade , Receptores de Dopamina D4/genética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Peroxidação de Lipídeos , Masculino , Polimorfismo de Nucleotídeo Único
13.
J Pathol Clin Res ; 3(4): 279-293, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29085668

RESUMO

Molecular subclassification of endometrial carcinoma (EC) with Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifies four subtypes [DNA polymerase epsilon (POLE) mutant, mismatch repair-deficient, p53 wild-type (wt), and p53 abnormal]. The aim of this study was to evaluate additional EC biomarkers in the context of these subtypes. Tissue microarrays encompassing 460 previously characterized ECs were assessed for L1-cell adhesion molecule (L1CAM), progesterone receptor (PR), estrogen receptor (ER) alpha, stathmin, and phosphatase and tensin homolog (PTEN), by immunohistochemistry (IHC). Associations with clinicopathological parameters, molecular subtype, and outcomes were determined. About 413 ECs (75% endometrioid, >15% serous) had complete data. L1CAM overexpression was found in 16%, associated with older age, lower body mass index (BMI), advanced stage, grade 3 (97%), non-endometrioid histology (84%), deep myometrial invasion, lymphovascular space invasion (LVSI), and ER-negative, PR-negative status. Tumours overexpressing L1CAM were associated with poor outcomes {hazard ratio (HR) [95% confidence interval (CI)] 3.35 [2.10-5.23] for disease-specific survival [DSS], p < 0.0001}. PR positivity was associated with younger women, higher BMI, early stage (77% stage I), low grade (61%), endometrioid histology (90%) without LVSI or nodal disease, ER positivity (90%), p53wt tumours (55%), and favourable outcomes [HR (CI) 0.39 (0.25-0.62) for DSS, p < 0.0001]. ER positive tumours were early stage (73%), low grade, endometrioid histology, with improved DSS. Stathmin and PTEN IHC were not associated with outcomes. There was minimal agreement between IHC and mutation status for PTEN. L1CAM overexpression was significantly associated with the p53 abnormal molecular subtype, which accounted for more than 70% of the tumours overexpressing L1CAM. PR expression also correlated with molecular subtype, with most PR negative tumours being p53 abnormal. Multivariable analysis demonstrated that only ProMisE subtype [overall survival (OS), DSS, and progression-free survival] and age (OS only) maintained an association with outcomes. The prognostic significance of the single biomarkers tested could be explained based on their being covariable with the ProMisE molecular subtype.

14.
Environ Sci Technol ; 51(11): 6422-6429, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28490175

RESUMO

Prenatal exposure to nonylphenol (NP) and/or bisphenol A (BPA) has been reported to be associated with adverse birth outcomes; however, the underlying mechanisms remain unclear. The primary mechanism is endocrine disruption of the binding affinity for the estrogen receptor, but oxidative stress and inflammation might also play a contributory role. We aimed to investigate urinary NP and BPA levels in relation to biomarkers of oxidative/nitrative stress and inflammation and to explore whether changes in oxidative/nitrative stress are a function of prenatal exposure to NP/BPA and inflammation in 241 mother-fetus pairs. Third-trimester urinary biomarkers of oxidative/nitrative stress were simultaneously measured, including products of oxidatively and nitratively damaged DNA (8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-nitroguanine (8-NO2Gua)) as well as products of lipid peroxidation (8-iso-prostaglandin F2α (8-isoPF2α) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)). The antioxidant glutathione peroxidase (GPx) and inflammation biomarkers, including C-reactive protein (CRP) and a panel of cytokines (interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)), were analyzed in maternal and umbilical cord plasma samples. In adjusted models, we observed significant positive associations between NP exposure and 8-OHdG and 8-NO2Gua levels, between BPA and 8-isoPF2α levels, and between maternal CRP levels and HNE-MA levels. Additionally, BPA and TNF-α levels in cord blood were inversely associated with maternal and GPx levels in cord blood as well as maternal TNF-α levels were inversely associated with maternal GPx levels. These results support a role for exposure to NP and BPA and possibly inflammation in increasing oxidative/nitrative stress and decreasing antioxidant activity during pregnancy.


Assuntos
Compostos Benzidrílicos/toxicidade , Dano ao DNA , Inflamação , Estresse Oxidativo , Fenóis/toxicidade , Adulto , Biomarcadores , Estudos de Coortes , Feminino , Sangue Fetal , Humanos , Exposição Materna , Gravidez , Fator de Necrose Tumoral alfa/sangue
15.
Arch Gerontol Geriatr ; 70: 38-43, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28042985

RESUMO

This study aimed to assess the benefit of adding physical function evaluations and interventions to routine elderly health examination. This is a Quasi-experimental controlled trial. 404 elderly adults (aged 70 and over) scoring 3-6 on the Canadian Study of Health and Aging Clinical Frailty Scale Chinese In-Person Interview Version (CSHA-CFS) in a 2012 annual elderly health examination were enrolled. Both the control and experimental groups received the routine annual health examination with the latter further provided with functional evaluations, exercise instruction, and nutrition education. 112 (84.8%) persons in the experiment group and 267 (98.2%) in the control group completed the study. CSHA-CFS performance of the experimental group was more likely to improve (odds ratio=9.50, 95% confidence interval (CI)=4.62-19.56) and less likely to deteriorate (OR=0.04, 95% CI=0.01-0.31) one year after intervention. Within the experimental group, Fried Frailty Index improvement percentage surpassed the deterioration percentage (29.5% vs. 0.9%, p<0.001), five-meter walk speed rose from 1.0±0.2 to 1.2±0.2m/s (p<0.001), grip strength escalated from 22.3±7.1 to 24.8±6.7kg (p<0.001), Short-form Physical Performance Battery increased from 10.0±1.6 to 11.6±0.9 (p<0.001), and timed up and go test decreased from 10.9±2.9 to 8.9±2.7s (p<0.001). However, no statistical difference was detected in composite adverse endpoints, including hospitalization, emergency department visit and falls, between the two groups, though the incidence was higher in the control group. Adding functional evaluations, exercise and nutrition interventions to the annual elderly health examination appeared to benefit the health of adults aged 70 years and older.


Assuntos
Exercício Físico , Avaliação Geriátrica , Fenômenos Fisiológicos da Nutrição , Educação de Pacientes como Assunto , Idoso , Idoso de 80 Anos ou mais , Teste de Esforço , Feminino , Força da Mão , Humanos , Masculino
16.
Cancer ; 123(5): 802-813, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28061006

RESUMO

BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs. METHODS: Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]). RESULTS: ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P < .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802-13. © 2016 American Cancer Society.


Assuntos
Reparo de Erro de Pareamento de DNA/genética , DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Patologia Molecular , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/patologia , Feminino , Humanos , Instabilidade de Microssatélites , Mutação , Mutação de Sentido Incorreto , Estadiamento de Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose , Fatores de Risco
17.
J Mol Diagn ; 19(1): 126-136, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27810330

RESUMO

Adult granulosa cell tumors (AGCTs) of the ovary are molecularly characterized by the pathognomonic FOXL2 402C>G (C134W) mutation. To improve diagnostics and follow-up, we developed a specific digital droplet PCR (ddPCR) assay to detect the FOXL2 mutation in the circulating tumor DNA (ctDNA) of AGCT patients. Optimization of the ddPCR assay was performed using a TaqMan primer/probe with the RainDance RainDrop digital PCR system. The ddPCR assay was performed on circulating cell-free DNA extracted from 120 serial plasma samples collected prospectively from 35 AGCT patients. The ddPCR assay included a preamplification step that is sensitive and specific for detecting the FOXL2-mutated ctDNA at levels as low as 0.05%. FOXL2 ctDNA mutations were detected in the plasma of 12 of 33 AGCT patients (36%), with both primary (6 of 17, 35%) and recurrent (6 of 31, 19%) tumors. The median tumor size was significantly larger in ctDNA mutation-positive compared with mutation-negative samples (13.5 cm versus 7.5 cm; P = 0.003). The ctDNA FOXL2 mutation was detected in four patients without clinical disease, of which one relapsed during follow-up. As proof of concept, we established that specific molecular diagnosis of AGCT and detection of AGCT recurrence can be achieved noninvasively using ctDNA FOXL2 mutation testing. Further studies are needed to determine the clinical value of ctDNA mutation testing.


Assuntos
Análise Mutacional de DNA , DNA de Neoplasias/sangue , Fatores de Transcrição Forkhead/genética , Tumor de Células da Granulosa/sangue , Neoplasias Ovarianas/sangue , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Proteína Forkhead Box L2 , Frequência do Gene , Tumor de Células da Granulosa/diagnóstico , Humanos , Limite de Detecção , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Neoplasias Ovarianas/diagnóstico
19.
Artigo em Inglês | MEDLINE | ID: mdl-27384573

RESUMO

Attention deficit/hyperactivity disorder (ADHD) is one of the most common childhood neurobehavioral conditions. Evidence of the negative effects of sugar-sweetened beverages (SSBs) on mental health has not been convincing, although a few studies have found an association between high SSB levels and attention problems in children. This study aimed to test the hypothesis that SSB consumption is associated with ADHD among children. Doctor-diagnosed ADHD cases (n = 173) and non-ADHD controls (n = 159) between age 4 to 15 were recruited. SSB consumption, socio-demographic and lifestyle characteristics of the children, as well as of their mothers' characteristics during pregnancy, were collected using a questionnaire. Blood lead levels and polymorphisms of two commonly verified dopaminergic-related genes (the D4 dopamine receptor gene DRD4 and the dopamine transporter gene DAT1) were also analyzed. There was a dose-response relationship between SSB consumption and ADHD. After covariates were adjusted, children who consumed SSBs at moderate levels and high levels had 1.36 and 3.69 odds, respectively, of having ADHD, compared with those who did not consume SSBs (p for trend < 0.05). Similar results were obtained when females were excluded. Our findings highlighted the adverse correlation between SSB consumption and ADHD and indicated a dose-response effect even after covariates were adjusted.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Bebidas , Edulcorantes , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Pré-Escolar , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Humanos , Chumbo/sangue , Masculino , Polimorfismo Genético , Receptores de Dopamina D4/genética , Inquéritos e Questionários
20.
Gynecol Oncol ; 143(1): 46-53, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27421752

RESUMO

OBJECTIVE: Categorization and risk stratification of endometrial carcinomas is inadequate; histomorphologic assessment shows considerable interobserver variability, and risk of metastases and recurrence can only be derived after surgical staging. We have developed a Proactive Molecular Risk classification tool for Endometrial cancers (ProMisE) that identifies four distinct prognostic subgroups. Our objective was to assess whether molecular classification could be performed on diagnostic endometrial specimens obtained prior to surgical staging and its concordance with molecular classification performed on the subsequent hysterectomy specimen. METHODS: Sequencing of tumors for exonuclease domain mutations (EDMs) in POLE and immunohistochemistry for mismatch repair (MMR) proteins and p53 were applied to both pre- and post-staging archival specimens from 60 individuals to identify four molecular subgroups: MMR-D, POLE EDM, p53 wild type, p53 abn (abnormal). Three gynecologic subspecialty pathologists assigned histotype and grade to a subset of samples. Concordance of molecular and clinicopathologic subgroup assignments were determined, comparing biopsy/curetting to hysterectomy specimens. RESULTS: Complete molecular and pathologic categorization was achieved in 57 cases. Concordance metrics for pre- vs. post-staging endometrial samples categorized by ProMisE were highly favorable; average per ProMisE class sensitivity(0.9), specificity(0.96), PPV(0.9), NPV(0.96) and kappa statistic 0.86(95%CI, 0.72-0.93), indicating excellent agreement. We observed the highest level of concordance for 'p53 abn' tumors, the group associated with the worst prognosis. In contrast, grade and histotype assignment from original pathology reports pre- vs. post-staging showed only moderate levels of agreement (kappa=0.55 and 0.44 respectively); even with subspecialty pathology review only moderate levels of agreement were observed. CONCLUSION: Molecular classification can be achieved on diagnostic endometrial samples and accurately predicts the molecular features in the final hysterectomy specimens, demonstrating concordance superior to grade and histotype. This biologically relevant information, available at initial diagnosis, has the potential to inform management (surgery, adjuvant therapy) from the earliest time point in cancer care.


Assuntos
Neoplasias do Endométrio/genética , Histerectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico
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