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1.
Sci Rep ; 11(1): 3490, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568707

RESUMO

The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

2.
BMC Public Health ; 21(1): 368, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596889

RESUMO

BACKGROUND: Corona Virus Disease 19 (COVID-19) is a new pandemic, declared a public health emergency by the World Health Organization, which could have negative consequences for pregnant and postpartum women. The scarce evidence published to date suggests that perinatal mental health has deteriorated since the COVID-19 outbreak. However, the few studies published so far have some limitations, such as a cross-sectional design and the omission of important factors for the understanding of perinatal mental health, including governmental restriction measures and healthcare practices implemented at the maternity hospitals. Within the Riseup-PPD COST Action, a study is underway to assess the impact of COVID-19 in perinatal mental health. The primary objectives are to (1) evaluate changes in perinatal mental health outcomes; and (2) determine the risk and protective factors for perinatal mental health during the COVID-19 pandemic. Additionally, we will compare the results between the countries participating in the study. METHODS: This is an international prospective cohort study, with a baseline and three follow-up assessments over a six-month period. It is being carried out in 11 European countries (Albania, Bulgaria, Cyprus, France, Greece, Israel, Malta, Portugal, Spain, Turkey, and the United Kingdom), Argentina, Brazil and Chile. The sample consists of adult pregnant and postpartum women (with infants up to 6 months of age). The assessment includes measures on COVID-19 epidemiology and public health measures (Oxford COVID-19 Government Response Tracker dataset), Coronavirus Perinatal Experiences (COPE questionnaires), psychological distress (BSI-18), depression (EPDS), anxiety (GAD-7) and post-traumatic stress symptoms (PTSD checklist for DSM-V). DISCUSSION: This study will provide important information for understanding the impact of the COVID-19 pandemic on perinatal mental health and well-being, including the identification of potential risk and protective factors by implementing predictive models using machine learning techniques. The findings will help policymakers develop suitable guidelines and prevention strategies for perinatal mental health and contribute to designing tailored mental health interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04595123 .

3.
Am J Obstet Gynecol ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33493488

RESUMO

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.

4.
N Engl J Med ; 384(5): 428-439, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471991

RESUMO

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
5.
Clin Chem ; 2020 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-33280026

RESUMO

BACKGROUND: Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene. METHODS: Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants. RESULTS: Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%. CONCLUSIONS: Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management.

6.
7.
Psicol. teor. prát ; 22(2): 15-17, May-Aug. 2020.
Artigo em Inglês | LILACS-Express | LILACS, Index Psicologia - Periódicos técnico-científicos | ID: biblio-1125445
8.
Infant Behav Dev ; 60: 101451, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32512275

RESUMO

Joint attention abilities of preterm and full-term Brazilian infants were assessed at 12- and 18-months, age corrected for prematurity. Results showed that preterm infants displayed significantly lower levels of correct responses to others' bids for joint attention at both time-points, compared to full-term infants. Both groups improved their responding to joint attention from 12 to 18 months of age. Contrastingly, prematurity did not impact infants' initiating joint attention behaviors, which remained stable over time for both groups. Findings were discussed in terms of the specific mental processes involved in distinct behavioural dimensions of joint attention.

9.
Br J Cancer ; 123(5): 793-802, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32555365

RESUMO

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

10.
Horm Behav ; 122: 104733, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32179059

RESUMO

A growing body of literature suggests that OT administration may affect not only prosocial outcomes, but also regulate adversarial responses in the context of intergroup relations. However, recent reports have challenged the view of a fixed role of OT in enhancing ingroup favoritism and outgroup derogation. Studying the potential effects of OT in modulating threat perception in a context characterized by racial miscegenation (Brazil) may thus afford additional clarification on the matter. In a double-blind, placebo-controlled study, White Brazilian participants completed a first-person shooter task to assess their responses towards potential threat from racial ingroup (White) or outgroup (Black) members. OT administration enhanced the social salience of the outgroup, by both increasing the rate at which participants refrained from shooting unarmed Black targets to levels similar to White targets, and by further increasing the rate of correct decisions to shoot armed Black targets (versus White armed targets). In summary, our results indicate that a single dose of OT may promote accurate behavioral responses to potential threat from members of a racial outgroup, thus offering support to the social salience hypothesis.

11.
J Natl Cancer Inst ; 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32107557

RESUMO

BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analysed data from 6178 families, 125 with pathogenic variants in RAD51C; and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families, while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C RR = 7.55, 95%CI:5.60-10.19, p = 5 × 10-40; RAD51D RR = 7.60, 95%CI:5.61-10.30, p = 5 × 10-39) and BC (RAD51C RR = 1.99, 95%CI:1.39-2.85, p = 1.55 × 10-4; RAD51D RR = 1.83, 95%CI:1.24-2.72, p = 0.002). For both RAD51C and RAD51D, there was a suggestion that the TOC RRs increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 were 11% (95%CI:6-21%) for RAD51C and 13% (95%CI:7-23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 were 21% (95%CI:15-29%) for RAD51C and 20% (95%CI:14-28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C/D pathogenic variant carriers varied by cancer family history, and could be as high as 32-36% for TOC, for carriers with two first degree relatives diagnosed with TOC; or 44-46% for BC, for carriers with two first degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counselling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

12.
Cancers (Basel) ; 12(2)2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991861

RESUMO

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

13.
Cancer Epidemiol Biomarkers Prev ; 29(2): 368-378, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792088

RESUMO

BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential. METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HRP) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR = 1.25; 95% CI, 1.01-1.55 and HRP = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk. CONCLUSIONS: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation. IMPACT: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

14.
Child Neuropsychol ; 26(5): 635-648, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31752569

RESUMO

There is evidence that school-aged children with cerebral palsy (CP) may present deficits in executive functions (EF) greater than would be expected considering their intellectual ability. However, no studies have focused on characterizing EF in this group at an earlier critical period - the preschool years. Furthermore, and given evidence from typically-developing (TD) children, deficits in EF are associated with potential detrimental effects on social and educational development - which can include drawing. Our aim was to compare preschool children with CP, matched in chronological age and intellectual ability with a group of TD children, regarding their executive functioning and drawing abilities. In addition, we examined the relationships between these variables in each of the groups. Twenty-eight children were evaluated in executive functions and drawing tasks. Differences were found in some aspects of cognitive flexibility and inhibitory control, but not in working memory. Additionally, the quality of the drawings was significantly poorer in the CP group. In the TD group, there was an association between greater inhibitory control (but not cognitive flexibility or working memory) and drawing quality. In the CP group, although non-significant, medium-sized correlations were observed between drawing and several aspects of executive functioning. Overall, our results suggest more similarities than differences in the executive functioning of children with CP (and preserved cognitive ability) and TD children. However, there were still important between-group differences in their drawing abilities. There was also a distinct pattern of associations between drawing and executive functions in the clinical group.

15.
Cureus ; 11(7): e5078, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31516788

RESUMO

Introduction  Breast sarcomas are tumors of a mesenchymal origin, with an incidence of less than 1% of the total breast tumors. The diagnosis of this disease is a challenge for pathologists, radiologists, and breast surgeons.  Aim To describe the diagnostic, therapeutic, and outcomes approach of patients with breast sarcoma treated at the National Cancer Institute (NCI) in Bogota, Colombia.  Materials and methods It is a descriptive and retrospective case series study of patients diagnosed with breast sarcoma treated at the NCI during the period between August 1, 2016 and March 30, 2019.  Results  We identified 14 patients diagnosed with breast sarcoma, 10 (71.4%) patients with primary breast sarcomas, and four (28.6%) with sarcomas associated with radiotherapy. The most frequent histological subtype in both, primary and secondary sarcomas, was angiosarcoma (n = 5, 35.7%). 100% (n = 14) of patients received surgical management as primary treatment. Eight (57.1%) patients presented recurrence (disease-free survival (DFS) follow-up of 5.95 months). A total of five deaths were recorded, representing 35.7% of patients (overall survival (OS) follow-up of 23.5 months). Conclusion Breast sarcomas are characterized by aggressive clinical behavior, which is why it is important to make a precise histological diagnosis and thus provide patients with radical surgical procedures that ensure local control of the disease and improve DFS.

16.
Psychiatry Res ; 279: 315-322, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31196691

RESUMO

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) has been suggested as an alternative treatment to postnatal depression (PPD). OBJECTIVES: This systematic review aims to examine and summarise evidence on rTMS efficacy in treating depression during the postnatal period. METHODS: We included randomized and non-randomized, single arm, and case report studies, with active rTMS and theta-burst stimulation, sham rTMS, pharmacotherapy or no treatment as comparators. Participants included women with PPD, who were administered rTMS after delivery and up to 12 months postpartum. The observed outcomes were response rate and acceptability. RESULTS: rTMS shows promising results, with clinically significant decreases in Edinburgh Postnatal Depression Scale (EPDS) scores at week 4 and an overall low risk of dropout. LIMITATIONS: The reduced number of reports, the lack of complete datasets and the serious/high risk of bias of the studies warrant cautious interpretations. CONCLUSIONS AND IMPLICATIONS: Despite the promising results, existing evidence on rTMS efficacy is limited, and questions remain on what the most beneficial stimulation parameters should be. Future multicentre randomized clinical trials are needed to better ascertain the clinical efficacy of rTMS in the treatment of depression in the postpartum period.


Assuntos
Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/terapia , Estimulação Magnética Transcraniana/métodos , Estimulação Magnética Transcraniana/normas , Depressão Pós-Parto/epidemiologia , Feminino , Humanos , Gravidez , Escalas de Graduação Psiquiátrica/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Resultado do Tratamento
17.
Hum Mutat ; 40(5): 566-577, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30817846

RESUMO

There is still around 50% of the familial breast cancer (BC) cases with an undefined genetic cause, here we have used next-generation sequencing (NGS) technology to identify new BC susceptibility genes. This approach has led to the identification of RECQL5, a member of RECQL-helicases family, as a new BC susceptibility candidate, which deserves further study. We have used a combination of whole exome sequencing in a family negative for mutations in BRCA1/2 throughout (BRCAX), in which we found a probably deleterious variant in RECQL5, and targeted NGS of the complete coding regions and exon-intron boundaries of the candidate gene in 699 BC Spanish BRCAX families and 665 controls. Functional characterization and in silico inference of pathogenicity were performed to evaluate the deleterious effect of detected variants. We found at least seven deleterious or likely deleterious variants among the cases and only one in controls. These results prompt us to propose RECQL5 as a gene that would be worth to analyze in larger studies to explore its possible implication in BC susceptibility.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Predisposição Genética para Doença , RecQ Helicases/genética , RecQ Helicases/metabolismo , Processamento Alternativo , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Perda de Heterozigosidade , Família Multigênica , Linhagem , Sequenciamento Completo do Exoma
18.
Mol Oncol ; 13(5): 1110-1120, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30747491

RESUMO

Single nucleotide polymorphisms (SNPs) in DNA glycosylase genes involved in the base excision repair (BER) pathway can modify breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We previously found that SNP rs34259 in the uracil-DNA glycosylase gene (UNG) might decrease ovarian cancer risk in BRCA2 mutation carriers. In the present study, we validated this finding in a larger series of familial breast and ovarian cancer patients to gain insights into how this UNG variant exerts its protective effect. We found that rs34259 is associated with significant UNG downregulation and with lower levels of DNA damage at telomeres. In addition, we found that this SNP is associated with significantly lower oxidative stress susceptibility and lower uracil accumulation at telomeres in BRCA2 mutation carriers. Our findings help to explain the association of this variant with a lower cancer risk in BRCA2 mutation carriers and highlight the importance of genetic changes in BER pathway genes as modifiers of cancer susceptibility for BRCA1 and BRCA2 mutation carriers.


Assuntos
Proteína BRCA2/genética , Predisposição Genética para Doença , Mutação , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Uracila-DNA Glicosidase/genética , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco
19.
J Autism Dev Disord ; 49(1): 216-226, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30143949

RESUMO

This study compared maternal responsiveness to children with two neurodevelopmental disorders sharing different but, in some cases, overlapping social phenotypes-Williams syndrome (WS) and autism spectrum disorder (ASD)-and explored the relations between maternal responsiveness and child emotional/behavioural problems (EBP). The sample included 16 pre-schoolers with WS and 43 with ASD, and their mothers. Responsiveness was assessed during a mother-child interaction task. Mothers completed the CBCL 1½-5, providing a measure of EBP. No significant differences emerged between groups, and most dyads were characterized by less responsive behaviours. Maternal responsiveness proved related to child developmental age, but not with EBP. These results provide further insight into the rearing environment of children with neurodevelopmental disorders, highlighting the need for early relationship-based interventions.


Assuntos
Sintomas Afetivos/psicologia , Transtorno do Espectro Autista/psicologia , Relações Mãe-Filho/psicologia , Comportamento Problema/psicologia , Síndrome de Williams/psicologia , Adulto , Sintomas Afetivos/diagnóstico , Sintomas Afetivos/epidemiologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Mães/psicologia , Poder Familiar/psicologia , Síndrome de Williams/diagnóstico , Síndrome de Williams/epidemiologia
20.
J Electrocardiol ; 52: 11-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30476632

RESUMO

BACKGROUND: The potential for thromboembolism in atrial flutter (AFL) is different from atrial fibrillation. AFL cycle length (AFL-CL) may be related to reduced left atrial appendage (LAA) function. Very rapid AFL-CL can lead to mechanical and electrophysiological disorders that contribute to lower LAA emptying velocity (LAEV). The aim of this study is to relate atrial flutter cycle length with LAEV and its role in thrombogenesis. METHODS: Cross-sectional study of patients with atrial flutter AFL who underwent transoesophageal echocardiography (TEE) before catheter ablation or electric cardioversion. AFL-CL in milliseconds was measured with a 12-lead EKG or in intracardiac records. RESULTS: We included 123 patients. There was correlation between AFL-CL and LAEV (r = 0.34; p = 0.003) in typical AFL. Cycle length, LA size and atypical flutter were predictors of low LAEV on multivariate analysis. An index multiplying atrial rate (bpm) during the arrhythmia versus left atrial size(mm) >11,728 was associated with spontaneous echogenic contrast and/or left atrial thrombus on TEE (C-statistic = 0.71; CI95%0.60-0.81). CONCLUSIONS: There was a significant relationship between the AFL-CL and LAEV. The LAEV was affected by the LA size, the type of atrial flutter and the AFL-CL. A new index, relating the atrial rate with the left atrial size, was able to identify a higher occurrence of spontaneous echogenic contrast and/or left atrial thrombus.


Assuntos
Apêndice Atrial/fisiopatologia , Flutter Atrial/complicações , Flutter Atrial/fisiopatologia , Trombose Coronária/etiologia , Trombose Coronária/fisiopatologia , Idoso , Apêndice Atrial/diagnóstico por imagem , Flutter Atrial/diagnóstico por imagem , Trombose Coronária/diagnóstico por imagem , Estudos Transversais , Ecocardiografia Transesofagiana , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Risco
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