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1.
Sci Rep ; 9(1): 12099, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431662

RESUMO

This retrospective cohort study aimed to investigate the effect of placental location on birthweight discordance among diamniotic-dichorionic twin pregnancies. Medical records and sonographic reports of 978 diamniotic-dichorionic twin pregnancies delivered at Foshan Maternal and Fetal Health Hospital were reviewed. Pregnancies with congenital malformation, intrauterine death or placenta previa were excluded. The placental location for each twin was determined by last sonographic examination before delivery, and the pregnancies were grouped by different versus same placental location in each pregnancy. Maternal and fetal characteristics were summarized. The primary outcome of interest was birthweight discordance (BWD) ≥20%, and secondary outcomes included small for gestational age (SGA) as a binary outcome and mean value and absolute difference in birthweight as continuous outcomes. Student's t test and the chi-square test were used for univariate analyses, while multivariate regressions were used to adjust for confounders. General estimated equation (GEE) models were used to address the correlation between fetuses when assessing SGA. A total of 866 eligible subjects were included in the analysis. In total, 460 pregnancies had placentas with different locations, and 406 had placentas with same locations. The gestational age at delivery was slightly younger in the same placental location group than in the different placental location group (35.8 ± 0.1 vs. 36.1 ± 0.1 weeks, P = 0.067). Other maternal and fetal characteristics were comparable between the two study groups. There was no significant difference in BWD ≥20% (aOR = 1.06; 95% CI: 0.71-1.59) or SGA (aOR = 1.32; 95% CI: 0.76-2.28) between the same and different placental location groups. Neither the mean value nor the absolute difference in birth weight was associated with placental location combination (P = 0.478 and P = 0.162, respectively). In conclusion, discordant birthweight is not affected by same location of diamniotic-dichorionic placentas.

2.
BMC Pregnancy Childbirth ; 19(1): 262, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340779

RESUMO

BACKGROUND: Gestational weight gain (GWG) has implications for perinatal outcomes, the guidelines for maternal weight gain, however, remain understudied among twin pregnancies. This study aimed to assess the associations between perinatal outcomes and GWG among twin pregnancies, based on the US institute of Medicine (IOM) 2009 guidelines. METHODS: A retrospective cohort study of pregnant women with viable twins ≥26 weeks of gestation, was conducted in Foshan, China, during July 2015 and June 2018. Maternal BMI was categorized based on Chinese standard and GWG was categorized as below, within and above the IOM 2009 recommendations. Underweight women were excluded for analysis. Perinatal outcomes were compared among these groups. To assess the independent impact of GWG on the perinatal outcomes, conventional multivariable regression and general estimated equation (GEE) were utilized for maternal outcomes and neonatal outcomes, respectively. RESULTS: A total of 645 mothers with twin pregnancies were included, of whom 15.0, 41.4 and 43.6% gained weight below, within and above guidelines, respectively. Compared to weight gain within guidelines, inadequate weight gain was associated with increased risks in spontaneous preterm birth < 37 weeks (aOR:3.55; 95% CI: 1.73-7.28) and < 35 weeks (aOR:2.63; 95% CI: 1.16-5.97). Women who gained weight above guidelines were more likely to have gestational hypertension disorder (aOR: 2.36; 95% CI: 1.32-4.21), pre-eclampsia (aOR: 2.59; 95% CI: 1.29-5.21) and have fetuses weighted >90th percentile and less likely to have fetuses weighted < 2500 g and < 1500 g. CONCLUSIONS: Maintenance of gestational weight gain within the normal range could decrease the risk of adverse perinatal outcomes. However, the causality between pre-eclampsia and gestational weight gain requires further investigations.

3.
Lancet Respir Med ; 7(10): 881-891, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326317

RESUMO

BACKGROUND: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. METHODS: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. FINDINGS: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10-8, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; ptrend=2·02 × 10-9). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. INTERPRETATION: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations. FUNDING: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.

4.
Hepatology ; 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31148184

RESUMO

To identify hepatocellular carcinoma (HCC)-implicated long noncoding RNAs (lncRNAs), we performed an integrative omics analysis by integrating mRNA and lncRNA expression profiles in HCC tissues. We identified a collection of candidate HCC-implicated lncRNAs. Among them, we demonstrated that an lncRNA, which is named as p53-stabilizing and activating RNA (PSTAR), inhibits HCC cell proliferation and tumorigenicity through inducing p53-mediated cell cycle arrest. We further revealed that PSTAR can bind to heterogeneous nuclear ribonucleoprotein K (hnRNP K) and enhance its SUMOylation and thereby strengthen the interaction between hnRNP K and p53, which ultimately leads to the accumulation and transactivation of p53. PSTAR is down-regulated in HCC tissues, and the low PSTAR expression predicts poor prognosis in patients with HCC, especially those with wild-type p53. Conclusion: This study sheds light on the tumor suppressor role of lncRNA PSTAR, a modulator of the p53 pathway, in HCC.

5.
Mol Cancer ; 18(1): 112, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31230592

RESUMO

BACKGROUND: Colorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism for gene expression and methyltransferase-like 3 (METTL3) participates in tumor progression in several cancer types. However, its role in CRC remains unexplored. METHODS: Western blot, quantitative real-time PCR (RT-qPCR) and immunohistochemical (IHC) were used to detect METTL3 expression in cell lines and patient tissues. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3. The biological functions of METTL3 were investigated in vitro and in vivo. RNA pull-down and RNA immunoprecipitation assays were conducted to explore the specific binding of target genes. RNA stability assay was used to detect the half-lives of the downstream genes of METTL3. RESULTS: Using TCGA database, higher METTL3 expression was found in CRC metastatic tissues and was associated with a poor prognosis. MeRIP-seq revealed that SRY (sex determining region Y)-box 2 (SOX2) was the downstream gene of METTL3. METTL3 knockdown in CRC cells drastically inhibited cell self-renewal, stem cell frequency and migration in vitro and suppressed CRC tumorigenesis and metastasis in both cell-based models and PDX models. Mechanistically, methylated SOX2 transcripts, specifically the coding sequence (CDS) regions, were subsequently recognized by the specific m6A "reader", insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), to prevent SOX2 mRNA degradation. Further, SOX2 expression positively correlated with METTL3 and IGF2BP2 in CRC tissues. The combined IHC panel, including "writer", "reader", and "target", exhibited a better prognostic value for CRC patients than any of these components individually. CONCLUSIONS: Overall, our study revealed that METTL3, acting as an oncogene, maintained SOX2 expression through an m6A-IGF2BP2-dependent mechanism in CRC cells, and indicated a potential biomarker panel for prognostic prediction in CRC.

6.
Nat Commun ; 10(1): 1858, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015415

RESUMO

N6-methyladenosine (m6A) modification is an important mechanism in miRNA processing and maturation, but the role of its aberrant regulation in human diseases remained unclear. Here, we demonstrate that oncogenic primary microRNA-25 (miR-25) in pancreatic duct epithelial cells can be excessively maturated by cigarette smoke condensate (CSC) via enhanced m6A modification that is mediated by NF-κB associated protein (NKAP). This modification is catalyzed by overexpressed methyltransferase-like 3 (METTL3) due to hypomethylation of the METTL3 promoter also caused by CSC. Mature miR-25, miR-25-3p, suppresses PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2), resulting in the activation of oncogenic AKT-p70S6K signaling, which provokes malignant phenotypes of pancreatic cancer cells. High levels of miR-25-3p are detected in smokers and in pancreatic cancers tissues that are correlated with poor prognosis of pancreatic cancer patients. These results collectively indicate that cigarette smoke-induced miR-25-3p excessive maturation via m6A modification promotes the development and progression of pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/patologia , Metiltransferases/metabolismo , MicroRNAs/metabolismo , Neoplasias Pancreáticas/patologia , Fumaça/efeitos adversos , Tabaco/toxicidade , Adenosina/análogos & derivados , Adenosina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/mortalidade , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Proteínas Correpressoras/metabolismo , Metilação de DNA , Progressão da Doença , Células Epiteliais/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Metiltransferases/genética , MicroRNAs/sangue , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Ductos Pancreáticos/citologia , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/mortalidade , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Prognóstico , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Fumar/efeitos adversos , Fumar/sangue , Regulação para Cima
7.
Mol Cancer ; 18(1): 9, 2019 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-30636640

RESUMO

BACKGROUND: Breast cancer is one of the most common malignancies and the major cause of cancer-related death in women. Although the importance of PIWI-interacting RNAs (piRNAs) in cancer has been increasingly recognized, few studies have been explored the functional mechanism of piRNAs in breast cancer development and progression. METHODS: We examined the top 20 highly expressed piRNAs based on the analysis of TCGA breast cancer data in two patient cohorts to test the roles of piRNAs in breast cancer. The effects of piRNA-36,712 on the malignant phenotypes and chemosensitivity of breast cancer cells were detected in vitro and in vivo. MS2-RIP and reporter gene assays were conducted to identify the interaction and regulation among piRNA-36,712, miRNAs and SEPW1P. Kaplan-Meier estimate with log-rank test was used to compare patient survival by different piRNA-36,712 expression levels. RESULTS: We found piRNA-36,712 level was significantly lower in breast cancer than in normal breast tissues and low level was correlated with poor clinical outcome in patients. Functional studies demonstrated that piRNA-36,712 interacts with RNAs produced by SEPW1P, a retroprocessed pseudogene of SEPW1, and subsequently inhibits SEPW1 expression through competition of SEPW1 mRNA with SEPW1P RNA for microRNA-7 and microRNA-324. We also found that higher SEPW1 expression due to downregulation of piRNA-36,712 in breast cancer may suppress P53, leading to the upregulated Slug but decreased P21 and E-cadherin levels, thus promoting cancer cell proliferation, invasion and migration. Furthermore, we found that piRNA-36,712 had synergistic anticancer effects with the paclitaxel and doxorubicin, two chemotherapeutic agents for breast cancer. CONCLUSIONS: These findings suggest that piRNA-36,712 is a novel tumor suppressor and may serve as a potential predictor for the prognosis of breast cancer patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , RNA Interferente Pequeno/genética , Selenoproteína W/genética , Animais , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , MicroRNAs/genética , Paclitaxel/farmacologia , Prognóstico , Pseudogenes , RNA Mensageiro/genética , RNA Interferente Pequeno/biossíntese , Regulação para Cima
8.
Cancer Res Treat ; 51(3): 1198-1206, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30590005

RESUMO

PURPOSE: Mismatch repair (MMR) deficiency plays a critical role in rectal cancer. This study aimed to explore the associations between genetic variations in seven MMR genes and adverse events (AEs) and survival of patients with rectal cancer treated with postoperative chemoradiotherapy (CRT). MATERIALS AND METHODS: Fifty single nucleotide polymorphisms in seven MMR (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) genes were genotyped by Sequenom MassARRAY method in 365 patients with locally advanced rectal cancer receiving postoperative CRT. The associations between genotypes and AEs were measured by odds ratios and 95% confidence intervals (CIs) by unconditional logistic regression model. The associations between genetic variations and survival were computed by the hazard ratios and 95% CIs by Cox proportional regression model. RESULTS: The most common grade ≥ 2 AEs in those 365 patients, in decreasing order, were diarrhea (44.1%), leukopenia (29.6%), and dermatitis (18.9%). Except 38 cases missing, 61 patients (18.7%) died during the follow-up period. We found MSH3 rs12513549, rs33013 and rs6151627 significantly associated with the risk of grade ≥ 2 diarrhea. PMS1 rs1233255 had an impact on the occurrence of grade ≥2 dermatitis. Meanwhile, PMS1 rs4920657, rs5743030, and rs5743100 were associated with overall survival (OS) time of rectal cancer. CONCLUSION: These results suggest that MSH3 and PMS1 polymorphisms may play important roles in AEs prediction and prognosis of rectal cancer patients receiving postoperative CRT, which can be potential genetic biomarkers for rectal cancer personalized treatment.

9.
Theranostics ; 8(19): 5213-5230, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555542

RESUMO

Although PIWI-interacting RNAs (piRNAs) have recently been linked to human diseases, their roles and functions in malignancies remain unclear. This study aimed to investigate the significance of some piRNAs in colorectal cancer (CRC). Methods: We first analyzed the expression profile of piRNAs in CRC using the TCGA and GEO databases. The top 20 highly expressed piRNAs were selected and tested in our CRC tumor and non-tumor tissue samples. We then examined the relevance of the significantly differentially expressed piRNA to the CRC outcomes in 218 patients receiving postoperative chemotherapy and 317 patients receiving neoadjuvant chemotherapy. A series of biochemical and molecular biological assays were conducted to elucidate the functional mechanism of a piRNA of interest in CRC. Furthermore, experiments with mice xenografts were performed to evaluate the therapeutic effect of an inhibitor specific to the piRNA. Results: We found that among the examined 20 piRNAs, only piRNA-54265 was overexpressed in CRC compared with non-tumor tissues and higher levels in tumor or in serum were significantly associated with poor survival in patients. Functional assays demonstrated that piRNA-54265 binds PIWIL2 protein and this is necessary for the formation of PIWIL2/STAT3/phosphorylated-SRC (p-SRC) complex, which activates STAT3 signaling and promotes proliferation, metastasis and chemoresistance of CRC cells. Treatment with a piRNA-54265 inhibitor significantly suppressed the growth and metastasis of implanted tumors in mice. Conclusion: These results indicate that piRNA-54265 is an oncogenic RNA in CRC and thus might be a therapeutic target.


Assuntos
Carcinógenos/metabolismo , Carcinoma/patologia , Neoplasias Colorretais/patologia , RNA Interferente Pequeno/metabolismo , Animais , Proteínas Argonauta/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/fisiopatologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/fisiopatologia , Biologia Computacional , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Transplante de Neoplasias , RNA Interferente Pequeno/antagonistas & inibidores , RNA Interferente Pequeno/genética , Resultado do Tratamento
10.
J Matern Fetal Neonatal Med ; : 1-261, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458694

RESUMO

BACKGROUND: Velamentous cord insertion (VCI) has been proposed to be associated with some specific complications among monochorionic (MC) twin pregnancies. This meta-analysis and systematic review aims to determine the role of VCI in MC twin pregnancies. METHODS: The PubMed, Embase and Web of Science databases and reference lists were searched for relevant studies. Outcomes of interest included twin-to-twin transfusion syndrome (TTTS), birthweight discordance (BWD) and selective intrauterine growth restriction (sIUGR). The methodological quality of the included studies was assessed by using the Newcastle-Ottawa Scale. The pooled results were calculated by means of a random or fixed effect model to obtain odds ratio with 95% confidential interval (CI). Subgroup analyses were utilized to detect the sources of heterogeneity. RESULTS: Twenty studies were eligible for inclusion. The pooled result suggested a significant association between VCI and TTTS (OR, 1.542; 95% CI, 1.116-2.129) with a moderate level of heterogeneity (Q test: p = 0.024; I2 = 50.2%). Subgroup analysis reported single-center study, methodological quality and exclusion of laser-coagulated TTTS as the sources of heterogeneity. Another analysis revealed an increased risk of BWD among twin pregnancies with VCI (OR, 2.945; 95% CI, 2.176-3.984) with a low heterogeneity (Q test: p = 0.347; I2 = 10.5%). None of study level characteristics was found to be an influencing factor. Three studies reporting on sIUGR suggested a significant association between VCI and sIUGR. CONCLUSIONS: The meta-analysis and systematic review suggests an association between VCI and BWD and sIUGR. However, the association between VCI and TTTS may be overestimated and high-quality studies with a representative sample are needed in further research.

11.
Nat Commun ; 9(1): 3688, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206226

RESUMO

Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48-2.12, P = 5.35 × 10-10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50-2.27, P = 4.34 × 10-9), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72-3.16, P = 4.21 × 10-8). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and thus enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease.

12.
Genomics Proteomics Bioinformatics ; 16(4): 262-268, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30208340

RESUMO

Esophageal squamous-cell carcinoma (ESCC) is one of the most lethal malignancies in the world and occurs at particularly higher frequency in China. While several genome-wide association studies (GWAS) of germline variants and whole-genome or whole-exome sequencing studies of somatic mutations in ESCC have been published, there is no comprehensive database publically available for this cancer. Here, we developed the Chinese Cancer Genomic Database-Esophageal Squamous Cell Carcinoma (CCGD-ESCC) database, which contains the associations of 69,593 single nucleotide polymorphisms (SNPs) with ESCC risk in 2022 cases and 2039 controls, survival time of 1006 ESCC patients (survival GWAS) and gene expression (expression quantitative trait loci, eQTL) in 94 ESCC patients. Moreover, this database also provides the associations between 8833 somatic mutations and survival time in 675 ESCC patients. Our user-friendly database is a resource useful for biologists and oncologists not only in identifying the associations of genetic variants or somatic mutations with the development and progression of ESCC but also in studying the underlying mechanisms for tumorigenesis of the cancer. CCGD-ESCC is freely accessible at http://db.cbi.pku.edu.cn/ccgd/ESCCdb.

13.
Hum Genet ; 137(6-7): 431-436, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29855708

RESUMO

Genotype imputation is now routinely performed in genomic analysis. Reference panel size, that is, the number of haplotypes in the reference panel, has been well established to be one major driving factor of imputation accuracy. For that reason, huge efforts have been made worldwide to provide large reference panels, with the Haplotype Reference Consortium (HRC) being currently the largest available in the public domain. The imputation performance of HRC, whose major samples are Europeans, has been mainly evaluated in Europeans. We conducted whole-genome genotype imputation on two independent genome-wide genotyping datasets, one with 1000 European samples and the other with 1000 Han Chinese samples. We compared the results obtained using HRC with those using Phase III of the 1000 Genomes Project (1000G) reference panel. For the European dataset, using HRC improved imputation quality, especially for rare variants with minor allele-frequency (MAF) < 0.1%. However, 1000G demonstrates better performance in the Han Chinese dataset, in both imputation quality and number of well-imputed variants. We validated the performance of 1000G reference panel in a second, independent cohort of Han Chinese (N = 2402). Our study showcases the limitations of HRC for Han Chinese populations, strongly suggesting the necessity of building population-specific reference panels.

14.
Theranostics ; 8(12): 3366-3379, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29930735

RESUMO

Genetic variation (rs372883C/T) in the 3'-untranslated region of BTB and CNC homology 1 (BACH1) has been associated with pancreatic ductal adenocarcinoma (PDAC) risk in our previous genome-wide association study; however, the action roles of this genetic variation in PDAC remains unknown. Methods:BACH1 expression was measured by quantitative real-time PCR, Western blot and immunohistochemistry. The effects of BACH1 on cell proliferation and sensitivity to gemcitabine were examined by alteration of BACH1 expression in PDAC cells. Angiogenesis was determined in vitro using a human umbilical vein endothelial cell model. Reporter gene assays were conducted to compare the effects of microRNA-1257 on rs372883 variation. The associations between rs372883 variants and survival time in patients treated with gemcitabine were estimated by logistic regression. Results: We found substantially lower BACH1 expression in PDAC compared with normal pancreatic tissues and the rs372883T allele had significantly lower BACH1 levels than the rs372883C allele in both tumor and normal tissues. Knockdown of BACH1 expression provoked proliferation of PDAC cells and angiogenesis, which might result from upregulation of hemeoxygenase-1 that evokes oncogenic AKT and ERK signaling. The rs372883T>C change inhibits interaction of BACH1 with microRNA-1257, resulting in increased BACH1 expression. PDAC patients with the rs372883T allele were more resistant to gemcitabine and had shorter survival time compared with those with the rs372883C allele. Conclusion: These results shed light on the mechanism underlying the associations of BACH1 rs372883 variation with risk of developing PDAC and differential gemcitabine sensitivity in patients.

15.
Infect Drug Resist ; 11: 555-565, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29731644

RESUMO

Background: Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), in mothers can cause serious outcomes in neonates. We aimed to elucidate the associations of S. aureus and MRSA carriage between mothers and neonates. Methods: A prospective cohort study was conducted between August and November 2015 in two hospitals in Shenzhen, China. Chinese pregnant women and their neonates who met the inclusion criteria were included in this study; samples and relevant information were collected. We assessed maternal-neonatal associations by using Poisson regression models. Results: Overall, 1834 mothers and their neonates were included in this study. The prevalence of isolate carriage among the mothers was as follows: S. aureus (nasal, 25.8%; vaginal, 7.3%; and nasal and vaginal, 3.3%) and MRSA (nasal, 5.7%; vaginal, 1.7%; and nasal and vaginal, 0.5%). The incidences of S. aureus and MRSA carriage among neonates were 3.3% and 0.8%, respectively. Of the 21 maternal-neonatal pairs with S. aureus carriage, 14 were concordant pairs with the same phenotypic and molecular characteristics. After adjustment, the relative risks and 95% confidence intervals (CIs) between the S. aureus carriage of neonates and nasal S. aureus carriage, vaginal S. aureus carriage, and both nasal and vaginal S. aureus carriage of mothers were 2.8 (95% CI, 1.6-4.8), 7.1 (95% CI, 4.1-12.4), and 9.6 (95% CI, 4.2-22.4), respectively. Conclusion: S. aureus carriage in mothers increases the risk for neonates.

16.
Cancer Commun (Lond) ; 38(1): 13, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29764514

RESUMO

BACKGROUND: Pancreatic duct adenocarcinoma (PDAC) remains a major health problem because conventional cancer treatments are relatively ineffective against it. Microarray studies have linked many genes to pancreatic cancer, but the available data have not been extensively mined for potential insights into PDAC. This study attempted to identify PDAC-associated genes and signaling pathways based on six microarray-based profiles of gene expression in pancreatic cancer deposited in the gene expression omnibus database. METHODS: Pathway network methods were used to analyze core pathways in six publicly available pancreatic cancer gene (GSE71989, GSE15471, GSE16515, GSE32676, GSE41368 and GSE28735) expression profiles. Genes potentially linked to PDAC were assessed for potential impact on survival time based on data in The Cancer Genome Atlas and International Cancer Genome Consortium databases, and the expression of one candidate gene (CKS2) and its association with survival was examined in 102 patients with PDAC from our hospital. Effects of CKS2 knockdown were explored in the PDAC cell lines BxPC-3 and CFPAC-1. RESULTS: The KEGG signaling pathway called "pathway in cancer" may play an important role in pancreatic cancer development and progression. Five genes (BIRC5, CKS2, ITGA3, ITGA6 and RALA) in this pathway were significantly associated with survival time in patients with PDAC. CKS2 was overexpressed in PDAC samples from our hospital, and higher CKS2 expression in these patients was associated with shorter survival time. CKS2 knockdown substantially inhibited PDAC cell proliferation in vitro. CONCLUSIONS: Analysis integrating existing microarray datasets allowed identification of the "pathway in cancer" as an important signaling pathway in PDAC. This integrative approach may be powerful for identifying genes and pathways involved in cancer.

17.
Oncogene ; 37(25): 3356-3368, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29559747

RESUMO

Snail is a key regulator of epithelial-mesenchymal transition (EMT) and plays an important role in tumor progression and metastasis. Snail is rapidly degraded in the cells and its protein level is critically controlled. Although several E3 ligases regulating Snail degradation have been defined, the deubiquitinases (DUBs) responsible for Snail deubiquitination are less studied. We identified ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) as a DUB that stabilizes Snail through preventing its ubiquitination and proteasomal degradation. Functionally, OTUB1 facilitates metastasis of esophageal squamous cell carcinoma (ESCC) through promoting Snail protein stability. Moreover, OTUB1 is highly expressed in ESCC and higher expression of OTUB1 predicts poor prognosis. These findings suggest that OTUB1 is an essential regulator of Snail and plays a critical role in facilitating esophageal cancer progression.

18.
Int J Radiat Oncol Biol Phys ; 100(4): 1026-1033, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29485044

RESUMO

PURPOSE: The aim of this study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the seed regions of microRNAs and acute adverse events (AEs) and survival in patients with rectal cancer receiving postoperative chemoradiation therapy. METHODS AND MATERIALS: Eighteen SNPs were genotyped in 365 patients with rectal cancer receiving postoperative chemoradiation therapy. The associations between genotypes and AEs were estimated by odds ratios and 95% confidence intervals (CIs), which were computed by using multivariate logistic regression models. The hazard ratios and 95% CIs to assess the death of patients for different genotypes were calculated by Cox proportional regression models. Overall survival and disease-free survival of patients with different genotypes were estimated by Kaplan-Meier plots, and the statistical significance was determined by using the log-rank test. RESULTS: In these patients, the most common grade ≥2 AEs were diarrhea (44.1%), leukopenia (29.6%), and dermatitis (18.9%). With false discovery rate correction, SNP rs2273626 was significantly associated with a decreased risk of grade ≥2 leukopenia (odds ratio, 0.48; 95% CI, 0.31-0.74; P = .0009). In addition, SNP rs202195689 was associated with overall survival and disease-free survival in patients receiving postoperative chemoradiation therapy, with the hazard ratios for death being 2.02 (95% CI, 1.36-3.01; P = .0006) and 1.91 (95% CI, 1.36-2.70; P = .0002), respectively. However, no significant association between these SNPs and diarrhea and dermatitis was observed. CONCLUSIONS: These results suggest that rs2273626 and rs202195689 in microRNA seed regions might serve as independent biomarkers for predicting AEs and prognosis in patients with rectal cancer receiving postoperative chemoradiation therapy. Independent replication of these findings is required to confirm these results.

19.
Sci Rep ; 8(1): 3393, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29467433

RESUMO

The percentages of low birth weight (LBW) increased from 7.7% in 2005 to 11.3% in 2011 and declined to 8.1% in 2017. For very low birth weight (VLBW) individuals, the proportion declined -1.0% annually, from 2.5% in 2005 to 1.4% in 2017. Among moderately low birth weight (MLBW) individuals, the proportion first increased 12.8% annually, from 5.0% in 2005 to 9.3% in 2011, and then declined -3.8% annually, from 9.4% in 2011 to 7.0% in 2017. The percentages of macrosomia monotone decreased from 4.0% in 2005 to 2.5% in 2017, an annual decline of -4.0%. Multiple regression analyses showed that boys, maternal age, hypertensive disorders complicating pregnancy (HDCP), and diabetes were significant risk factors for LBW. Boys, maternal age, gestational age, HDCP, diabetes, and maternal BMI were significant risk factors for macrosomia. Although the relevant figures declined slightly in our study, it is likely that LBW and macrosomia will remain a major public health issue over the next few years in China. More research aimed at control and prevention of these risk factors for LBW and macrosomia and their detrimental outcome in the mother and perinatal child should be performed in China.

20.
Res Microbiol ; 169(2): 101-107, 2018 Feb - Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29378338

RESUMO

Streptococcus agalactiae (GBS) remains a major cause of invasive infections in neonates and pregnant women. Our aim was to evaluate the phenotypic and molecular characteristics of GBS isolates in order to reveal potential relationships among molecular characteristics and differences in genotype-phenotype characteristics between ST17 and ST19. A total of 104 GBS isolates were collected from pregnant women. All isolates were tested for antibiotic susceptibility by disk diffusion method and molecular characteristics, including antibiotic-resistant genes, virulence genes, serotypes and STs. The prevalence of GBS colonization in pregnant women was 4.9%. All isolates were susceptible to penicillin, but a high prevalence of resistance was observed for tetracycline (76.9%) and erythromycin (72.1%), with the predominant resistant genes being tet(M), tet(O), erm(B) and mef (A/E). The most frequent serotypes were III, Ia and V, and the predominant STs were ST19, ST17, ST12, ST10 and ST651. A potential correlation existed between STs, serotypes and alp genes, with ST19/III/rib and ST17/III/rib as the most prevalent clones. Notably, we observed significant differences in phenotypic and genotypic characteristics between ST17 [levofloxacin-susceptible and tet(O)-positive] and ST19 [levofloxacin-resistant and tet(O)-negative]. Our findings reveal a high prevalence of ST19/III and ST17/III and significant characteristic differences between them.


Assuntos
Complicações na Gravidez/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus agalactiae/genética , Streptococcus agalactiae/isolamento & purificação , Adulto , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana , Eritromicina/farmacologia , Feminino , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Fenótipo , Gravidez , Gestantes , Streptococcus agalactiae/classificação , Streptococcus agalactiae/efeitos dos fármacos , Fatores de Virulência/genética , Fatores de Virulência/metabolismo , Adulto Jovem
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