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1.
Mol Cell Probes ; 55: 101689, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33338586

RESUMO

A multiplex PCR (mPCR) assay was established to detect five pathogenic Vibrio species and Plesiomonas shigelloides. Twelve genes were included: ompW, ctxA, rfbN, and wbfR from V. cholerae; tl, tdh, and trh from V. parahaemolyticus; toxR and vmhA from V. mimicus; toxR from V. fluvialis; vvhA from V. vulnificus; and the 23S rRNA gene from P. shigelloides. The specificity of the mPCR assay was 100% for the detection of 136 strains and the limits of detection (LoD) were 12.5-50 pg/reaction. The assay exhibited higher sensitivity than cultivation methods in the detection of APW cultures of 113 diarrhea samples. In the analysis of 369 suspected Vibrio populations from estuarine water samples, the specificity of the mPCR for V. cholerae and V. parahaemolyticus was 100% for both, while the sensitivities were 100% and 96.1%, respectively. The assay can be applied to screen enrichment cultures and suspected colonies from environmental and clinical samples.

2.
Biochim Biophys Acta Rev Cancer ; 1875(1): 188484, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33246025

RESUMO

Pancreatic ductal adenocarcinoma is one of the most lethal malignancies and is known for its high resistance and low response to treatment. Cancer treatments can reshape the microbiota and in turn, the microbiota influences the therapeutic efficacy by regulating immune response and metabolism. This crosstalk is bidirectional, heterogeneous, and dynamic. In this review, we elaborated on the interactions between the microbiota and therapeutic resistance in pancreatic ductal adenocarcinoma. Regulating the microbiota in pancreatic tumor microenvironment may not only generate direct anti-cancer but also synergistic effects with other treatments, providing new directions in cancer therapy.

3.
Nat Genet ; 52(12): 1314-1332, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33230300

RESUMO

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

4.
Nanoscale ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206083

RESUMO

A green biomass-derived nanoporous carbon network (NCN) has been prepared and integrated with V2O5 sub-micron bricks (SMBs). The large surface area and high pore volume of the NCN can not only provide abundant sites for electrochemical reactions but also stabilize the structure of the V2O5 SMBs. The NCN@V2O5 SMB composite, acting as a novel cathode material, delivers a high areal capacitance of 786 mF cm-2 at 0.2 mA cm-2 and superior cycling stability with 89.5% capacitance retention after 5000 cycles. Besides, the electrode achieves an ultra-high rate capability (82% capacitance retention as the current density increases from 0.2 to 5 mA cm-2) since the contribution from the non-diffusion-controlled process is estimated to be as high as 95.5%-98.5% according to the kinetic analysis. Furthermore, the micropores are more favorable than the mesopores at lower current densities (0.2-2 mA cm-2), while the contribution of the external surface area becomes more significant for current densities higher than 2 mA cm-2. Moreover, an asymmetric supercapacitor assembled using this cathode and the NCN anode shows superior electrochemical properties, such as wide operating voltage, long cycle life and large energy density (72.2 µW h cm-2). Their excellent electrochemical features and good eco-friendliness confirm the potential of the NCN@V2O5 SMBs for use as supercapacitors.

5.
PLoS One ; 15(11): e0240902, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33180769

RESUMO

INTRODUCTION: Police employees undertake challenging duties which may adversely impact their health. This study explored the prevalence of and risk factors for probable mental disorders amongst a representative sample of UK police employees. The association between mental illness and alterations in blood pressure was also explored. METHODS: Data were used from the Airwave Health Monitoring Study which was established to monitor the possible physical health impacts of a new communication system on police employees. Data included sociodemographic characteristics, lifestyle habits, depression, anxiety, and post-traumatic stress disorder (PTSD) symptoms and blood pressure. Descriptive statistics were used to explore the prevalence of probable mental disorders and associated factors. Stepwise linear regression was conducted, controlling for confounding variables, to examine associations between mental disorders and blood pressure. RESULTS: The sample included 40,299 police staff, police constable/sergeants and inspectors or above. Probable depression was most frequently reported (9.8%), followed by anxiety (8.5%) and PTSD (3.9%). Groups at risk for probable mental disorders included police staff, and police employees who reported drinking heavily. Police employees exposed to traumatic incidents in the past six months had a doubling in rates of anxiety or depression and a six-fold increase in PTSD compared to those with no recent trauma exposure. Adjusted logistic regression models did not reveal any significant association between probable mental disorders and systolic blood pressure but significantly elevated diastolic blood pressure (≈1mmHg) was found across mental disorders. CONCLUSIONS: These results show lower rates of probable mental disorders, especially PTSD, than reported in other studies focusing on police employees. Although mental ill health was associated with increased diastolic blood pressure, this was unlikely to be clinically significant. These findings highlight the importance of continued health monitoring of members of the UK police forces, focusing on employees recently exposed to traumatic incidents, heavy drinkers and police staff.


Assuntos
Ansiedade/epidemiologia , Depressão/epidemiologia , Polícia/psicologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Adulto , Ansiedade/complicações , Ansiedade/fisiopatologia , Pressão Sanguínea , Estudos Transversais , Depressão/complicações , Depressão/fisiopatologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Reino Unido
6.
Int J Cancer ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33236361

RESUMO

Splenectomy is routinely performed during distal or total pancreatectomy (DP or TP) for pancreatic ductal adenocarcinoma (PDAC), but information about its oncological value is limited. TER cells, nonimmune cells discovered in the spleens of tumour-bearing mice, are elicited by tumours and promote tumour progression, while their role in the clinical outcomes of patients with PDAC remains unclear. In our study, postoperative specimens from 622 patients who underwent DP or TP with splenectomy were analysed by flow cytometry or immunofluorescence, and the relationship between splenic TER cell count and clinical parameters was calculated. We also purified human TER cells for functional experiments and mechanistic studies. We found that TER cell numbers were increased only in the spleens of patients with PDAC but not in PDAC tissue and adjacent pancreatic tissue. High splenic TER cell counts independently predicted poor prognosis (P < .001) and indicated large tumour size, lymph node metastasis, advanced 8th AJCC/mAJCC stage and high CA19-9 classification (all P < .050) in patients with PDAC. Mechanistic analysis showed that TER cells express artemin, which facilitates the proliferation and invasion of PDAC cells by activating GFRα3-ERK signalling. Our study reveals that TER cell count is an indicator of poor prognosis of PDAC, while splenectomy during pancreatic surgery might provide oncological benefits in addition to ensuring the radical resection of PDAC.

7.
Nanoscale ; 12(40): 20710-20718, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33029601

RESUMO

A transition metal phosphide is an excellent candidate for supercapacitors due to its superior electrical conductivity and high theoretical capacity. In addition, compared with traditional 3D nano-materials, 2D nanosheets possess a greater specific surface area and shorter electron transport distance. In this study, a reasonable approach is proposed for the synthesis of ZIF-67 nanosheets on nickel foam with subsequent phosphorization by chemical vapor deposition (CVD) to obtain flake-like CoP combined with Ni2P (NCP/NF), in which nickel foam serves as the current collector as well as the resource of Ni to form Ni2P. Benefiting from the nanosheet array of CoP, the NCP/NF can improve the capacity of Ni2P from 0.57 C cm-2 to 1.43 C cm-2 at 1 mA cm-2. Furthermore, the NPC/NF/reduced graphene oxide (RGO) asymmetric supercapacitor (ASC) shows an energy density of 26.9 µW h cm-2 at a power density of 0.896 mW cm-2, and excellent cycling performance with a capacity retention of 93.75% after 5000 cycles at 10 mA cm-2.

8.
J Immunother Cancer ; 8(2)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33055204

RESUMO

BACKGROUND: Tertiary lymphoid structures (TLS) are associated with favorable survival and play a critical role in most solid tumors. However, investigations of TLS are lacking in patients with grade 1 or grade 2 (G1/G2) non-functional pancreatic neuroendocrine tumors (NF-PanNETs). This study aimed to investigate the presence, cellular composition, association with tumor-infiltrating immune cells, and prognostic value of TLS in G1/G2 NF-PanNETs. METHODS: Tumor tissues from a 182-patient Fudan cohort and a 125-patient external validation set were assessed by H&E staining, immunohistochemistry, and/or multispectral fluorescent immunohistochemistry. RESULTS: TLS were identified in more than one-third of patients with G1/G2 NF-PanNETs and were located peritumorally, either just outside the tumor tissue or in the stromal area. TLS were mainly composed of B-cell follicles with germinal centers and T-cell zones with dendritic cells. Kaplan-Meier analyses showed that the presence of TLS correlated with both longer recurrence-free survival (RFS, p<0.001) and overall survival (OS, p=0.001), but the number of TLS had no prognostic significance. Multivariate Cox-regression analyses demonstrated that the presence of TLS, WHO classification, and 8th edition American Joint Committee on Cancer (AJCC8th) tumor-node-metastasis (TNM) stage were independent prognostic factors for RFS (p=0.004, p=0.001, and p<0.001, respectively) and OS (p=0.009, p=0.008, and p=0.019, respectively). These results were confirmed using an external validation set. Finally, a nomogram incorporating the presence of TLS was constructed to predict the probability of 5-year RFS of resected G1/G2 NF-PanNETs, which improved on the current WHO classification and AJCC8th TNM stage. CONCLUSIONS: The presence of TLS is an independent and favorable predictor of resected G1/G2 NF-PanNETs, which may play a role in cancer immunobiology.

9.
Oncogene ; 39(36): 5825-5838, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32753651

RESUMO

Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.


Assuntos
Carcinoma Ductal Pancreático/genética , Moléculas de Adesão Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Proteínas Hedgehog/metabolismo , Oxigenases de Função Mista/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas/genética , Biomarcadores Tumorais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Ilhas de CpG , Metilação de DNA , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Regiões Promotoras Genéticas , Transdução de Sinais
10.
Parasit Vectors ; 13(1): 421, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807211

RESUMO

BACKGROUND: Dengue virus (DENV) is a flavivirus transmitted by mosquitoes that is prevalent in tropical and subtropical countries and has four serotypes (DENV1-4). Aedes aegypti, as the main transmission vector of DENV, exhibits strong infectivity and transmission. With the aim of obtaining a better understanding of the Ae. aegypti-DENV interaction, the transcriptome changes in DENV-2-infected Aag2 cells were studied to describe the immune responses of mosquitoes using the Ae. aegypti Aag2 cell line as a model. METHODS: RNAseq technology was used to sequence the transcripts of the Ae. aegypti Aag2 cell line before and after infection with DENV-2. A bioinformatics analysis was then performed to assess the biological functions of the differentially expressed genes, and the sequencing data were verified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: The transcriptome analysis generated 8866 unigenes that were found in both groups, 225 unigenes that were only found in the infection group, and 683 unigenes that only existed in the control group. A total of 1199 differentially expressed genes, including 1014 upregulated and 185 downregulated genes, were identified. The bioinformatics analysis showed that the differentially expressed genes were mainly involved in the longevity regulating pathway, circadian rhythm, DNA replication, and peroxisome, purine, pyrimidine, and drug metabolism. The qRT-PCR verification results showed the same trend, which confirmed that the expression of the differentially expressed genes had changed, and that the transcriptome sequencing data were reliable. CONCLUSIONS: This study investigated the changes in the transcriptome levels in the DENV-2-infected Ae. aegypti Aag2 cell line, which provides a faster and effective method for discovering genes related to Ae. aegypti pathogen susceptibility. The findings provide basic data and directions for further research on the complex mechanism underlying host-pathogen interactions.

12.
Ying Yong Sheng Tai Xue Bao ; 31(4): 1267-1277, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32530202

RESUMO

Habitat quality is an important index to evaluate regional ecological security. Revealing its spatial and temporal responses to urbanization is conducive to the in-depth implementation of new urbanization. Based on land use data, we analyzed the spatio-temporal characteristics of Changchun's landscape pattern, habitat quality and its sample zone from the grid scale with comprehensive utilization of spatial analysis and ecological model analysis. We further discussed the responses of habitat quality during urbanization. The results showed that the low values of patch density (PD), edge density (ED) and Shannon diversity index (SHDI) were distributed in the western plains, while the high aggregation index (AI) showed a patchy distribution in eastern and southern of the city. During 2000-2015, the habitat quality of Changchun showed a trend of degradation and significant spatial heterogeneity, showing a distribution of "high in the east, and low in the west". The expansion of construction land and the transportation infrastructure played a leading role in the degradation of regional habitat quality. The changes of habitat quality differed significantly in different zones. The overall variation of water belt was relatively small, while the variation frequency and amplitude of mountain, urban expansion, and traffic belt were relatively high. Natural factors including slope and elevation basically shaped the overall distribution pattern of habitat quality in Changchun, while urbanization factors including population density, GDP and night light index showed significant negative correlation with habitat quality. To alleviate the ecological pressure of urbanization and promote habitat quality, we proposed differentiated development strategies, such as preventing deforestation in the Dahei Mountains, using ecological strategies to restore habitat degradation areas, improving land use efficiency in built-up urban areas, promoting "smart growth" in urban areas, setting red line of farmland in hilly areas, and strengthening ecological infrastructure construction.


Assuntos
Ecossistema , Urbanização , China , Cidades , Conservação dos Recursos Naturais
13.
J Orthop Surg Res ; 15(1): 206, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493388

RESUMO

BACKGROUND: Osteonecrosis of the femoral head (ONFH) causes severe hip dysfunction. Left untreated, 80% of patients experience femoral head collapse, and 65-70% of patients require total hip arthroplasty (THA). Therefore, effective treatment is very important for ONFH. OBJECTIVE: To examine the effectiveness of fibula allografting for the treatment of early-stage ONFH METHODS: A systematic review was conducted by searching PubMed, EMBASE, and Web of Science databases using "avascular necrosis" or "ischemic necrosis" or "osteonecrosis" and "femoral head" and "fibula*," and checking the references of primary articles and reviews. Two independent authors completed the study selection separately. We extracted the following details from each article: characteristics of the patients, clinical efficacy evaluation (Harris hip score [HSS], radiographic outcomes, the rate of conversation to total hip arthroplasty [THA], and adverse effects). RESULTS: A total of 213 articles were selected from PubMed (n = 45), EMBASE (n = 77), Web of Science (n = 203), and other sources (n = 10). After checking the articles, five articles were included in the final analysis. The average age of patients involved in this review was 34.48 years. The studies investigated fibula allografts to treat ONFH in 394 hips with a mean follow-up of 49.06 months. HHS was improved from 62.73 to 86.94. Radiographic progression was found in 33.66% of hips. The failure rate of head-saving surgery by THA was 14.5%. No patients had serious postoperative complications. LIMITATIONS: The number of articles included in the study was small, and all studies were single-center studies. Most studies were retrospective with a low level of evidence. Surgical procedures were not identical with different follow-up times. CONCLUSION: Although there are some limitations to our approach, this systematic review supports fibula allografting as a simple, effective treatment for early-stage ONFH, which presents less postoperative complications, and has a satisfactory clinical effect. We consider it to be worthy of promotion as a therapy for ONFH.

14.
Aging Cell ; 19(6): e13149, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32363781

RESUMO

Markers of biological aging have potential utility in primary care and public health. We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks.

15.
J Clin Endocrinol Metab ; 105(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32285127

RESUMO

OBJECTIVE: This study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). METHODS: Tumor tissues from the 109-patient Fudan cohort and a 73-patient external validation set were evaluated by immunohistochemistry for 9 immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ natural killer (NK) cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells. RESULTS: TINs were primarily distributed in the intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining 5 cell types were primarily present in peritumoral stroma. Total TINs (P < .001) and TAMs (P = .002) increased as NF-PanNET grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T-cell infiltration correlated with shorter recurrence-free survival (RFS, P = .010, P = .027, and P = .035, respectively) and overall survival (OS, P = .017, P = .029, and P = .045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P = .039). Multivariate Cox regression demonstrated that intratumoral TINs, World Health Organization (WHO) classification, and eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8th TNM) were independent factors for RFS (P = .043, P = .023, and P = .029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P = .010 and P = .007, respectively). Furthermore, the combination of TINs, WHO classification, and AJCC8th TNM remarkably improved prognostic accuracy for RFS. These results have been verified in the external validation set. CONCLUSION: Intratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.

16.
World J Gastroenterol ; 26(8): 828-838, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32148380

RESUMO

BACKGROUND: Systemic inflammation and nutrition status play an important role in cancer metastasis. The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP), consisting of haemoglobin, albumin, lymphocytes, and platelets, is considered as a novel marker to reflect both systemic inflammation and nutrition status. However, no studies have investigated the relationship between HALP and survival of patients with pancreatic cancer following radical resection. AIM: To evaluate the prognostic value of preoperative HALP in pancreatic cancer patients. METHODS: The preoperative serum levels of hemoglobin, albumin, lymphocyte counts, and platelet counts were routinely detected in 582 pancreatic adenocarcinoma patients who underwent radical resection. The relationship between postoperative survival and the preoperative level of HALP was investigated. RESULTS: Low levels of HALP were significantly associated with lymph node metastasis (P = 0.002), poor tumor differentiation (P = 0.032), high TNM stage (P = 0.008), female patients (P = 0.005) and tumor location in the head of the pancreas (P < 0.001). Low levels of HALP were associated with early recurrence [7.3 mo vs 16.3 mo, P < 0.001 for recurrence-free survival (RFS)] and short survival [11.5 mo vs 23.6 mo, P < 0.001 for overall survival (OS)] in patients with resected pancreatic adenocarcinoma. A low level of HALP was an independent risk factor for early recurrence and short survival irrespective of sex and tumor location. CONCLUSION: Low levels of HALP may be a significant risk factor for RFS and OS in patients with resected pancreatic cancer.


Assuntos
Adenocarcinoma/sangue , Plaquetas , Hemoglobinas/análise , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/sangue , Albumina Sérica/análise , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Contagem de Plaquetas , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento
17.
Infect Genet Evol ; 81: 104238, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32045711

RESUMO

In Vibrio cholerae, the lysogenic bacteriophage CTXΦ carries the cholera toxin genes ctxAB, which can be transferred from toxigenic strains to nontoxigenic strains through infection and lysogenic conversion of CTXΦ. This phage also has the precursor genome which does not harbor ctxAB, named pre-CTXΦ. Based on the sequences of the transcriptional regulator-encoding gene rstR alleles in CTXΦ/pre-CTXΦ, multiple types of these prophages have been classified and identified in toxigenic and nontoxigenic V. cholerae strains. In this study, by combining the short-read and long-read sequencing approaches of next generation sequencing, we obtained the complete genome sequence of the studied V. cholerae toxigenic serogroup O139 strain and identified the CTXΦ and a pre-CTXΦ genome type encoding a novel rstR allele, pre-CTXZHJΦ. This pre-CTX prophage integrates into the small chromosome of the V. cholerae host strain and coexists with a typical CTXETΦ prophage present in the large chromosome, which is commonly present in the seventh pandemic serogroup O1 and toxigenic serogroup O139 strains. RstRZHJ could bind to the ig-2 region in the RstAB promotor in the pre-CTXZHJΦ genome, and could repress the expression of its own rstAB genes but could not repress rstAB expression in CTXETΦ and CTXclassΦ, suggesting that the V. cholerae strains carrying the pre-CTXZHJΦ prophage cannot prevent the infection of these epidemic CTXΦs, hence have the potentiality to become toxigenic by acquiring and lysogenic conversion of CTXΦs. Our study identified a novel pre-CTXΦ type, and presents the new evidence for the complexity and diversity of the CTXΦ/pre-CTXΦ family in V. cholerae.

18.
Diabetes ; 69(4): 771-783, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31974142

RESUMO

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34-0.72), whereas no benefit was observed for other genotypes (P interaction = 3.7 × 10-4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11-a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.


Assuntos
Diabetes Mellitus Tipo 2/genética , Dislipidemias/tratamento farmacológico , Fenofibrato/uso terapêutico , Hipolipemiantes/uso terapêutico , PPAR alfa/genética , Polimorfismo de Nucleotídeo Único , Quimiocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/genética , Feminino , Genótipo , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Farmacogenética , Resultado do Tratamento
19.
Nat Commun ; 10(1): 4957, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673082

RESUMO

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.


Assuntos
Tamanho Corporal/genética , Cognição , Consanguinidade , Fertilidade/genética , Nível de Saúde , Depressão por Endogamia/genética , Assunção de Riscos , Alelos , Haplótipos , Homozigoto , Humanos
20.
Endocrinol Diabetes Metab ; 2(4): e00074, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31592155

RESUMO

Introduction: Type 2 diabetes (T2D) is multifactorial involving lifestyle, environmental and genetic risk factors. This study aims to investigate the impact of genetic interactions with alcohol and diet quality on glycated haemoglobin A1c (HbA1c) independent of obesity, in a British population. Methods: Cross-sectional study of 14 089 white British participants from Airwave Health Monitoring Study and a subsample of 3733 participants with dietary data. A T2D genetic risk score (GRS) was constructed, and its interactions with diet on HbA1c were assessed. Results: GRS was associated with a higher HbA1c% (ß = 0.03, P < 0.0001) and a higher risk of prediabetes (OR = 1.09, P < 0.0001) and T2D (OR = 1.14, P = 0.006). The genetic effect on HbA1c% was significantly higher in obese participants (ß = 1.88, P interaction = 0.03). A high intake of wholegrain attenuated the effect on HbA1c% in high-risk individuals P interaction = 0.04. Conclusion: The genetic effect on HbA1c was almost doubled in obese individuals, compared with those with a healthy weight, and independent of weight, there was a modest offset on HbA1c in high-genetic-risk individuals consuming a diet high in wholegrain. This supports the importance of a healthy diet high in wholegrains and along with maintaining a healthy weight in controlling HbA1c among high-genetic-risk groups.

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