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1.
Hum Mol Genet ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527138

RESUMO

Sexual dimorphism in cancer incidence and outcome is widespread. Understanding the underlying mechanisms is fundamental to improve cancer prevention and clinical management. Sex disparities are particularly striking in kidney cancer: across diverse populations, men consistently show unexplained two-fold increased incidence and worse prognosis. We have characterized genome-wide expression and regulatory networks of 609 renal tumors and 256 non-tumor renal tissues. Normal kidney displayed sex-specific transcriptional signatures, including higher expression of X-linked tumor suppressor genes in women. Sex-dependent genotype-phenotype associations unraveled women-specific immune regulation. Sex differences were markedly expanded in tumors, with male-biased expression of key genes implicated in metabolism, non-malignant diseases with male predominance, and carcinogenesis, including markers of tumor infiltrating leukocytes. Analysis of sex-dependent RCC progression and survival uncovered prognostic markers involved in immune response and oxygen homeostasis. In summary, human kidney tissues display remarkable sexual dimorphism at the molecular level. Sex-specific transcriptional signatures further shape renal cancer, with relevance for clinical management.

2.
Virchows Arch ; 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33403511

RESUMO

There are unexplained geographical variations in the incidence of kidney cancer with the high rates reported in Baltic countries, as well as eastern and central Europe. Having access to a large and well-annotated collection of "tumor/non-tumor" pairs of kidney cancer patients from the Czech Republic, Romania, Serbia, UK, and Russia, we aimed to analyze the morphology of non-neoplastic renal tissue in nephrectomy specimens. By applying digital pathology, we performed a microscopic examination of 1012 frozen non-neoplastic kidney tissues from patients with renal cell carcinoma. Four components of renal parenchyma were evaluated and scored for the intensity of interstitial inflammation and fibrosis, tubular atrophy, glomerulosclerosis, and arterial wall thickening, globally called chronic renal parenchymal changes. Moderate or severe changes were observed in 54 (5.3%) of patients with predominance of occurrence in Romania (OR = 2.67, CI 1.07-6.67) and Serbia (OR = 4.37, CI 1.20-15.96) in reference to those from Russia. Further adjustment for comorbidities, tumor characteristics, and stage did not change risk estimates. In multinomial regression model, relative probability of non-glomerular changes was 5.22 times higher for Romania and Serbia compared to Russia. Our findings show that the frequency of chronic renal parenchymal changes, with the predominance of chronic interstitial nephritis pattern, in kidney cancer patients varies by country, significantly more frequent in countries located in central and southeastern Europe where the incidence of kidney cancer has been reported to be moderate to high. The observed association between these pathological features and living in certain geographic areas requires a larger population-based study to confirm this association on a large scale.

3.
Neurochem Res ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206315

RESUMO

Clusterin (CLU; also known as apolipoprotein J, ApoJ) is a protein of inconstant structure known to be involved in diverse processes inside and outside of brain cells. CLU can act as a protein chaperon or protein solubilizer, lipid transporter as well as redox sensor and be anti- or proapoptotic, depending on context. Primary structure of CLU is encoded by CLU gene which contains single nucleotide polymorphisms (SNP's) associated with the risk of late-onset Alzheimer's disease (LOAD). Studying a sample of Czech population and using the case-control association approach we identified C allele of the SNP rs11136000 as conferring a reduced risk of LOAD, more so in females than in males. Additionally, data from two smaller subsets of the population sample suggested a possible association of rs11136000 with diabetes mellitus. In a parallel study, we found no association between rs11136000 and mild cognitive impairment (MCI). Our findings on rs11136000 and LOAD contradict those of some previous studies done elsewhere. We discuss the multiple roles of CLU in a broad range of molecular mechanisms that may contribute to the variability of genetic studies of CLU in various ethnic groups. The above discordance notwithstanding, our conclusions support the association of rs1113600 with the risk of LOAD.

4.
Mol Neurobiol ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33070267

RESUMO

Several single-nucleotide polymorphisms (SNPs) and rare variants of non-receptor tyrosine kinase 1 gene (TNK1) have been associated with Alzheimer's disease (AD). To date, none of the associations have proven to be of practical importance in predicting the risk of AD either because the evidence is not conclusive, or the risk alleles occur at very low frequency. In the present study, we are evaluating the associations between rs11867353 polymorphism of TNK1 gene and both AD and mild cognitive impairment (MCI) in a group of 1656 persons. While the association with AD was found to be highly statistically significant (p < 0.0001 for the risk genotype CC), no statistically significant association with MCI could be established. Possible explanation of the apparent discrepancy could be rapid progression of MCI to AD in persons with the CC genotype. Additional findings of the study are statistically significant associations of rs11867353 polymorphism with body mass index, body weight, and body height. The patients with AD and CC genotype had significantly lower values of body mass index and body weight compared with patients with other genotypes. The main outcome of the study is the finding of a previously never described association between the rs11867353 polymorphism of the TNK1 gene and AD. The rs11867353 polymorphism has a potential to become a significant genetic marker when predicting the risk of AD.

5.
Endokrynol Pol ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33125689

RESUMO

INTRODUCTION: Insulin resistance (IR) is a key and early pathogenetic mechanism of cardiometabolic diseases with huge potential if being early detected and mitigated, for lowering the burden of the diseases. Available data are conflicting to what extent adult thyroid dysfunction is associated with IR. Therefore, we aimed to investigate the association and to identify which thyroid parameters are predictors of IR. MATERIAL AND METHODS: After undergoing basic anthropometric and biochemical studies including thyroid hormones, oral glucose tolerance test (OGTT) and insulin, 1425 middle-aged individuals were divided into three groups according to the thyroid parameters: overt hypothyroidism (OH), subclinical hypothyroidism (SH) and euthyroidism (EU). RESULTS: The homeostasis model assessment of IR (HOMA-IR), fasting insulin and 2-hour glucose levels of OGTT showed a steady, yet insignificant, increase from EU through SH to OH. The strongest noted correlations were those of insulin levels with free triiodothyronine/free thyroxine (FT3/FT4) ratio (r = 0.206, p < 0.001) and FT3 (r = 0.205, p < 0.001). Also in the case of HOMA-IR, the only statistically significant correlations were observed with FT3 (r = 0.181, p < 0.001) and the FT3/FT4 ratio (r = 0.165, p < 0.001). Among other thyroid hormones, linear logistic regression proved the FT3/FT4 ratio as the only significant predictor of HOMA-IR (linear coefficient = 5.26, p = 0.027) and insulin levels (linear coefficient = 18.01, p = 0.023), respectively. Thyroid-stimulating hormone was not associated with IR in either correlation or regression analysis. CONCLUSIONS: The FT3/FT4 ratio should be more emphasised in the diagnosis and treatment of thyroid disorders. Patients could benefit from a pharmacological reduction of the FT3/FT4 ratio, potentially leading to a decrease in insulin resistance, and thus a risk of the cardiometabolic diseases.

6.
Occup Environ Med ; 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33115922

RESUMO

OBJECTIVES: We evaluated the risk of lung cancer associated with ever working as a painter, duration of employment and type of painter by histological subtype as well as joint effects with smoking, within the SYNERGY project. METHODS: Data were pooled from 16 participating case-control studies conducted internationally. Detailed individual occupational and smoking histories were available for 19 369 lung cancer cases (684 ever employed as painters) and 23 674 age-matched and sex-matched controls (532 painters). Multivariable unconditional logistic regression models were adjusted for age, sex, centre, cigarette pack-years, time-since-smoking cessation and lifetime work in other jobs that entailed exposure to lung carcinogens. RESULTS: Ever having worked as a painter was associated with an increased risk of lung cancer in men (OR 1.30; 95% CI 1.13 to 1.50). The association was strongest for construction and repair painters and the risk was elevated for all histological subtypes, although more evident for small cell and squamous cell lung cancer than for adenocarcinoma and large cell carcinoma. There was evidence of interaction on the additive scale between smoking and employment as a painter (relative excess risk due to interaction >0). CONCLUSIONS: Our results by type/industry of painter may aid future identification of causative agents or exposure scenarios to develop evidence-based practices for reducing harmful exposures in painters.

7.
NAR Genom Bioinform ; 2(2): lqaa021, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32363341

RESUMO

The emergence of next-generation sequencing (NGS) has revolutionized the way of reaching a genome sequence, with the promise of potentially providing a comprehensive characterization of DNA variations. Nevertheless, detecting somatic mutations is still a difficult problem, in particular when trying to identify low abundance mutations, such as subclonal mutations, tumour-derived alterations in body fluids or somatic mutations from histological normal tissue. The main challenge is to precisely distinguish between sequencing artefacts and true mutations, particularly when the latter are so rare they reach similar abundance levels as artefacts. Here, we present needlestack, a highly sensitive variant caller, which directly learns from the data the level of systematic sequencing errors to accurately call mutations. Needlestack is based on the idea that the sequencing error rate can be dynamically estimated from analysing multiple samples together. We show that the sequencing error rate varies across alterations, illustrating the need to precisely estimate it. We evaluate the performance of needlestack for various types of variations, and we show that needlestack is robust among positions and outperforms existing state-of-the-art method for low abundance mutations. Needlestack, along with its source code is freely available on the GitHub platform: https://github.com/IARCbioinfo/needlestack.

8.
Am J Respir Crit Care Med ; 202(3): 412-421, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32330394

RESUMO

Rationale: Millions of workers around the world are exposed to respirable crystalline silica. Although silica is a confirmed human lung carcinogen, little is known regarding the cancer risks associated with low levels of exposure and risks by cancer subtype. However, little is known regarding the disease risks associated with low levels of exposure and risks by cancer subtype.Objectives: We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks.Methods: Subjects from 14 case-control studies from Europe and Canada with detailed smoking and occupational histories were pooled. A quantitative job-exposure matrix was used to estimate silica exposure by occupation, time period, and geographical region. Logistic regression models were used to estimate exposure-disease associations and the joint effects of silica exposure and smoking on risk of lung cancer. Stratified analyses by smoking history and cancer subtypes were also performed.Measurements and Main Results: Our study included 16,901 cases and 20,965 control subjects. Lung cancer odds ratios ranged from 1.15 (95% confidence interval, 1.04-1.27) to 1.45 (95% confidence interval, 1.31-1.60) for groups with the lowest and highest cumulative exposure, respectively. Increasing cumulative silica exposure was associated (P trend < 0.01) with increasing lung cancer risks in nonsilicotics and in current, former, and never-smokers. Increasing exposure was also associated (P trend ≤ 0.01) with increasing risks of lung adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Supermultiplicative interaction of silica exposure and smoking was observed on overall lung cancer risks; superadditive effects were observed in risks of lung cancer and all three included subtypes.Conclusions: Silica exposure is associated with lung cancer at low exposure levels. An exposure-response relationship was robust and present regardless of smoking, silicosis status, and cancer subtype.


Assuntos
Adenocarcinoma de Pulmão/epidemiologia , Carcinoma de Células Pequenas/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Exposição Ocupacional/estatística & dados numéricos , Dióxido de Silício , Silicose/epidemiologia , Adulto , Idoso , Canadá/epidemiologia , Fumar Cigarros , Europa (Continente)/epidemiologia , Feminino , Humanos , Exposição por Inalação , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade
9.
Am J Respir Crit Care Med ; 202(3): 402-411, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32330395

RESUMO

Rationale: Although the carcinogenicity of diesel engine exhaust has been demonstrated in multiple studies, little is known regarding exposure-response relationships associated with different exposure subgroups and different lung cancer subtypes.Objectives: We expanded on a previous pooled case-control analysis on diesel engine exhaust and lung cancer by including three additional studies and quantitative exposure assessment to evaluate lung cancer and subtype risks associated with occupational exposure to diesel exhaust characterized by elemental carbon (EC) concentrations.Methods: We used a quantitative EC job-exposure matrix for exposure assessment. Unconditional logistic regression models were used to calculate lung cancer odds ratios and 95% confidence intervals (CIs) associated with various metrics of EC exposure. Lung cancer excess lifetime risks (ELR) were calculated using life tables accounting for all-cause mortality. Additional stratified analyses by smoking history and lung cancer subtypes were performed in men.Measurements and Main Results: Our study included 16,901 lung cancer cases and 20,965 control subjects. In men, exposure response between EC and lung cancer was observed: odds ratios ranged from 1.09 (95% CI, 1.00-1.18) to 1.41 (95% CI, 1.30-1.52) for the lowest and highest cumulative exposure groups, respectively. EC-exposed men had elevated risks in all lung cancer subtypes investigated; associations were strongest for squamous and small cell carcinomas and weaker for adenocarcinoma. EC lung cancer exposure response was observed in men regardless of smoking history, including in never-smokers. ELR associated with 45 years of EC exposure at 50, 20, and 1 µg/m3 were 3.0%, 0.99%, and 0.04%, respectively, for both sexes combined.Conclusions: We observed a consistent exposure-response relationship between EC exposure and lung cancer in men. Reduction of workplace EC levels to background environmental levels will further reduce lung cancer ELR in exposed workers.


Assuntos
Adenocarcinoma de Pulmão/epidemiologia , Carcinoma de Células Grandes/epidemiologia , Carcinoma de Células Pequenas/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Fumar Cigarros/epidemiologia , Neoplasias Pulmonares/epidemiologia , Exposição Ocupacional/estatística & dados numéricos , Emissões de Veículos , Adulto , Idoso , Canadá/epidemiologia , Carbono , Europa (Continente)/epidemiologia , Feminino , Humanos , Exposição por Inalação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores Sexuais
10.
Cent Eur J Public Health ; 28(1): 65-69, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32228820

RESUMO

OBJECTIVE: The study aimed at assessing the potential benefit of prostate health index (PHI) for early detection of prostate cancer (PCa) and the use of PHI as a marker predicting the presence of PCa before performing prostate biopsy. METHODS: The study comprised 55 males who underwent prostate biopsy. Before the procedure, blood samples were collected to test prostate specific antigen (PSA) and free/total PSA ratio (%fPSA) and PHI was calculated. Receiver operating characteristic (ROC) analysis was used to assess the benefit of these values for predicting the presence of PCa. RESULTS: Based on histological examination 31 males were diagnosed with PCa, the remaining 24 were negative. Among the PCa patients, 39% had a Gleason score of 6, 26% had a score of 7 and 35% had a score of 8-10. There were statistically significant differences in PHI and PSA between males with and without PCa. The areas under the ROC curve for %fPSA, total PSA and PHI were 0.712, 0.746 and 0.789, respectively. PHI showed the best predictive ability to estimate biopsy results. If the cut-off criterion PHI > 36.4 (77.42% sensitivity, 66.67% specificity) had been used, 41.7% of males would have avoided unnecessary biopsy. CONCLUSION: The use of PHI may considerably improve the accuracy of PCa detection in patients with elevated PSA and thus reduce the number of unnecessary biopsies.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias da Próstata/diagnóstico , Biópsia , Estudos Epidemiológicos , Humanos , Masculino , Antígeno Prostático Específico/sangue , Reprodutibilidade dos Testes
11.
EBioMedicine ; 55: 102462, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32249202

RESUMO

BACKGROUND: The DNA released into the bloodstream by malignant tumours· called circulating tumour DNA (ctDNA), is often a small fraction of total cell-free DNA shed predominantly by hematopoietic cells and is therefore challenging to detect. Understanding the biological properties of ctDNA is key to the investigation of its clinical relevance as a non-invasive marker for cancer detection and monitoring. METHODS: We selected 40 plasma DNA samples of pancreatic cancer cases previously reported to carry a KRAS mutation at the 'hotspot' codon 12 and re-screened the cell-free DNA using a 4-size amplicons strategy (57 bp, 79 bp, 167 bp and 218 bp) combined with ultra-deep sequencing in order to investigate whether amplicon lengths could impact on the capacity of detection of ctDNA, which in turn could provide inference of ctDNA and non-malignant cell-free DNA size distribution. FINDINGS: Higher KRAS amplicon size (167 bp and 218 bp) was associated with lower detectable cell-free DNA mutant allelic fractions (p < 0·0001), with up to 4·6-fold (95% CI: 2·6-8·1) difference on average when comparing the 218bp- and the 57bp-amplicons. The proportion of cases with detectable KRAS mutations was also hampered with increased amplicon lengths, with only half of the cases having detectable ctDNA using the 218 bp assay relative to those detected with amplicons less than 80 bp. INTERPRETATION: Tumour-derived mutations are carried by shorter cell-free DNA fragments than fragments of wild-type allele. Targeting short amplicons increases the sensitivity of cell-free DNA assays for pancreatic cancer and should be taken into account for optimized assay design and for evaluating their clinical performance. FUNDING: IARC; MH CZ - DRO; MH SK; exchange program between IARC and Sao Paulo medical Sciences; French Cancer League.

12.
Eur J Hum Genet ; 27(10): 1589-1598, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31231134

RESUMO

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.


Assuntos
Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Renais/epidemiologia , Neoplasias Renais/genética , Biologia Computacional , Feminino , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores Sexuais
13.
Medicina (Kaunas) ; 55(5)2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108989

RESUMO

Background and Objectives: The key pathogenetic mechanism of glucose metabolism disorders, insulin resistance (IR), can be assessed using the Homeostasis Model Assessment of IR (HOMA-IR). However, its application in clinical practice is limited due to the absence of cut-offs. In this study, we aimed to define the cut-offs for the Czech population. Methods: After undergoing anthropometric and biochemical studies, the sample of 3539 individuals was divided into either nondiabetics, including both subjects with normal glucose tolerance (NGT, n = 1947) and prediabetics (n = 1459), or diabetics (n = 133). The optimal HOMA-IR cut-offs between subgroups were determined to maximize the sum of the sensitivity and specificity for diagnosing type 2 diabetes mellitus (T2DM) or prediabetes. The predictive accuracy was illustrated using receiver operating characteristic (ROC) curves. Logistic regression was performed to assess the association between a target variable (presence/absence of T2DM) depending on the HOMA-IR score as well as on the age and sex. Results: The HOMA-IR cut-off between nondiabetics and diabetics for both sexes together was 3.63, with a sensitivity of 0.56 and a specificity of 0.86. The area under the ROC curve was 0.73 for T2DM diagnosing in both sexes. The HOMA-IR cut-off between the NGT subjects and prediabetics was 1.82, with a sensitivity of 0.60 and a specificity of 0.66. Logistic regression showed that increased HOMA-IR is a risk factor for the presence of T2DM (odds ratio (OR) 1.2, 95% confidence interval (CI) 1.14-1.28, p < 0.0001). The predictive ability of HOMA-IR in diagnosing T2DM is statistically significantly lower in females (OR 0.66, 95% CI 0.44-0.98). The results are valid for middle-aged European adults. Conclusions: The results suggest the existence of HOMA-IR cut-offs signaling established IR. Introduction of the instrument into common clinical practice, together with the known cut-offs, may contribute to preventing T2DM.


Assuntos
Homeostase/fisiologia , Resistência à Insulina/fisiologia , Adulto , Idoso , Colesterol/análise , Colesterol/sangue , Estudos Transversais , República Tcheca , Feminino , Glucose/análise , Teste de Tolerância a Glucose/métodos , Homeostase/efeitos dos fármacos , Humanos , Insulina/análise , Insulina/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Determinação de Necessidades de Cuidados de Saúde , Razão de Chances
14.
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756

RESUMO

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

15.
PLoS Med ; 16(1): e1002724, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605491

RESUMO

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.


Assuntos
Carcinoma de Células Renais/etiologia , Neoplasias Renais/etiologia , Obesidade/complicações , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Carcinoma de Células Renais/genética , Diabetes Mellitus Tipo 2/complicações , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Insulina/sangue , Neoplasias Renais/genética , Lipídeos/sangue , Masculino , Análise da Randomização Mendeliana , Obesidade/genética , Fatores de Risco
16.
Klin Mikrobiol Infekc Lek ; 25(3): 84-88, 2019 Sep.
Artigo em Tcheco | MEDLINE | ID: mdl-31904102

RESUMO

OBJECTIVE: The diagnosis of Bartonella henselae by polymerase chain reaction (PCR) in lymph nodes removed in 10 patients with serologically confirmed evidence cat-scratch disease. MATERIAL AND METHODS: The 2015-2018 group consisted of 10 patients with serologically confirmed cat-scratch disease, all of them having positive IgG antibodies and 6 patients also positive IgM antibodies against B. henselae. The group included 4 men and 6 women, 7 children and 3 adults, aged 5-52 years. Eleven lymph nodes obtained from the 10 patients were formalin-fixed paraffin-embedded. Variants of granulomatous inflammation were found in 9 patients; a 13-year-old boy had Hodgkin's lymphoma. DNA isolation was performed with cobas® DNA Sample Preparation Kit (Roche). DNA of Bartonella spp. was detected by real-time PCR with BactoReal® Kit Bartonella spp. (Ingenetix) detecting the gltA gene specific for the genus Bartonella. RESULTS: Four of the 10 patients tested positive or borderline positive for Bartonella when their histological material was analyzed by PCR. One patient with 2 lymph nodes examined showed a positive result for only 1 lymph node. One adult male had a positive result; three children showed borderline positive results. Of those, two patients had suppurative granulomatous and the other 2 patients had necrotizing suppurative granulomatous inflammation as histological findings. All 4 patients had positive IgM antibodies against B. henselae. The boy with lymphoma had a negative PCR result. CONCLUSION: Serological tests combined with histological examination of lymph nodes and PCR may improve the diagnosis of cat- scratch disease.


Assuntos
Bartonella henselae , Doença da Arranhadura de Gato , Reação em Cadeia da Polimerase em Tempo Real , Adulto , Bartonella henselae/genética , Doença da Arranhadura de Gato/diagnóstico , Doença da Arranhadura de Gato/microbiologia , Criança , DNA Bacteriano/genética , Feminino , Humanos , Linfonodos/microbiologia , Masculino
17.
J Natl Cancer Inst ; 111(4): 372-379, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137376

RESUMO

BACKGROUND: We applied a training and testing approach to develop and validate a plasma metabolite panel for the detection of early-stage pancreatic ductal adenocarcinoma (PDAC) alone and in combination with a previously validated protein panel for early-stage PDAC. METHODS: A comprehensive metabolomics platform was initially applied to plasmas collected from 20 PDAC cases and 80 controls. Candidate markers were filtered based on a second independent cohort that included nine invasive intraductal papillary mucinous neoplasm cases and 51 benign pancreatic cysts. Blinded validation of the resulting metabolite panel was performed in an independent test cohort consisting of 39 resectable PDAC cases and 82 matched healthy controls. The additive value of combining the metabolite panel with a previously validated protein panel was evaluated. RESULTS: Five metabolites (acetylspermidine, diacetylspermine, an indole-derivative, and two lysophosphatidylcholines) were selected as a panel based on filtering criteria. A combination rule was developed for distinguishing between PDAC and healthy controls using the Training Set. In the blinded validation study with early-stage PDAC samples and controls, the five metabolites yielded areas under the curve (AUCs) ranging from 0.726 to 0.842, and the combined metabolite model yielded an AUC of 0.892 (95% confidence interval [CI] = 0.828 to 0.956). Performance was further statistically significantly improved by combining the metabolite panel with a previously validated protein marker panel consisting of CA 19-9, LRG1, and TIMP1 (AUC = 0.924, 95% CI = 0.864 to 0.983, comparison DeLong test one-sided P= .02). CONCLUSIONS: A metabolite panel in combination with CA19-9, TIMP1, and LRG1 exhibited substantially improved performance in the detection of early-stage PDAC compared with a protein panel alone.


Assuntos
Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/patologia , Carcinoma Papilar/patologia , Metaboloma , Neoplasias Pancreáticas/patologia , Transcriptoma , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/metabolismo , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Estudos de Casos e Controles , Seguimentos , Humanos , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo
18.
Carcinogenesis ; 40(3): 432-440, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30590402

RESUMO

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.


Assuntos
Desoxirribonuclease I/metabolismo , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
19.
Cas Lek Cesk ; 157(3): 146-151, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30441948

RESUMO

A retrospective evaluation of a group of patients with cat-scratch disease which is focused on epidemiological context, clinical picture, serological diagnosis and treatment in children and adults. Seventy-three patients with catch-scratch disease (CSD) were diagnosed at the Clinic of infectious medicine in 2008-2017, the group consisted of 37 children and 36 adults. Injury, or at least contact with cat, localization of lymph node syndrome and other clinical signs were investigated. Serological diagnosis was based on detection of IgM and IgG antibodies against Bartonella henselae. Duration of lymph node syndrome and antibodies against B. henselae were observed. Findings of granulomatous inflammation in extirpated lymph node supported suspicion of CSD. 66 of 73 patients had contact with cat, only 22 patients reported injury caused by cat. Cervical lymph nodes were affected the most often, in 32 patients. Extirpation of lymph node was performed in 19 patients. Positive IgM antibodies were detected in 47 patients. Between the group of children and adults important differences in any followed parameters were not observed. In the group of 73 patients with cat-scratch disease cervical lymph nodes were affected the most often. Positive IgM antibodies were detected in 47 patients, lymph node extirpation was performed in 19 patients. Considerable differences in course of disease in children and adults were not found out. Keywords: cat-scratch disease, lymph node syndrome, serology, extirpation.


Assuntos
Bartonella henselae , Doença da Arranhadura de Gato , Linfonodos , Adulto , Anticorpos Antibacterianos , Bartonella henselae/imunologia , Doença da Arranhadura de Gato/complicações , Criança , Humanos , Linfonodos/imunologia , Estudos Retrospectivos , Síndrome
20.
Medicine (Baltimore) ; 97(38): e12313, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30235682

RESUMO

An increased prevalence of familial neurodegenerative parkinsonism or cognitive deterioration was recently found in a small region of southeastern Moravia.The aim of the study was to assess the genetic background of this familial disease.Variants in the ADH1C, EIF4G1, FBXO7, GBA + GBAP1, GIGYF2, HTRA2, LRRK2, MAPT, PRKN, DJ-1, PINK1, PLA2G6, SNCA, UCHL1, VPS35 genes were examined in 12 clinically positive probands of the pedigree in which familial atypical neurodegenerative parkinsonism was identified in previous epidemiological studies. Libraries were sequenced by massive parallel sequencing (MPS) on the Personal Genome Machine (PGM; Ion Torrent). Data were analyzed using Torrent Suite and IonReporter software. All variants were then verified and confirmed by Sanger sequencing.We identified 31 rare heterozygous variants: 11 missense variants, 3 synonymous variants, 8 variants in the UTR region, and 9 intronic variants. Six variants (rs1801334, rs33995883, rs35507033, rs781737269, rs779760087, and rs63750072) were evaluated as pathogenic by at least one in-silico predictor.No single "founder" pathogenic variant associated with parkinsonism has been found in any of the probands from researched pedigree. It may rather be assumed that the familial occurrence of this disease is caused by the combined influence of several "small-effect" genetic variants that accumulate in the population with long-lasting inbreeding behavior.


Assuntos
Doença de Parkinson/genética , Linhagem , República Tcheca/epidemiologia , Eletroencefalografia , Eletromiografia , Potencial Evocado Motor , Predisposição Genética para Doença , Humanos , Testes Neuropsicológicos , Doença de Parkinson/etnologia
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