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1.
Artigo em Inglês | MEDLINE | ID: mdl-31397051

RESUMO

PURPOSE: To explore treatment patterns among patients with prostate cancer and bone metastasis and to compare clinical outcomes following use of different hormone therapies including combined androgen blockade (CAB), nonsteroidal antiandrogen (NSAA) monotherapy, and castration monotherapy. METHODS: We conducted a population-based cohort study using data from the Urban Employee Basic Medical Insurance database (2011-2014) in Beijing. We identified 475 patients with newly diagnosed bone metastatic prostate cancer with at least one prescription for hormone therapy and described their treatment patterns over a median follow-up of 20.7 months. Cox proportional hazards model was used to compare time to chemotherapy initiation between patients starting on different hormone therapies. RESULTS: Hormone therapy and/or bisphosphonate therapy with zoledronic acid were the initial treatments in the majority of patients (87.8%); chemotherapy, radiotherapy, and surgery were usually given later in the treatment pathway. CAB was the most common hormone treatment (73.7%). For time to chemotherapy initiation, hazard ratios (95% confidence intervals) were 2.43 (1.08-5.44) for NSAA alone vs CAB and 1.29 (0.78-2.13) for castration alone vs CAB. CONCLUSIONS: Our findings show that while a wide range of therapies are used to treat patients with prostate cancer and bone metastasis in Beijing, hormone therapy and bisphosphonate therapy are the most commonly prescribed, and use of CAB was seen to be advantageous in delaying time to chemotherapy initiation over NSAA monotherapy. Future studies should explore longer-term treatment patterns, including use of newly approved treatments.

2.
Analyst ; 144(17): 5098-5107, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31373344

RESUMO

Simultaneous detection and regulation of tumor-related genes presents a promising strategy for early diagnosis and treatment of cancer, but achieving this has been a huge challenge for both chemical and biomedical communities. Towards this objective, we have devised a novel aptamer-tethered, DNAzyme-embedded molecular beacon (MB) for multiple functions in cancer cells. In this design, a tumor targeting aptamer was employed to specifically deliver the sensor into cancer cells for target gene detection, and an RNA-cleaving DNAzyme was embedded to realize gene regulation. Both aptamer-tethering and DNAzyme-embedding had little influence on the sensor performance, with a detection limit of ∼2 nM and high specificity. After delivering into tumor cells, our device could monitor the tumor-related genes by producing detectable fluorescence signals, and regulate the gene expression at both mRNA and protein levels as evidenced by the RT-PCR and western blot analyses. This study provides a simple and efficient strategy to rationally combine various functional nucleic acids for multi-functional applications in living cells, which hold great potential for cancer diagnosis and therapy.


Assuntos
Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/métodos , DNA Catalítico/química , Genes Neoplásicos , Linhagem Celular Tumoral , Humanos , Limite de Detecção
3.
BMC Complement Altern Med ; 19(1): 138, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221141

RESUMO

BACKGROUND: Oxymatrine (OM), a quinolizidine alkaloid extracted from a herb Sophorae Flavescentis Radix, has been used to treat liver fibrotic diseases. However, the mechanism of its anti-fibrosis effects is still unclear. TGF-ß/Smad signaling and miR-195 have been proved to paly an important role in hepatic stellate cells (HSCs) activation and liver fibrosis. In this study, we investigated whether OM could inhibit HSCs activation through TGF-ß1/miR-195/Smads signaling or not. METHODS: First, the effects of OM on HSC-T6 in different concentrations and time points were tested by MTT assay. We choose three appropriate concentrations of OM as treatment concentrations in following experiment. By Quantitative Real-time PCR and Western Blot, then we investigated the effect of OM on miR-195, Smad7 and α-SMA's expressions to prove the correlation between OM and the TGF-ß1/miR-195/Smads signaling. Last, miR-195 mimic and INF-γ were used to investigate the relation between miR-195 and OM in HSC activation. RESULTS: Our results showed that the proliferation of HSC was significantly inhibited when OM concentration was higher than 200 µg/mL after 24 h, 100 µg/mL after 48 h and 10 µg/mL after 72 h. The IC50 of OM after 24, 48 and 72 h were 539, 454, 387 µg/mL respectively. OM could down-regulate miR-195 and α-SMA (P < 0.01), while up-regulate Smad7 (P < 0.05). In HSC-T6 cells transfected with miR-195 mimic and pretreated with OM, miR-195 and α-SMA were up-regulated (P < 0.05), and Smad7 was down-regulated (P < 0.05) . CONCLUSIONS: Given these results, OM could inhibit TGF-ß1 induced activation of HSC-T6 proliferation in a dose-dependent and time-dependent manner to some extent. We proved that OM inhibited HSC activation through down-regulating the expression of miR-195 and up-regulating Smad7.


Assuntos
Alcaloides/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , MicroRNAs/metabolismo , Extratos Vegetais/farmacologia , Quinolizinas/farmacologia , Proteína Smad7/metabolismo , Sophora/química , Fator de Crescimento Transformador beta1/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Interferon gama/genética , Interferon gama/metabolismo , MicroRNAs/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad7/genética , Fator de Crescimento Transformador beta1/genética
4.
Int J Cancer ; 145(12): 3321-3333, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173346

RESUMO

Somatic mutation signatures may represent footprints of genetic and environmental exposures that cause different cancer. Few studies have comprehensively examined their association with germline variants, and none in an indigenous African population. SomaticSignatures was employed to extract mutation signatures based on whole-genome or whole-exome sequencing data from female patients with breast cancer (TCGA, training set, n = 1,011; Nigerian samples, validation set, n = 170), and to estimate contributions of signatures in each sample. Association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants were examined using linear regression. Nine stable signatures were inferred, and four signatures (APOBEC C>T, APOBEC C>G, aging and homologous recombination deficiency) were highly similar to known COSMIC signatures and explained the majority (60-85%) of signature contributions. There were significant heritable components associated with APOBEC C>T signature (h2 = 0.575, p = 0.010) and the combined APOBEC signatures (h2 = 0.432, p = 0.042). In TCGA dataset, seven common SNPs within or near GNB5 were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21-0.45) of APOBEC signature contribution at genome-wide significance, while rare germline mutations in MTCL1 was also significantly associated with a higher contribution of this signature (p = 6.1 × 10-6 ). This is the first study to identify associations between germline variants and mutational patterns in breast cancer across diverse populations and geography. The findings provide evidence to substantiate causal links between germline genetic risk variants and carcinogenesis.

5.
J Proteomics ; 199: 123-134, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30849524

RESUMO

Zinc (Zn) deficiency reduces chlorophyll content and damages chloroplast structure in leaves. However, little is known about the responses of chlorophyll synthesis and chloroplast structure of plants to Zn deficiency stress at the transcriptomic and proteomic level. In the present study, maize seedlings of cultivar ZD958 were grown in nutrient solution with 0 and 1.0 µmol·L-1 Zn treatments. Zn deficiency stress reduced photosynthetic rate at 10 and 15 days after treatment (DAT) and the chlorophyll content (SPAD value) at 15 DAT. Eight differentially expressed genes and 6 differential abundance proteins were involved in chlorophyll biosynthetic process in Zn deficient leaves. Genes related with the key enzymes catalyzing the chlorophyll synthesis including magnesium-chelatase subunit ChlH chloroplastic, magnesium protoporphyrin IX methyltransferase chloroplastic showed down-regulated trend by Zn deficiency at the transcriptome or proteome levels. The defective chloroplast structure of Zn-deficient leaves showed less grana granule and loose membrane. Seven changed genes in transcriptome profile were assigned to thylakoid membrane organization in Zn-deficient leaves while 8 differential abundance proteins in proteome data. The expression of the genes related with thylakoid membrane organization process such as protein PHOTOSYSTEM I ASSEMBLY 2, chloroplastic were down-regulated under limited Zn deficiency at both transcriptome and proteome levels.

6.
Int J Pharm ; 558: 101-109, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30634030

RESUMO

Isoniazid (INH) is a first-line therapy for bone tuberculosis (TB), but its clinic benefits are limited by severe side-effects after long-time administration. While nano-drug delivery systems present as promising strategies for INH delivery, the therapeutic efficacies are usually suboptimal due to ineffective drug accumulation at diseased sites. Local delivery system can achieve high drug concentration at focus sites with minimal systemic exposure, and herein we aimed to employ this strategy to develop a novel liposome-in-hydrogel system for localized treatment of bone TB. To achieve sustainable drug release, a derivative of INH called DINH was loaded because of its hydrophobicity, as well as its better activity and higher biosafety than INH. The hybrid system was demonstrated for thermo-responsive and self-healing properties via phase transition test and rheological studies, which were particularly useful for intra-articular administration. In vivo microdialysis studies revealed that the system can rapidly release drug into synovial fluid to reach effective inhibitory concentrations after localized injection, followed by a steady-state drug release. The optical image studies were performed to study its long-term behavior in vivo, which suggested a sustained drug release profile for several days. This work provides a promising drug delivery system for bone TB therapy.


Assuntos
Antituberculosos , Hidrogéis , Isoniazida/análogos & derivados , Animais , Antituberculosos/administração & dosagem , Antituberculosos/química , Antituberculosos/farmacocinética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Hidrogéis/administração & dosagem , Hidrogéis/química , Hidrogéis/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , Isoniazida/administração & dosagem , Isoniazida/química , Isoniazida/farmacocinética , Lipossomos , Masculino , Camundongos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Poliglactina 910/administração & dosagem , Poliglactina 910/química , Poliglactina 910/farmacocinética , Coelhos , Ratos Sprague-Dawley , Temperatura Ambiente , Tuberculose Osteoarticular/tratamento farmacológico
8.
Nat Commun ; 9(1): 4181, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30327465

RESUMO

Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR + /HER2 - tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mutations, and greater structural variation-indicating aggressive biology. GATA3 mutations are also more frequent in Nigerians regardless of subtype. Higher proportions of APOBEC-mediated substitutions strongly associate with PIK3CA and CDH1 mutations, which are underrepresented in Nigerians and Blacks. PLK2, KDM6A, and B2M are also identified as previously unreported significantly mutated genes in breast cancer. This dataset provides novel insights into potential molecular mechanisms underlying outcome disparities and lay a foundation for deployment of precision therapeutics in underserved populations.

9.
J Natl Cancer Inst ; 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312457

RESUMO

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

10.
Clin Respir J ; 12(11): 2573-2580, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30207643

RESUMO

INTRODUCTION: Venous thromboembolism (VTE) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is not rare, which would affect the patient's prognosis. OBJECTIVES: To examine the prevalence, risk factors and clinical characteristics of AECOPD patients with VTE. METHODS: We performed this multi-center, prospective, observational study that involved 16 hospitals in China. Patients admitted to hospital due to AECOPD were consecutively enrolled. Baseline characteristics, VTE risk factors, symptoms, signs and auxiliary examination results were collected. Lower limb venous ultrasound and computed tomography pulmonary angiography were examined. RESULTS: Between June 2009 and October 2010, a total of 1144 AECOPD patients (the average age 72.0 ± 9.1 years, 761 males) were enrolled in this study. Seventy-eight (6.8%) were diagnosed with VTE, including 24 PE, 64 DVT, 10 combined PE and DVT. VTE patients were older than non-VTE patients. History of venous thromboembolism and lower extremity varicose vein, and presence of longer immobility (≥3 days), lower limbs problems of swelling, pain and walking difficulties, diuretics use, fever, syncope, higher d-dimer and lower hemoglobin were more common in VTE patients than in non-VTE patients. After adjusting the covariates, venous thrombosis history, prolonged immobility (≥3 days), lower limb pain before hospitalization, higher d-dimer independently associated with VTE development. Regular glucocorticoid use was not associated with increased risk of VTE in this set of patients. CONCLUSION: VTE is relatively common among hospitalized AECOPD patients. Conventional prophylactic anticoagulant therapy may be considered for those hospitalized AECOPD patients with risk factors.

11.
J Clin Oncol ; 36(28): 2820-2825, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130155

RESUMO

PURPOSE: Among Nigerian women, breast cancer is diagnosed at later stages, is more frequently triple-negative disease, and is far more frequently fatal than in Europe or the United States. We evaluated the contribution of an inherited predisposition to breast cancer in this population. PATIENTS AND METHODS: Cases were 1,136 women with invasive breast cancer (mean age at diagnosis, 47.5 ± 11.5 years) ascertained in Ibadan, Nigeria. Patients were selected regardless of age at diagnosis, family history, or prior genetic testing. Controls were 997 women without cancer (mean age at interview, 47.0 ± 12.4 years) from the same communities. BROCA panel sequencing was used to identify loss-of-function mutations in known and candidate breast cancer genes. RESULTS: Of 577 patients with information on tumor stage, 86.1% (497) were diagnosed at stage III (241) or IV (256). Of 290 patients with information on tumor hormone receptor status and human epidermal growth factor receptor 2, 45.9% (133) had triple-negative breast cancer. Among all cases, 14.7% (167 of 1,136) carried a loss-of-function mutation in a breast cancer gene: 7.0% in BRCA1, 4.1% in BRCA2, 1.0% in PALB2, 0.4% in TP53, and 2.1% in any of 10 other genes. Odds ratios were 23.4 (95% CI, 7.4 to 73.9) for BRCA1 and 10.3 (95% CI, 3.7 to 28.5) for BRCA2. Risks were also significantly associated with PALB2 (11 cases, zero controls; P = .002) and TP53 (five cases, zero controls; P = .036). Compared with other patients, BRCA1 mutation carriers were younger ( P < .001) and more likely to have triple-negative breast cancer ( P = .028). CONCLUSION: Among Nigerian women, one in eight cases of invasive breast cancer is a result of inherited mutations in BRCA1, BRCA2, PALB2, or TP53, and breast cancer risks associated with these genes are extremely high. Given limited resources, prevention and early detection services should be especially focused on these highest-risk women.

12.
Eur J Pharm Sci ; 121: 319-329, 2018 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-29906508

RESUMO

Cisplatin (CisPt) is one of the most effective antitumor drugs against a wide range of solid cancers, and recent studies have indicated that combination of CisPt and RNA interference (RNAi) agents would effectively enhance therapeutic index, while the development of simple yet robust dual-delivery systems still remains a challenge. Here, we demonstrated that platinated graphene oxide is an excellent platform to achieve such goal. Nano-Graphene oxide (NGO) was easily platinated by CisPt, and the resulting CisPt/NGO was characterized by several aspects. As a proof-of-concept, an antisense microRNA-21 (Anti-miR-21) was employed as a potential RNAi agent. While most previous work functionalized NGO with cationic polymers for gene delivery, we demonstrated that platinated NGO is a potent carrier to load Anti-miR-21 with improved capacity and adsorption stability. With Anti-miR-21 loading, the system displayed significantly enhanced cytotoxicity to cancer cells, suggesting a synergistic effect. Finally, the underlying mechanism of the improved efficacy was explored, which can be ascribed to the cell apoptosis induced by Anti-miR-21 for gene silencing. This work demonstrated platinated graphene oxide as an effective nanocarrier to co-deliver CisPt and gene therapy for the treatment of cancer.

13.
Mol Carcinog ; 57(10): 1311-1318, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29873413

RESUMO

Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r2 < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (Padj = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, Padj = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.

14.
Cancer Epidemiol Biomarkers Prev ; 27(6): 636-643, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29678902

RESUMO

Background: Risk prediction models have been widely used to identify women at higher risk of breast cancer. We aimed to develop a model for absolute breast cancer risk prediction for Nigerian women.Methods: A total of 1,811 breast cancer cases and 2,225 controls from the Nigerian Breast Cancer Study (NBCS, 1998-2015) were included. Subjects were randomly divided into the training and validation sets. Incorporating local incidence rates, multivariable logistic regressions were used to develop the model.Results: The NBCS model included age, age at menarche, parity, duration of breastfeeding, family history of breast cancer, height, body mass index, benign breast diseases, and alcohol consumption. The model developed in the training set performed well in the validation set. The discriminating accuracy of the NBCS model [area under ROC curve (AUC) = 0.703, 95% confidence interval (CI), 0.687-0.719] was better than the Black Women's Health Study (BWHS) model (AUC = 0.605; 95% CI, 0.586-0.624), Gail model for white population (AUC = 0.551; 95% CI, 0.531-0.571), and Gail model for black population (AUC = 0.545; 95% CI, 0.525-0.565). Compared with the BWHS and two Gail models, the net reclassification improvement of the NBCS model were 8.26%, 13.45%, and 14.19%, respectively.Conclusions: We have developed a breast cancer risk prediction model specific to women in Nigeria, which provides a promising and indispensable tool to identify women in need of breast cancer early detection in Sub-Saharan Africa populations.Impact: Our model is the first breast cancer risk prediction model in Africa. It can be used to identify women at high risk for breast cancer screening. Cancer Epidemiol Biomarkers Prev; 27(6); 636-43. ©2018 AACR.

15.
Drug Saf Case Rep ; 5(1): 14, 2018 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-29626263

RESUMO

A 66-year-old male patient with a 10-year course of Parkinson's disease (PD) was admitted for hallucination lasting a half a month. After treatment with levodopa/carbidopa, selegiline, and piribedil, the patient's motor symptoms were improved while no significant effects were observed on psychotic symptoms. A clinical pharmacist analyzed the pharmacologic and pharmacokinetic characteristics of selegiline and piribedil, summarized the scheme of PD with psychotic symptoms in the literature, and discovered that selegiline might potentiate psychotic side effects of piribedil, while the use of levodopa/carbidopa cannot be ruled out either. Finally, the clinical pharmacist proposed to reduce the dosage of levodopa/carbidopa, increase the dosage of selegiline and quetiapine, and discontinue piribedil. The clinician accepted this suggestion. After the adjustment of medication, the patient's motor symptoms were absolutely improved and the psychotic symptoms were notably improved. This case study suggests that long-term treatment with levodopa/carbidopa and piribedil, along with the progression of the disease itself, could contribute to the emergence of psychotic symptoms in PD. Additionally, selegiline could potentiate psychotic side effects of piribedil. Neurology clinical pharmacists should work alongside neurology clinicians at the bedside to optimize pharmacotherapy, improve patient safety, and contribute to scholarly efforts.

16.
Endocrine ; 60(2): 282-291, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29492904

RESUMO

PURPOSE: Metabolic syndrome (MetS) has been extensively studied for its long-term health effects, typically through conventional Cox proportional hazards regression modeling of the overall association of MetS with a single outcome. Such an approach neglects the inherent links between MetS-related disease outcomes and fails to provide sufficient insights into the impact of each component of MetS over time. METHODS: We therefore conducted a retrospective cohort study of 63,680 individuals who received health check-ups at the MJ Health Screening Center in Taiwan from 1997-2005 to study the subsequent risks of hypertension, type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) simultaneously for MetS and its components. Multivariate-adjusted hazard ratios (HRs) were calculated using Cox models for multiple failure outcomes. RESULTS: At baseline, MetS was identified in 7835 participants. Over a median follow-up of 3 years, 8252, 1634, and 6714 participants developed hypertension, T2DM and CKD, respectively. The HR for MetS was 2.41 (95% CI 2.29-2.53) for hypertension, 5.17 (95% CI 4.68-5.71) for T2DM and 1.22 (95% CI 1.15-1.31) for CKD. Three MetS components showed the strongest association with each of the outcomes: elevated blood pressure with hypertension (HR = 3.62, 95% CI 3.46-3.79), raised fasting plasma glucose with T2DM (HR = 8.89, 95% CI 7.86-10.06) and elevated triglycerides with CKD (HR = 1.14, 95% CI 1.08-1.21). CONCLUSIONS: MetS may help identify individuals with metabolic profiles that confer incremental risks for multiple diseases. Additionally, several components of the syndrome should be considered by clinicians, as they show stronger associations with specific diseases than MetS.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Hipertensão/epidemiologia , Síndrome Metabólica/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Adulto , Idoso , Diabetes Mellitus Tipo 2/etiologia , Feminino , Humanos , Hipertensão/etiologia , Incidência , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Medição de Risco , Taiwan/epidemiologia
17.
Twin Res Hum Genet ; 21(2): 126-135, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29559026

RESUMO

The prevalence of overweight and obesity is growing rapidly in many countries. Socioeconomic inequalities might be important for this increase. The aim of this study was to determine associations of body mass index (BMI), overweight and obesity with educational level and marital status in Chinese twins. Participants were adult twins recruited through the Chinese National Twin Registry (CNTR), aged 18 to 79 years, and the sample comprised 10,448 same-sex twin pairs. Current height, weight, educational attainment, and marital status were self-reported. Regression analyses and structural equation models were conducted to evaluate BMI, overweight, and obesity associated with educational level and marital status in both sexes. At an individual level, both educational level and marital status were associated with higher BMI and higher risk of being overweight and obesity in men, while in women the effects of educational level on BMI were in the opposite direction. In within-Monozygotic (MZ) twin-pair analyses, the effects of educational level on BMI disappeared in females. Bivariate structural equation models showed that genetic factors and shared environmental confounded the relationship between education and BMI in females, whereas marital status was associated with BMI on account of significant positive unique environmental correlation apart in both sexes. The present data suggested that marital status and BMI were associated, independent of familiar factors, for both sexes of this study population, while common genetic and shared environmental factors contributed to education-associated disparities in BMI in females.

18.
Breast Cancer Res Treat ; 168(3): 703-712, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29302764

RESUMO

BACKGROUND: Few studies have evaluated the performance of existing breast cancer risk prediction models among women of African ancestry. In replication studies of genetic variants, a change in direction of the risk association is a common phenomenon. Termed flip-flop, it means that a variant is risk factor in one population but protective in another, affecting the performance of risk prediction models. METHODS: We used data from the genome-wide association study (GWAS) of breast cancer in the African diaspora (The Root consortium), which included 3686 participants of African ancestry from Nigeria, USA, and Barbados. Polygenic risk scores (PRSs) were constructed from the published odds ratios (ORs) of four sets of susceptibility loci for breast cancer. Discrimination capacity was measured using the area under the receiver operating characteristic curve (AUC). RESULTS: Flip-flop phenomenon was observed among 30~40% of variants across studies. Using the 34 variants with consistent directionality among previous studies, we constructed a PRS with AUC of 0.531 (95% confidence interval [CI]: 0.512-0.550), which is similar to the PRS using 93 variants and ORs from European ancestry populations (AUC = 0.525, 95% CI: 0.506-0.544). Additionally, we found the 34-variant PRS has good discriminative accuracy in women with family history of breast cancer (AUC = 0.586, 95% CI: 0.532-0.640). CONCLUSIONS: We found that PRS based on variants identified from prior GWASs conducted in women of European and Asian ancestries did not provide a comparable degree of risk stratification for women of African ancestry. Further large-scale fine-mapping studies in African ancestry populations are desirable to discover population-specific genetic risk variants.

19.
Cancer Epidemiol Biomarkers Prev ; 27(1): 116-118, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29254938

RESUMO

Background: Pancreatic cancer mutation signatures closely resemble breast cancer, suggesting that both cancers may have common predisposition mechanisms that may include commonly inherited SNPs.Methods: We examined 23 genetic variants known to be associated with pancreatic cancer as breast cancer risk factors in the Root genome-wide association study (GWAS; 1,657 cases and 2,029 controls of African diaspora) and GAME-ON/DRIVE GWAS (16,003 cases and 41,335 controls of European ancestry).Results: None of the pancreatic cancer susceptibility variants were individually associated with breast cancer risk after adjustment for multiple testing (at α = 0.002) in the two populations. In Root GWAS, a change by one SD in the polygenic risk score (PRS) was not significantly associated with breast cancer. In addition, we did not observe a trend in the relationship between PRS percentiles and breast cancer risk.Conclusions: The association between reported pancreatic cancer genetic susceptibility variants and breast cancer development in women of African or European ancestry is likely weak, if it does exist.Impact: Known GWAS-derived susceptibility variants of pancreatic cancer do not explain its shared genetic etiology with breast cancer. Cancer Epidemiol Biomarkers Prev; 27(1); 116-8. ©2017 AACR.

20.
Int J Cancer ; 142(1): 36-43, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28891071

RESUMO

The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP-level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level p = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24-1.91, padj = 0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non-vitamin D relevant mechanism but further studies are needed.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Vitamina D/genética , Adulto , Grupo com Ancestrais do Continente Africano , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
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