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1.
N Engl J Med ; 384(5): 440-451, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471974

RESUMO

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
2.
Artigo em Inglês | MEDLINE | ID: mdl-33277321

RESUMO

BACKGROUND: Clinical use of breast cancer risk prediction requires simplified models. We evaluate a simplified version of the validated Rosner-Colditz model and add percent mammographic density (MD) and polygenic risk score (PRS), to assess performance from ages 45-74. We validate using prospective data from the Mayo Mammography Health Study (MMHS). METHODS: We derived the model in the Nurses' Health Study (NHS) based on: MD, 77SNP PRS and a questionnaire score (QS) (lifestyle and reproductive factors). 2799 invasive breast cancer cases were diagnosed from 1990-2000. MD (using Cumulus software) and PRS were assessed in a nested case-control study. We assess model performance using this case-control data set and evaluate 10-year absolute breast cancer risk. The prospective MMHS validation dataset includes 21.8% of women age <50, and 434 incident cases identified over 10 years of follow-up. RESULTS: In the NHS, MD has the highest odds ratio (OR) for 10-year risk prediction: OR per SD =1.48 (95% CI 1.31 - 1.68), followed by PRS, OR per SD = 1.37 (95% CI 1.21 - 1.55) and QS, OR per SD = 1.25 (95% CI 1.11 - 1.41). In MMHS, the AUC adjusted for age was 0.595; for age+MD 0.636; for age+MD+QS 0.650; for age+MD+QS+PRS 0.687. CONCLUSIONS: A simplified assessment of QS, MD and PRS performs consistently to discriminate those at high 10-year breast cancer risk. IMPACT: This simplified model provides accurate estimation of 10-year risk of invasive breast cancer that can be used in a clinic setting to identify women who may benefit from chemopreventive intervention.

3.
Am J Clin Nutr ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33236056

RESUMO

BACKGROUND: Carotenoids represent 1 of few modifiable factors to reduce breast cancer risk. Elucidation of interactions between circulating carotenoids and genetic predispositions or mammographic density (MD) may help inform more effective primary preventive strategies in high-risk populations. OBJECTIVES: We tested whether women at high risk for breast cancer due to genetic predispositions or high MD would experience meaningful and greater risk reduction from higher circulating levels of carotenoids in a nested case-control study in the Nurses' Health Studies (NHS and NHSII). METHODS: This study included 1919 cases and 1695 controls in a nested case-control study in the NHS and NHSII. We assessed both multiplicative and additive interactions. RR reductions and 95% CIs were calculated using unconditional logistic regressions, adjusting for matching factors and breast cancer risk factors. Absolute risk reductions (ARR) were calculated based on Surveillance, Epidemiology, and End Results incidence rates. RESULTS: We showed that compared with women at low genetic risk or low MD, those with higher genetic risk scores or high MD had greater ARRs for breast cancer as circulating carotenoid levels increase (additive P-interaction = 0.05). Among women with a high polygenic risk score, those in the highest quartile of circulating carotenoids had a significant ARR (28.6%; 95% CI, 14.8-42.1%) compared to those in the lowest quartile of carotenoids. For women with a high percentage MD (≥50%), circulating carotenoids were associated with a 37.1% ARR (95% CI, 21.7-52.1%) when comparing the highest to the lowest quartiles of circulating carotenoids. CONCLUSIONS: The inverse associations between circulating carotenoids and breast cancer risk appeared to be more pronounced in high-risk women, as defined by germline genetic makeup or MD.

4.
J Natl Cancer Inst ; 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427313

RESUMO

BACKGROUND: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. METHODS: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. RESULTS: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. CONCLUSIONS: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.

5.
Cancer Epidemiol Biomarkers Prev ; 29(6): 1271-1277, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32245787

RESUMO

BACKGROUND: Risk prediction models may be useful for precision breast cancer screening. We aimed to evaluate the performance of breast cancer risk models developed in European-ancestry studies in a Korean population. METHODS: We compared discrimination and calibration of three multivariable risk models in a cohort of 77,457 women from the Korean Cancer Prevention Study (KCPS)-II. The first incorporated U.S. breast cancer incidence and mortality rates, U.S. risk factor distributions, and RR estimates from European-ancestry studies. The second recalibrated the first by using Korean incidence and mortality rates and Korean risk factor distributions, while retaining the European-ancestry RR estimates. Finally, we derived a Korea-specific model incorporating the RR estimates from KCPS. RESULTS: The U.S. European-ancestry breast cancer risk model was well calibrated among Korean women <50 years [expected/observed = 1.124 (0.989, 1.278)] but markedly overestimated the risk for those ≥50 years [E/O = 2.472 (2.005, 3.049)]. Recalibrating absolute risk estimates using Korean breast cancer rates and risk distributions markedly improved the calibration in women ≥50 [E/O = 1.018 (0.825, 1.255)]. The model incorporating Korean-based RRs had similar but not clearly improved performance relative to the recalibrated model. CONCLUSIONS: The poor performance of the U.S. European-ancestry breast cancer risk model among older Korean women highlights the importance of tailoring absolute risk models to specific populations. Recalibrating the model using Korean incidence and mortality rates and risk factor distributions greatly improved performance. IMPACT: The data will provide valuable information to plan and evaluate actions against breast cancer focused on primary prevention and early detection in Korean women.

6.
J Org Chem ; 84(21): 14209-14216, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584815

RESUMO

We described a trifluoromethylation of alkenes using PhICF3Cl as bifunctional reagent. Chlorotrifluoromethylated products were obtained when nonconjugated alkenes were treated with PhICF3Cl in 1,4-dioxane at 60 °C, while vinyl C-H trifluoromethylated products were obtained by further elimination of hydrochloride in the case of those conjugated alkene substrates in DMF. Broad substrate scope, especially including complex alkenes bearing biological active motifs, suggests that this mild reaction is feasible for late-stage modification in drug discovery.

7.
Sci Rep ; 9(1): 12524, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467304

RESUMO

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.


Assuntos
Neoplasias da Mama/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Deleção de Sequência , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Anemia de Fanconi/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/metabolismo , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos
8.
Int J Epidemiol ; 48(3): 781-794, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243447

RESUMO

BACKGROUND: Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk. METHODS: Summary-level genotype data from 23andMe, Inc (breast size, n = 33 790), the Breast Cancer Association Consortium (breast cancer risk, n = 228 951) and the Genetic Investigation of ANthropometric Traits (BMI, n = 183 507) were used for our analyses. In assessing causal relationships, four complementary MR techniques [inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression] were used to test the robustness of the results. RESULTS: The genetic correlation (rg) estimated between BMI and breast size was high (rg = 0.50, P = 3.89x10-43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size [odds ratio (ORIVW): 2.06 (1.80-2.35), P = 1.38x10-26] and lower overall breast cancer risk [ORIVW: 0.81 (0.74-0.89), P = 9.44x10-6]. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P > 0.050). CONCLUSION: Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/epidemiologia , Mama/anatomia & histologia , Tamanho do Órgão/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , Desequilíbrio de Ligação , Análise da Randomização Mendeliana , Receptores Estrogênicos/metabolismo
9.
J Breast Cancer ; 22(4): 522-532, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31897327

RESUMO

Purpose: Our previous studies have shown that kinesin family member 11 (KIF11) is markedly overexpressed in human breast cancer cells or tissues and positively correlated with distant metastasis and prognosis in patients with breast cancer, suggesting an important role in the regulation of cancer stem cells. Herein, we examined the role of KIF11 in breast cancer stem cells. Methods: In the current study, we validated our previous findings through analysis of data collected in The Cancer Genome Atlas. Endogenous KIF11 was stably silenced in MCF-7 and SKBR-3 cells. Flow cytometry was used to measure the proportion of side-population (SP) cells. Mammosphere culture and tumor implantation experiments in immunodeficient mice were used to assess the self-renewal ability of breast cancer cells. Real-time polymerase chain reaction, western blot, immunofluorescence staining, luciferase reporter assays and Wnt agonist treatment were conducted to investigate the signaling pathways regulated by KIF11. Results: We found that the expression level of KIF11 was positively correlated with stem cell-enrichment genes. The proportion of SP cells was significantly reduced in KIF11-silenced cells. Silencing endogenous KIF11 not only reduced the size and number of mammospheres in vitro, but also reduced the ability of breast cancer cells to form tumors in mice. Simultaneously, we found that KIF11 was involved in regulating the activation of the Wnt/ß-catenin signaling pathway. Conclusion: Endogenous KIF11 enhances the self-renewal of breast cancer cells by activating the Wnt/ß-catenin signaling pathway, thereby enhancing the characteristics of breast cancer stem cells.

10.
J Food Sci ; 83(5): 1249-1257, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29663390

RESUMO

This study examined the ability of five Amberlite resins coupled with ultrasound-assisted water extraction for the recovery and enrichment of bioactive procyanidins and total phenolics from cranberry pomace. Static adsorption showed that XAD-7HP had the highest adsorption capacity for procyanidins (52.2 mg/g resin) and total phenolics (99.1 mg/g resin) whereas XAD-761 had the lowest. Adsorption of procyanidins fitted better to pseudo-second-order kinetics than pseudo-first-order kinetics. Isotherm adsorption on XAD-7HP suggested that Langmuir isotherm was a better model to describe the adsorption of procyanidins while Kemkin-Pyzhev equation was better for total phenolics based on higher coefficient of determinations (R2 ). Dynamic tests on XAD-7HP suggested that the flow rate of 7 and 8 mL/min were the optimum conditions for adsorption and desorption of procyanidins, respectively. Measurements using HPLC revealed that adsorption increased the contents of procyanidins and total phenolics by 4.57- and 4.73-folds, respectively, compared to the initial extracts. This research showed that Amberlite XAD-7HP resin adsorption coupled with ultrasound-assisted water extraction is an efficient method to separate and concentrate procyanidins from cranberry pomace.


Assuntos
Biflavonoides/análise , Catequina/análise , Proantocianidinas/análise , Resinas Sintéticas/química , Vaccinium macrocarpon/química , Adsorção , Cromatografia Líquida de Alta Pressão , Frutas/química , Compostos Fitoquímicos/análise , Extratos Vegetais/análise , Açúcares/análise
11.
Front Plant Sci ; 9: 101, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29487604

RESUMO

Leaf width (LW) influences canopy architecture of population-cultured maize and can thus contribute to density breeding. In previous studies, almost all maize LW-related mutants have extreme effect on leaf development or accompanied unfavorable phenotypes. In addition, the identification of quantitative trait loci (QTLs) has been resolution-limited, with cloning and fine-mapping rarely performed. Here, we constructed a bin map for 670 recombinant inbred lines (RILs) using ∼1.2 billion 100-bp re-sequencing reads. QTL analysis of the LW trait directly narrowed the major effect QTL, qLW4, to a ∼270-kb interval. A fine-mapping population and near-isogenic lines (NILs) were quickly constructed using a key RIL harboring heterozygous genotypes across the qLW4 region. A recombinant-derived progeny testing strategy was subsequently used to further fine-map qLW4 to a 55-kb interval. Examination of NILs revealed that qLW4 has a completely dominant effect on LW, with no additional effect on leaf length. Candidate gene analysis suggested that this locus may be a novel LW controlling allele in maize. Our findings demonstrate the advantage of large-population high-density bin mapping, and suggest a strategy for efficiently fine-mapping or even cloning of QTLs. These results should also be helpful for further dissection of the genetic mechanism of LW variation, and benefit maize density breeding.

12.
J Sci Food Agric ; 98(13): 4876-4884, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29572909

RESUMO

BACKGROUND: Muscadine grape pomace, a by-product of juicing and wine-making, contains significant amounts of anthocyanin 3,5-diglucosides, known to be beneficial to human health. RESULTS: The objective of this research was to use mathematical modeling to investigate the adsorption/desorption characteristics of these anthocyanins from muscadine grape pomace on Amberlite FPX66 resin in a fixed bed column. Anthocyanins were extracted using hot water and ultrasound, and the extracts were loaded onto a resin column at five bed depths (5, 6, 8, 10 and 12 cm) using three flow rates (4, 6 and 8 mL min-1 ). It was found that adsorption on the column fitted the bed depth service time (BDST) model and the empty bed residence time (EBRT) model. Desorption was achieved by eluting the column using ethanol at four concentrations (25, 40, 55 and 70% v/v) and could be described with an empirical sigmoid model. The breakthrough curves of anthocyanins fitted the BDST model for all three flow rates with R2 values of 0.983, 0.992 and 0.984 respectively. The EBRT model was successfully employed to find the operating lines, which allow for column scale-up while still achieving similar results to those found in a laboratory operation. Desorption with 40% (v/v) ethanol achieved the highest recovery rate of anthocyanins at 79.6%. CONCLUSION: The mathematical models established in this study can be used in designing a pilot/industrial- scale column for the separation and concentration of anthocyanins from muscadine juice pomace. © 2018 Society of Chemical Industry.


Assuntos
Antocianinas/química , Sucos de Frutas e Vegetais/análise , Extratos Vegetais/química , Resinas Sintéticas/química , Vitis/química , Adsorção , Antocianinas/isolamento & purificação , Cromatografia/instrumentação , Cromatografia/métodos , Modelos Teóricos , Extratos Vegetais/isolamento & purificação , Resinas Sintéticas/isolamento & purificação
13.
J Agric Food Chem ; 66(9): 2159-2167, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29430926

RESUMO

The objective of this study was to develop a thiolysis HPLC method to quantify total procyanidins, the ratio of A-type linkages, and A-type procyanidin equivalents in cranberry products. Cysteamine was utilized as a low-odor substitute of toluene-α-thiol for thiolysis depolymerization. A reaction temperature of 70 °C and reaction time of 20 min, in 0.3 M of HCl, were determined to be optimum depolymerization conditions. Thiolytic products of cranberry procyanidins were separated by RP-HPLC and identified using high-resolution mass spectrometry. Standards curves of good linearity were obtained on thiolyzed procyanidin dimer A2 and B2 external standards. The detection and quantification limits, recovery, and precision of this method were validated. The new method was applied to quantitate total procyanidins, average degree of polymerization, ratio of A-type linkages, and A-type procyanidin equivalents in cranberry products. Results showed that the method was suitable for quantitative and qualitative analysis of procyanidins in cranberry products.


Assuntos
Biflavonoides/análise , Catequina/análise , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/análise , Proantocianidinas/análise , Vaccinium macrocarpon/química , Frutas/química , Estrutura Molecular
14.
BMC Plant Biol ; 18(1): 17, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29347909

RESUMO

BACKGROUND: Plant Architecture Related Traits (PATs) are of great importance for maize breeding, and mainly controlled by minor effect quantitative trait loci (QTLs). However, cloning or even fine-mapping of minor effect QTLs is very difficult in maize. Theoretically, large population and high density genetic map can be helpful for increasing QTL mapping resolution and accuracy, but such a possibility have not been actually tested. RESULTS: Here, we employed a genotyping-by-sequencing (GBS) strategy to construct a linkage map with 16,769 marker bins for 1021 recombinant inbred lines (RILs). Accurately mapping of well studied genes P1, pl1 and r1 underlying silk color demonstrated the map quality. After QTL analysis, a total of 51 loci were mapped for six PATs. Although all of them belong to minor effect alleles, the lengths of the QTL intervals, with a minimum and median of 1.03 and 3.40 Mb respectively, were remarkably reduced as compared with previous reports using smaller size of population or small number of markers. Several genes with known function in maize were shown to be overlapping with or close neighboring to these QTL peaks, including na1, td1, d3 for plant height, ra1 for tassel branch number, and zfl2 for tassel length. To further confirm our mapping results, a plant height QTL, qPH1a, was verified by an introgression lines (ILs). CONCLUSIONS: We demonstrated a method for high resolution mapping of minor effect QTLs in maize, and the resulted comprehensive QTLs for PATs are valuable for maize molecular breeding in the future.


Assuntos
Técnicas de Genotipagem/métodos , Locos de Características Quantitativas , Zea mays/genética , Melhoramento Vegetal , Zea mays/anatomia & histologia
15.
Oncol Lett ; 14(6): 6618-6626, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29181100

RESUMO

The present study aimed to clarify the association between kinesin family member 11 (KIF11) and human breast cancer, and the effect of KIF11 on breast cancer cell progression. Western blot analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, retroviral infection, immunohistochemistry staining, MTT assay, anchorage-independent growth ability assay and tumorigenicity assay were all used in the present study. Western blot and RT-qPCR analysis revealed that the expression of KIF11 was markedly increased in malignant cells compared with that in non-tumorous cells at the mRNA and protein level. Immunohistochemical analysis revealed that KIF11 expression was upregulated in 256/268 (95.8%) paraffin-embedded archival breast cancer biopsies. Statistical analysis demonstrated a significant association between the upregulation of KIF11 expression and the progression of breast cancer. Multivariate analysis revealed that KIF11 upregulation represents an independent prognostic indicator for the survival of patients with breast cancer. Tumorigenicity experiments were further used to evaluate the effect of KIF11 in non-obese diabetic/severe combined immunodeficient mice. Silencing endogenous KIF11 by short hairpin RNAs inhibited the proliferation of breast cancer cells in vitro and in vivo. The present results suggest that KIF11 may serve an important function in the proliferation of breast cancer and may represent a novel and useful prognostic marker for breast cancer.

16.
J Agric Food Chem ; 65(4): 769-776, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28112913

RESUMO

The objective of this study was to determine the anti-inflammatory effects of phytochemical extracts from muscadine grapes or wine on dextran sulfate sodium (DSS)-induced colitis in mice and to investigate cellular mechanisms. Two groups of C57BL/6J mice were gavaged with muscadine grape phytochemicals (MGP) or muscadine wine phytochemicals (MWP), respectively, for 14 days. Acute colitis was induced by 3% DSS in drinking water for 7 days. An additional two groups of mice served as healthy and disease controls. Results indicated that MGP or MWP significantly prevented weight loss, reduced disease activity index, and preserved colonic length compared to the colitis group (p ≤ 0.05). MGP or MWP significantly decreased myeloperoxidase activity as well as the levels of IL-1ß, IL-6, and TNF-α in colon (p ≤ 0.05). MGP or MWP caused down-regulation of the NF-κB pathway by inhibiting the phosphorylation and degradation of IκB in a dose-dependent manner. These findings suggest that phytochemicals from muscadine grape or wine mitigate ulcerative colitis via attenuation of pro-inflammatory cytokine production and modulation of the NF-κB pathway.


Assuntos
Anti-Inflamatórios/administração & dosagem , Colite/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Vitis/química , Vinho/análise , Animais , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/imunologia
17.
Sci Rep ; 6: 31121, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27487993

RESUMO

Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex. An increase of one standard deviation (SD) in BMI (4.65 Kg/m(2)) raised the risk for lung cancer overall (OR = 1.13; P = 0.10). This was driven by associations with squamous cell (SQ) carcinoma (OR = 1.45; P = 1.2 × 10(-3)) and small cell (SC) carcinoma (OR = 1.81; P = 0.01). An inverse trend was seen for adenocarcinoma (AD) (OR = 0.82; P = 0.06). In stratified analyses, a 1 SD increase in BMI was inversely associated with overall lung cancer in never smokers (OR = 0.50; P = 0.02). These results indicate that higher BMI may increase the risk of certain types of lung cancer, in particular SQ and SC carcinoma.


Assuntos
Neoplasias Pulmonares/patologia , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Fatores de Risco , Fumar/patologia
18.
Int J Epidemiol ; 45(3): 896-908, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27427428

RESUMO

BACKGROUND: Adiposity traits have been associated with risk of many cancers in observational studies, but whether these associations are causal is unclear. Mendelian randomization (MR) uses genetic predictors of risk factors as instrumental variables to eliminate reverse causation and reduce confounding bias. We performed MR analyses to assess the possible causal relationship of birthweight, childhood and adult body mass index (BMI), and waist-hip ratio (WHR) on the risks of breast, ovarian, prostate, colorectal and lung cancers. METHODS: We tested the association between genetic risk scores and each trait using summary statistics from published genome-wide association studies (GWAS) and from 51 537 cancer cases and 61 600 controls in the Genetic Associations and Mechanisms in Oncology (GAME-ON) Consortium. RESULTS: We found an inverse association between the genetic score for childhood BMI and risk of breast cancer [odds ratio (OR) = 0.71 per standard deviation (s.d.) increase in childhood BMI; 95% confidence interval (CI): 0.60, 0.80; P = 6.5 × 10(-5)). We also found the genetic score for adult BMI to be inversely associated with breast cancer risk (OR = 0.66 per s.d. increase in BMI; 95% CI: 0.57, 0.77; P = 2.5 × 10(-7)), and positively associated with ovarian cancer (OR = 1.35; 95% CI: 1.05, 1.72; P = 0.017), lung cancer (OR = 1.27; 95% CI: 1.09, 1.49; P = 2.9 × 10(-3)) and colorectal cancer (OR = 1.39; 95% CI: 1.06, 1.82, P = 0.016). The inverse association between genetically predicted adult BMI and breast cancer risk remained even after adjusting for directional pleiotropy via MR-Egger regression. CONCLUSIONS: Findings from this study provide additional understandings of the complex relationship between adiposity and cancer risks. Our results for breast and lung cancer are particularly interesting, given previous reports of effect heterogeneity by menopausal status and smoking status.


Assuntos
Adiposidade/genética , Índice de Massa Corporal , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Relação Cintura-Quadril , Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Análise da Randomização Mendeliana , Neoplasias/epidemiologia , Razão de Chances , Neoplasias Ovarianas/genética , Fenótipo , Neoplasias da Próstata/genética , Análise de Regressão , Fatores de Risco
19.
Am J Respir Cell Mol Biol ; 54(2): 222-30, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26121126

RESUMO

The lung is enveloped by a layer of specialized epithelium, the pulmonary mesothelium. In other organs, mesothelial cells undergo epithelial-mesenchymal transition and contribute to organ stromal cells. The contribution of pulmonary mesothelial cells (PMCs) to the developing lung has been evaluated with differing conclusions. PMCs have also been indirectly implicated in lung fibrosis in the progressive, fatal lung disease idiopathic pulmonary fibrosis. We used fetal or postnatal genetic pulse labeling of PMCs to assess their fate in murine development, normal lung homeostasis, and models of pulmonary fibrosis. We found that most fetal PMC-derived mesenchymal cells (PMCDCs) expressed markers of pericytes and fibroblasts, only a small minority expressed smooth muscle markers, and none expressed endothelial cell markers. Postnatal PMCs did not contribute to lung mesenchyme during normal lung homeostasis or in models of lung fibrosis. However, fetal PMCDCs were abundant and actively proliferating within fibrotic regions in lung fibrosis models, suggesting that they actively participate in the fibrotic process. These data clarify the role of fetal and postnatal PMCDCs in lung development and disease.


Assuntos
Linhagem da Célula , Fibroblastos/patologia , Pulmão/patologia , Mesoderma/patologia , Fibrose Pulmonar/patologia , Animais , Biomarcadores/metabolismo , Bleomicina , Proliferação de Células , Rastreamento de Células , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Fibroblastos/metabolismo , Pulmão/metabolismo , Mesoderma/metabolismo , Camundongos Transgênicos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fenótipo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
20.
Ying Yong Sheng Tai Xue Bao ; 26(8): 2581-90, 2015 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-26685624

RESUMO

Green roof has a significant influence on reducing runoff volume, delaying runoff-yielding time, reducing the peak flow and improving runoff quality. This paper addressed the related research around the world and concluded from several aspects, i.e., the definition of green roof of different types, the mechanism how green roof manages runoff quantity and quality, the ability how green roof controls roof runoff, and the influence factors of green roof toward runoff quantity and quality. Afterwards, there was a need for more future work on research of green roof toward roof runoff, i.e., vegetation selection of green roof, efficient construction model selection of green roof, the regulating characteristics of green roof on roof runoff, the value assessment of green roof on roof runoff, analysis of source-sink function of green roof on the water pollutants of roof runoff and the research on the mitigation measures of roof runoff pollution. This paper provided a guideline to develop green roofs aiming to regulating roof runoff.


Assuntos
Conservação dos Recursos Naturais , Poluição Ambiental/prevenção & controle , Chuva , Movimentos da Água , Modelos Teóricos , Poluentes da Água
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