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1.
PLoS One ; 14(10): e0223679, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31581223

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0211373.].

2.
EBioMedicine ; 48: 203-211, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31629678

RESUMO

BACKGROUND: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. METHODS: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. FINDINGS: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P < 2·19 × 10-4. The associations for four variants reached P < 5 × 10-8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P < 5 × 10-8, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS. INTERPRETATION: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. FUND: National Institutes of Health.

3.
Sensors (Basel) ; 19(18)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527437

RESUMO

Transfer learning can enhance classification performance of a target domain with insufficient training data by utilizing knowledge relating to the target domain from source domain. Nowadays, it is common to see two or more source domains available for knowledge transfer, which can improve performance of learning tasks in the target domain. However, the classification performance of the target domain decreases due to mismatching of probability distribution. Recent studies have shown that deep learning can build deep structures by extracting more effective features to resist the mismatching. In this paper, we propose a new multi-source deep transfer neural network algorithm, MultiDTNN, based on convolutional neural network and multi-source transfer learning. In MultiDTNN, joint probability distribution adaptation (JPDA) is used for reducing the mismatching between source and target domains to enhance features transferability of the source domain in deep neural networks. Then, the convolutional neural network is trained by utilizing the datasets of each source and target domain to obtain a set of classifiers. Finally, the designed selection strategy selects classifier with the smallest classification error on the target domain from the set to assemble the MultiDTNN framework. The effectiveness of the proposed MultiDTNN is verified by comparing it with other state-of-the-art deep transfer learning on three datasets.

4.
PLoS One ; 14(8): e0211373, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31449533

RESUMO

With the exponential increase in malware, homology analysis has become a hot research topic in the malware detection field. This paper proposes MHAS, a malware homology analysis system based on ensemble learning and multifeatures. MHAS generates grayscale images from malware binary files and then uses the opcode tool IDA Pro to extract opcode sequences and system call graphs. Thus, RGB images and M-images are generated on the image matrix. Then, MHAS uses convolutional neural networks (CNNs) as base learners to perform bagging ensemble learning to learn features from the grayscale images, RGB images and M-images. Next, MHAS integrates the nine base learners using voting, learning and selective ensemble (in that order) and maps the integration results to the result matrix. Finally, the result matrix is again integrated using the learning method to obtain the final malware classification result. To verify the accuracy of MHAS, we performed a malware family classification experiment, that included samples of 10 malware families. The results showed that MHAS can reach an accuracy rate of 99.17%, meaning that it can effectively analyze and identify malware families.

5.
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.

6.
Lab Chip ; 19(11): 1953-1960, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31044199

RESUMO

The rope coiling observed in liquid ink with high viscosity has been exploited in additive printing to fabricate architectures with periodically curled structures and tune their mechanical properties. However, the control over the coiling path relying on mechanical motion restricts the spatiotemporal resolution. We develop an electrically assisted high-resolution technique to manipulate coiling paths of viscous ink and structures of the deposited filament. By spatially programming the voltage applied onto the viscous ink, we show that the switching between different filament structures can be accomplished at single wavelength resolution, facilitating the rapid and accurate construction of sophisticated patterns. Furthermore, translational guiding of the electrocoiling enables rapid printing of filaments with complex structures at a line speed of 102 mm s-1. With a simplified trajectory of the printing head, large-area and multiscale patterns can be printed at an unprecedented speed; for instance, centimeter-sized architectures constructed from nanofibers with micron-sized curled structures can be completed in a few minutes. By enabling the printing of complex fiber networks with tunable shape and density, our work provides a route towards custom-design of fiber architectures with unique features such as spatially varying mechanical properties.

7.
Breast Cancer Res ; 21(1): 68, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118087

RESUMO

BACKGROUND: Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk. METHODS: Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies. RESULTS: Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38-1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28-1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45-1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile. CONCLUSIONS: The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.

8.
Breast Cancer Res ; 21(1): 34, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819233

RESUMO

BACKGROUND: Use of cyclin D1 (CCND1) gene amplification as a breast cancer biomarker has been hampered by conflicting assessments of the relationship between cyclin D1 protein levels and patient survival. Here, we aimed to clarify its prognostic and treatment predictive potential through comprehensive long-term survival analyses. METHODS: CCND1 amplification was assessed using SNP arrays from two cohorts of 1965 and 340 patients with matching gene expression array and clinical follow-up data of over 15 years. Kaplan-Meier and multivariable Cox regression analyses were used to determine survival differences between CCND1 amplified vs. non-amplified tumours in clinically relevant patient sets, within PAM50 subtypes and within treatment-specific subgroups. Boxplots and differential gene expression analyses were performed to assess differences between amplified vs. non-amplified tumours within PAM50 subtypes. RESULTS: When combining both cohorts, worse survival was found for patients with CCND1-amplified tumours in luminal A (HR = 1.68; 95% CI, 1.15-2.46), luminal B (1.37; 1.01-1.86) and ER+/LN-/HER2- (1.66; 1.14-2.41) subgroups. In gene expression analysis, CCND1-amplified luminal A tumours showed increased proliferation (P < 0.001) and decreased progesterone (P = 0.002) levels along with a large overlap in differentially expressed genes when comparing luminal A and B-amplified vs. non-amplified tumours. CONCLUSIONS: Our results indicate that CCND1 amplification is associated with worse 15-year survival in ER+/LN-/HER2-, luminal A and luminal B patients. Moreover, luminal A CCND1-amplified tumours display gene expression changes consistent with a more aggressive phenotype. These novel findings highlight the potential of CCND1 to identify patients that could benefit from long-term treatment strategies.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Ciclina D1/genética , Amplificação de Genes/genética , Adulto , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Feminino , Seguimentos , Testes Genéticos/métodos , Humanos , Linfonodos/patologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Estudos Retrospectivos , Análise de Sobrevida
9.
PLoS One ; 14(3): e0213615, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30856210

RESUMO

INTRODUCTION: False-positive recall is an issue in national screening programmes. The aim of this study is to investigate the recall rate at first screen and to identify potential predictors of false-positive recall in a multi-ethnic Asian population-based breast cancer screening programme. METHODS: Women aged 50-64 years attending screening mammography for the first time (n = 25,318) were included in this study. The associations between potential predictors (sociodemographic, lifestyle and reproductive) and false-positive recall were evaluated using multivariable logistic regression models. RESULTS: The recall rate was 7.6% (n = 1,923), of which with 93.8% were false-positive. Factors independently associated with higher false-positive recall included Indian ethnicity (odds ratio [95% confidence interval]: 1.52 [1.25 to 1.84]), premenopause (1.23 [1.04 to 1.44]), nulliparity (1.85 [1.57 to 2.17]), recent breast symptoms (1.72 [1.31 to 2.23]) and history of breast lump excision (1.87 [1.53 to 2.26]). Factors associated with lower risk of false-positive recall included older age at screen (0.84 [0.73 to 0.97]) and use of oral contraceptives (0.87 [0.78 to 0.97]). After further adjustment of percent mammographic density, associations with older age at screening (0.97 [0.84 to 1.11]) and menopausal status (1.12 [0.95 to 1.32]) were attenuated and no longer significant. CONCLUSION: For every breast cancer identified, 15 women without cancer were subjected to further testing. Efforts to educate Asian women on what it means to be recalled will be useful in reducing unnecessary stress and anxiety.

10.
Sci Rep ; 9(1): 3527, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837593

RESUMO

Breast cancer patients commonly present with comorbidities which are known to influence treatment decisions and survival. We aim to examine agreement between self-reported and register-based medical records (National Patient Register [NPR]). Ascertainment of nine conditions, using individually-linked data from 64,961 women enrolled in the Swedish KARolinska MAmmography Project for Risk Prediction of Breast Cancer (KARMA) study. Agreement was assessed using observed proportion of agreement (overall agreement), expected proportion of agreement, and Cohen's Kappa statistic. Two-stage logistic regression models taking into account chance agreement were used to identify potential predictors of overall agreement. High levels of overall agreement (i.e. ≥86.6%) were observed for all conditions. Substantial agreement (Cohen's Kappa) was observed for myocardial infarction (0.74), diabetes (0.71) and stroke (0.64) between self-reported and NPR data. Moderate agreement was observed for preeclampsia (0.51) and hypertension (0.46). Fair agreement was observed for heart failure (0.40) and polycystic ovaries or ovarian cysts (0.27). For hyperlipidemia (0.14) and angina (0.10), slight agreement was observed. In most subgroups we observed negative specific agreement of >90%. There is no clear reference data source for ascertainment of conditions. Negative specific agreement between NPR and self-reported data is consistently high across all conditions.

11.
J Biosci Bioeng ; 128(1): 22-27, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30803783

RESUMO

Nucleoside deoxyribosyltransferase II (NDT) catalyzes the transglycosylation reaction of the 2'-deoxyribose moiety between purine and/or pyrimidine bases and has been widely used in the synthesis of nucleoside analogs. The high specificity of NDT for 2'-deoxyribose limits its applications. Because 2'C- and/or 3'C-modified nucleosides have been widely used as antiviral or antitumour agents, improving the activity of NDT towards these modified nucleosides by protein engineering is an area of interest to the pharmaceutical industry. NDT engineering is hindered by a lack of effective screening methods. This study developed a high-throughput screening system, which was established by nucleoside deoxyribosyltransferase II-cytidine deaminase co-expression, indophenol colorimetric assay and whole-cell catalysis. A high-throughput screening system for NDT was established for the first time. This system can be applied to detect NDT-specific activity for a variety of cytidine analogs with glycosyl and base modifications, such as 5-aza-2'-deoxycytidine, 2',3'-dideoxycytidine, cytosine-ß-d-arabinofuranoside. In this study, we adopted the semi-rational design of NDT and constructed a mutant library of NDT from Lactobacillus helveticus (LhNDT) by site-saturation mutagenesis. Over 600 mutants were screened, and a variant with up to a 5.2-fold higher conversion rate of 2',3'-dideoxyinosine was obtained.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Lactobacillus helveticus/genética , Proteínas Mutantes/isolamento & purificação , Pentosiltransferases/genética , Pentosiltransferases/isolamento & purificação , Pentosiltransferases/metabolismo , Catálise , Domínio Catalítico/genética , Ensaios Enzimáticos/métodos , Escherichia coli/enzimologia , Escherichia coli/genética , Regulação Enzimológica da Expressão Gênica , Mutagênese Sítio-Dirigida/métodos , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Nucleosídeos , Pentosiltransferases/química , Engenharia de Proteínas/métodos , Purinas , Pirimidinas , Relação Estrutura-Atividade , Especificidade por Substrato/genética
12.
Eur J Epidemiol ; 34(6): 591-600, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30737679

RESUMO

Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73-1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.


Assuntos
Peso ao Nascer , Neoplasias da Mama/epidemiologia , Peso ao Nascer/genética , Feminino , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Medição de Risco
13.
Int J Mol Sci ; 20(2)2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30654511

RESUMO

In a previous paper, we reported that triptolide (TP), a commonly used immunomodulator, could attenuate cardiac hypertrophy. This present study aimed to further explore the inhibition of cardiac fibrosis by TP and the possible mechanism from the perspective of the NOD-like receptor protein 3 (NLRP3) inflammasome. Hematoxylin-eosin and Masson's staining, immunohistochemistry, and immunofluorescence were performed to observe cardiac fibrotic changes in mice and mouse cardiac fibroblasts (CFs). The Western blot, colocalization, and immunoprecipitation were applied to detect protein expression and interactions. Results suggested that TP dose-dependently inhibited cardiac fibrosis induced by isoproterenol and collagen production of CFs induced by angiotensin II. TP exhibited an antifibrotic effect via inhibiting activation of the NLRP3 inflammasome, which sequentially decreased IL-1ß maturation, myeloid differentiation factor 88 (MyD88)-related phosphorylation of c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase 1/2 (ERK1/2), and TGF-ß1/Smad signaling, and ultimately resulted in less collagen production. Moreover, TP showed no antifibrotic effect in Nlrp3-knockout CFs. Notably, TP inhibited the expression of NLRP3 and apoptosis-associated speck-like proteins containing a caspase recruitment domain (ASC) as well as inflammasome assembly, by interrupting the NLRP3-ASC interaction to inhibit inflammasome activation. Finally, TP indeed inhibited the NLRP3-TGFß1-Smad pathway in vivo. Conclusively, TP was found to play a dual role in interrupting the activation of the NLRP3 inflammasome to attenuate cardiac fibrosis.


Assuntos
Diterpenos/farmacologia , Inflamassomos/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fenantrenos/farmacologia , Angiotensina II , Animais , Colágeno/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Ventrículos do Coração/patologia , Isoproterenol , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Cancer Res ; 78(21): 6329-6338, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385609

RESUMO

Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes-or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer-specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers (n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16-2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21-2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (<25%), non-BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12-3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64-0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection.Significance: These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. Cancer Res; 78(21); 6329-38. ©2018 AACR.

15.
Photomed Laser Surg ; 36(11): 614-620, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30227090

RESUMO

OBJECTIVE: To evaluate whether Er:YAG laser etching could be an alternative surface treatment to hydrofluoric (HF) acid etching. BACKGROUND: Surface treatment is important to bonding properties and utility times of computer aided design/computer aided manufacture (CAD/CAM) dental ceramics. The traditional method of HF acid etching is harmful to humans if not handled properly. MATERIALS AND METHODS: Four different CAD/CAM ceramics (Vita Mark II, IPS Empress CAD, IPS e.max CAD, and Vita Enamic) were cut into 72 blocks and divided into 6 groups according to different surface treatments (n = 12): Group A: no treatment; Group B: HF acid; and Group C to F: different Er:YAG laser power settings (300, 400, 500, and 600 mJ). Ten blocks of each group were measured for shear bond strength (SBS) and the failure modes were evaluated; the rest blocks were observed by scanning electronic microscopy (SEM). RESULTS: HF acid etching resulted in the highest SBS for Vita Mark II, IPS Empress CAD, and Vita Enamic; however, the difference was not statistically significant (p > 0.05) compared to the second highest group of laser with 600 mJ in IPS Empress CAD. For IPS e.max CAD, the highest SBS was obtained from laser group with 400 mJ. The SBS results were consistent with failure modes and surface characterizations in SEM images. CONCLUSIONS: Our results showed that Er:YAG laser had little impact on Vita Mark II and Vita Enamic; but proper power settings could be an alternative surface treatment to HF acid etching (600 mJ for IPS Empress CAD and 400 mJ for IPS e.max CAD).

16.
Int J Cancer ; 2018 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-30175445

RESUMO

Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety-two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.

17.
Front Physiol ; 9: 542, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867579

RESUMO

Inflammation is critical to the pathogenesis of cardiovascular diseases (CVDs). We have uncovered intrauterine inflammation induced by lipopolysaccharide (LPS) increases CVDs in adult offspring rats. The present study aimed to explore the role of prenatal exposure to LPS on the lipid profiles in male offspring rats and to further assess their susceptibility to high fat diet (HFD). Maternal LPS (0.79 mg/kg) exposure produced a significant increase in serum and hepatic levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate amino transferase as well as liver morphological abnormalities in 8-week-old offspring rats. Meanwhile, disturbed gene expressions involved in hepatic lipid metabolism and related signaling pathways were found, especially the up-regulated very-low density lipoprotein receptor (VLDLR) and down-regulated transmembrane 7 superfamily member 2 (TM7SF2). Following HFD treatment, however, the lipid profile shifts and liver dysfunction were exacerbated compared to the offsprings treated with prenatal LPS exposure alone. Compared with that in control offsprings, the hepatic mitochondria (Mt) in offspring rats solely treated with HFD exhibited remarkably higher ATP level, enforced Complex IV expression and a sharp reduction of its activity, whereas the offsprings from LPS-treated dams showed the loss of ATP content, diminished membrane potential, decline in protein expression and activity of mitochondrial respiratory complex IV, increased level of MtDNA deletion as well. Furthermore, treatment with HFD deteriorated these mitochondrial disorders in the prenatally LPS-exposed offspring rats. Taken together, maternal LPS exposure reinforces dyslipidemia in response to a HFD in adult offsprings, which should be associated with mitochondrial abnormalities and disturbed gene expressions of cholesterol metabolism.

18.
Breast Cancer Res ; 20(1): 30, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29665850

RESUMO

BACKGROUND: Mammographic density (MD) is a strong and heritable intermediate phenotype of breast cancer, but much of its genetic variation remains unexplained. METHODS: We conducted a genetic association study of volumetric MD in a Swedish mammography screening cohort (n = 9498) to identify novel MD loci. Associations with volumetric MD phenotypes (percent dense volume, absolute dense volume, and absolute nondense volume) were estimated using linear regression adjusting for age, body mass index, menopausal status, and six principal components. We also estimated the proportion of MD variance explained by additive contributions from single-nucleotide polymorphisms (SNP-based heritability [h2SNP]) in 4948 participants of the cohort. RESULTS: In total, three novel MD loci were identified (at P < 5 × 10- 8): one for percent dense volume (HABP2) and two for the absolute dense volume (INHBB, LINC01483). INHBB is an established locus for ER-negative breast cancer, and HABP2 and LINC01483 represent putative new breast cancer susceptibility loci, because both loci were associated with breast cancer in available meta-analysis data including 122,977 breast cancer cases and 105,974 control subjects (P < 0.05). h2SNP (SE) estimates for percent dense, absolute dense, and nondense volume were 0.29 (0.07), 0.31 (0.07), and 0.25 (0.07), respectively. Corresponding ratios of h2SNP to previously observed narrow-sense h2 estimates in the same cohort were 0.46, 0.72, and 0.41, respectively. CONCLUSIONS: These findings provide new insights into the genetic basis of MD and biological mechanisms linking MD to breast cancer risk. Apart from identifying three novel loci, we demonstrate that at least 25% of the MD variance is explained by common genetic variation with h2SNP/h2 ratios varying between dense and nondense MD components.

19.
Breast Cancer Res Treat ; 169(2): 371-379, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29392583

RESUMO

BACKGROUND: Mammographic density is a marker of breast cancer risk and diagnostics accuracy. Density change over time is a strong proxy for response to endocrine treatment and potentially a stronger predictor of breast cancer incidence. We developed STRATUS to analyse digital and analogue images and enable automated measurements of density changes over time. METHOD: Raw and processed images from the same mammogram were randomly sampled from 41,353 healthy women. Measurements from raw images (using FDA approved software iCAD) were used as templates for STRATUS to measure density on processed images through machine learning. A similar two-step design was used to train density measures in analogue images. Relative risks of breast cancer were estimated in three unique datasets. An alignment protocol was developed using images from 11,409 women to reduce non-biological variability in density change. The protocol was evaluated in 55,073 women having two regular mammography screens. Differences and variances in densities were compared before and after image alignment. RESULTS: The average relative risk of breast cancer in the three datasets was 1.6 [95% confidence interval (CI) 1.3-1.8] per standard deviation of percent mammographic density. The discrimination was AUC 0.62 (CI 0.60-0.64). The type of image did not significantly influence the risk associations. Alignment decreased the non-biological variability in density change and re-estimated the yearly overall percent density decrease from 1.5 to 0.9%, p < 0.001. CONCLUSIONS: The quality of STRATUS density measures was not influenced by mammogram type. The alignment protocol reduced the non-biological variability between images over time. STRATUS has the potential to become a useful tool for epidemiological studies and clinical follow-up.

20.
Sci Rep ; 8(1): 1201, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29352164

RESUMO

Breast size as a risk factor of breast cancer has been studied extensively with inconclusive results. Here we examined the associations between breast size and breast cancer risk factors in 24,353 Asian women aged 50 to 64 years old enrolled in a nationwide mammography screening project conducted between October 1994 and February 1997. Information on demographic and reproductive factors was obtained via a questionnaire. Breast size was ascertained as bust line measured at study recruitment and total breast area measured from a mammogram. The average bust line and total breast area was 91.2 cm and 102.3 cm2, respectively. The two breast measurements were moderately correlated (Spearman correlation coefficient = 0.65). Age, BMI, marital and working status were independently associated with bust line and total breast area. In the multivariable analyses, the most pronounced effects were observed for BMI (24.2 cm difference in bust line and 39.4 cm2 in breast area comparing women with BMI ≥30 kg/m2 to BMI <20 kg/m2). Ethnicity was a positive predictor for total breast area, but not bust line.


Assuntos
Grupo com Ancestrais do Continente Asiático , Mama/anatomia & histologia , Adulto , Idoso , Índice de Massa Corporal , Mama/diagnóstico por imagem , Densidade da Mama , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Feminino , Humanos , Mamografia , Pessoa de Meia-Idade , Tamanho do Órgão , Vigilância da População , Fatores de Risco , Singapura/epidemiologia
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