Search

Introduction: Gut microbiota has been reported to contribute to obesity and the pathology of obesity‐related diseases but the underlying mechanisms are largely unknown. Mucosal‐associated invariant T (MAIT) cells are a unique subpopulation of T cells characterized by the expression of a semi‐invariant T cell receptor (TCR) α chain (Vα19 in mice; Vα7.2 in humans). The expansion and maturation of MAIT cells require the gut microbiota and antigen‐presenting molecule MR1, suggesting that MAIT cells may play a unique role in bridging gut microbiota, obesity, and obesity‐associated inflammation. Methods: The levels of human MAIT cells from obese patients, as well as mouse MAIT cells from obese mouse models, were determined by flow cytometry. By comparing to controls, we analyzed the change of MAIT cells in obese subjects. Results: We found obese patients had fewer circulating MAIT cells than healthy‐weight donors and the difference was more distinct in male patients. Consistently, male mice (but not female mice) have shown reduced MAIT cells in the liver and adipose tissue after a 10‐week Western diet compared to mice on a control diet. We also explored the possibility of utilizing high‐throughput technology (i.e., quantitative polymerase chain reaction [qPCR]), other than flow cytometry, to determine the expression levels of the invariant TCR of human MAIT cells. But a minimal correlation (R2 = 0.23, p =.11) was observed between qPCR and flow cytometry data. Conclusion: Our study suggests that there is a sex discrepancy in the impact of obesity on MAIT cells: MAIT cells in male (but not female) humans and male mice are reduced by obesity. [ABSTRACT FROM AUTHOR]

Background Regular aspirin use reduces the risk for colorectal cancer (CRC), possibly through inhibition of WNT/cadherin-associated protein β1 (CTNNB1 or β-catenin) signaling. The single nucleotide polymorphism (SNP) rs6983267 on chromosome 8q24 is a CRC susceptibility locus that affects binding activity of transcription factor 7 like-2 (TCF7L2) to CTNNB1, thereby altering expression of target oncogenes, including MYC. Methods We evaluated regular aspirin use and CRC risk according to genotypes of SNP rs6983267 and CTNNB1 expression status in two prospective case–control studies (840 CRC case patients and 1686 age- and race-matched control subjects) nested within the Nurses’ Health Study and the Health Professionals Follow-up Study. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models. All statistical tests were two-sided. Results A lower risk of CRC was associated with regular aspirin use and the T allele of rs6983267. The effect of aspirin was confined to individuals with protective T allele of rs6983267 (additive matching factors–adjusted OR for T allele = 0.83; 95% CI = 0.74 to 0.94; Ptrend = .002; Pinteraction = .01). Additionally, the T allele of rs6983267 was associated with a reduced expression of MYC oncogene (Ptrend = .03). Moreover, among individuals with protective T allele, the effect of regular aspirin use was limited to those with positive nuclear CTNNB1 expression. In a functional analysis, in vitro treatment of LS174T cells (a cell line heterozygous for rs6983267) with aspirin was statistically significantly associated with higher G/T allelic ratio of TCF7L2 immunoprecipitated DNA (P = .03). Conclusions Our results support an influence of aspirin on WNT/CTNNB1 signaling and suggest that aspirin chemoprevention may be tailored according to rs6983267 genotype. [ABSTRACT FROM PUBLISHER]

The volatile components ofPrunella vulgarisL. were determined by headspace solid-phase microextraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC-MS). The optimal conditions for HS-SPME were 1.5 g of sample, extraction using a polydimethylsiloxane-divinylbenzene fiber for 50 min at 90°C, and a desorption time of 5 min. The volatile compounds ofPrunella vulgarisL. from different parts of the herb (cultivated in Jiangsu) and from different geographical regions (Jiangsu, Fujian, Guangxi, Hunan, and Zhejiang) were comparatively analyzed. There were 26, 28, 28, 28, and 34 compounds identified inPrunella vulgarisL. from Jiangsu, Fujian, Guangxi, Hunan, and Zhejiang, respectively. Among them, the following 12 were found in all origins: 1-nonanol, dodecane, tridecane, α-bourbonene, tetradecane, geranyl acetone, pentadecane, caryophyllene oxide, hexadecane, tetradecanal, isobutyl phthalate, and n-butyl hexadecanoate. In addition,Prunella vulgarisL. cultivated in Guangxi and Zhejiang had a high similarity in volatile components as didPrunella vulgarisL. cultivated in Fujian and Hunan. The results provided valuable information for the application ofPrunella vulgarisL. and suggested that the HS-SPME method was suitable for differentiating and determining the volatile components ofPrunella vulgarisL. [ABSTRACT FROM PUBLISHER]

Abstract: Purpose: To evaluate the influence of alcohol consumption on the risk of colorectal cancer according to folic acid fortification period in the United States. Methods: We evaluated the association between alcohol consumption and colorectal cancer by fortification period (before 1998 vs. after 1998) in 2 prospective cohort studies, the Nurses’ Health Study (NHS) of women and the Health Professionals Follow-up Study (HPFS) of men, in which 2793 cases of invasive colorectal cancer were documented. Results: Alcohol consumption was associated with an increased risk of colorectal cancer. Among nonusers of multivitamins and/or folic acid supplements, the pooled multivariate relative risk for ≥30 g/d drinkers versus nondrinkers was 1.36 (95% confidence interval [95% CI], 1.09–1.70; P for trend, 0.02). The effect of alcohol consumption was slightly stronger in the prefolic acid fortification period (1980 NHS/1986 HPFS-1998) than in the postfortification period (1998–2008); the pooled multivariate relative risks for ≥30 g/d drinkers versus nondrinkers were 1.31 (95% CI, 1.00–1.71; P for trend, 0.10) in the prefortification period and 1.07 (95% CI, 0.69–1.65; P for trend, 0.67) in the postfortification period. Conclusions: Folic acid fortification may attenuate the adverse effect of high alcohol consumption on the risk of colorectal cancer. [Copyright &y& Elsevier]

Background: Abnormal one-carbon metabolism may lead to general genomic (global) hypomethylation, which may predispose an individual to the development of colorectal neoplasia. Methods: We evaluated the association between pre-diagnostic leukocyte genomic DNA methylation level and the risk of colorectal cancer in a nested case-control study of 358 colorectal cancer cases and 661 matched controls within the all-female cohort of the Nurses’ Health Study (NHS). Among control subjects, we further examined major plasma components in the one-carbon metabolism pathway in relation to genomic DNA methylation level. Liquid chromatography/tandem mass spectrometry was used to examine leukocyte genomic DNA methylation level. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression. Results: Overall genomic DNA methylation level was not associated with the risk of colorectal cancer (p for trend, 0.45). Compared with women in the lowest quintile of methylation, the multivariate OR of colorectal cancer risk was 1.32 (95% CI, 0.82–2.13) for those in the highest quintile. We did not find significant associations between major plasma components of one-carbon metabolism or risk factors for colorectal cancer and genomic DNA methylation level (all p for trend >0.05). Also, neither one-carbon metabolism-related plasma components nor well-known risk factors for colorectal cancer modified the association between genomic DNA methylation level and the risk of colorectal cancer (all p for interaction >0.05). Conclusions: We found no evidence that hypomethylation of leukocyte genomic DNA increases risk of colorectal cancer among women. Additional studies are needed to investigate the association between pre-diagnostic genomic DNA methylation level and colorectal cancer risk among diverse populations. [ABSTRACT FROM AUTHOR]

The minor allele (G) of rs4939827, a SMAD7 (18q21) intronic variant, is associated with a lower risk of developing colorectal cancer (CRC) and poorer survival after diagnosis. Our objective was to evaluate the associations of this variant with different tumor phenotype and intratumoral molecular characteristics. We evaluated 1509 CRC cases and 2307 age-matched controls nested within the Nurses’ Health Study and the Health Professionals Follow-up Study. We used the TaqMan assay to genotype rs4939827 and logistic regression to assess the association of rs4939827 with risk of CRC according to different phenotypic and molecular characteristics. We found that the minor allele (G) in rs4939827 (SMAD7, 18q21) was associated with a lower risk of developing tumor stage pT1 or pT2 CRC [multivariate odds ratio (OR), 0.73; 95% confidence interval (CI) 0.62–0.87] but not tumor stage pT3 or pT4 (multivariate OR, 1.07; 95% CI 0.93–1.23, P for heterogeneity = 1.2 × 10−4). The association between rs4939827 and CRC also significantly differed by methylation of RUNX3 (P for heterogeneity = 0.005). Among those with CRC, the minor allele (G) in rs4939827 was significantly associated with poorer overall survival (hazards ratio, 1.20; 95% CI, 1.02–1.42). We can conclude that the minor allele (G) of the germline intronic SMAD7 variant rs4939827 is associated with a lower risk of CRC with earlier tumor stage and CRC without methylation of the tumor suppressor RUNX3. These findings suggest that individuals with this SMAD7 variant that develop CRC are more probably to have tumors with greater invasiveness and methylation of RUNX3, which potentially contributes to their poorer observed survival. [ABSTRACT FROM PUBLISHER]

Telomere-related genes play an important role in maintaining the integrity of the telomeric structure that protects chromosome ends, and telomere dysfunction may lead to tumorigenesis. We evaluated the associations between 39 SNPs, including 38 tag-SNPs in telomere-related genes ( TERT, TRF1, TRF2, TNKS2, and POT1) and one SNP (rs401681) in the TERT- CLPTM1L locus which has been identified as a susceptibility locus to skin cancer in the previous GWAS, and the risk of skin cancer in a case-control study of Caucasians nested within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. Of the 39 SNPs evaluated, ten showed a nominal significant association with the risk of at least one type of skin cancer. After correction for multiple testing within each gene, two SNPs in the TERT gene (rs2853676 and rs2242652) and one SNP in the TRF1 gene (rs2981096) showed significant associations with the risk of melanoma. Also, the SNP rs401681 in the TERT- CLPTM1L locus was replicated for the association with melanoma risk. The additive odds ratio (OR) [95% confidence interval (95% CI)] of these four SNPs (rs2853676[T], rs2242652[A], rs2981096[G], and rs401681[C]) for the risk of melanoma was 1.43 (1.14-1.81), 1.50 (1.14-1.98), 1.87 (1.19-2.91), and 0.73 (0.59-0.91), respectively. Moreover, we found that the rs401681[C] was associated with shorter relative telomere length ( P for trend, 0.05). We did not observe significant associations for SCC or BCC risk. Our study provides evidence for the contribution of genetic variants in the telomere-maintaining genes to melanoma susceptibility. [ABSTRACT FROM AUTHOR]

Cutaneous malignant melanoma (hereafter called melanoma) is one of the most aggressive cancers with increasing incidence and mortality rates worldwide. In this study, we performed a systematic investigation of the tumor microenvironmental and genetic factors associated with melanoma to identify prognostic biomarkers for melanoma. We calculated the immune and stromal scores of melanoma patients from the Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm and found that they were closely associated with patients' prognosis. Then the differentially expressed genes were obtained based on the immune and stromal scores, and prognostic immune‐related genes further identified. Functional analysis and the protein–protein interaction network further revealed that these genes enriched in many immune‐related biological processes. In addition, the abundance of six infiltrating immune cells was analyzed using prognostic immune‐related genes by TIMER algorithm. The unsupervised clustering analysis using immune‐cell proportions revealed eight clusters with distinct survival patterns, suggesting that dendritic cells were most abundant in the microenvironment and CD8+ T cells and neutrophils were significantly related to patients' prognosis. Finally, we validated these genes in three independent cohorts from the Gene Expression Omnibus database. In conclusion, this study comprehensively analyzed the tumor microenvironment and identified prognostic immune‐related biomarkers for melanoma. [ABSTRACT FROM AUTHOR]

Mitochondria are key cytoplasmic organelles in eukaryotic cells that generate adenosine triphosphate (ATP) through the electron transport chain and oxidative phosphorylation. Mitochondrial DNA (mtDNA) copy number (mtDNAcn) is considered a biomarker for both mitochondrial quantity and function as well as cellular oxidative stress level. Previous epidemiologic findings revealed that weight gain, higher body mass index (BMI), smoking, and high insulinemic potential of lifestyle were associated with lower leukocyte mtDNAcn. Carnitines are a group of compounds that play a critical role in energy production. We quantified the associations of plasma L-carnitine levels with leukocyte mtDNAcn. We then examined the association between mtDNAcn and L-carnitine (HMDB0000062) in 538 U.S. men without cancers, diabetes, or cardiovascular disease at blood collection from the Health Professionals Follow-Up Study (HPFS). We found a significant inverse association between L-carnitine and mtDNAcn (ρ = −0.1, P = 0.02). This implies that the carnitine metabolic pathway may be associated with mitochondrial function and oxidative stress. [ABSTRACT FROM AUTHOR]

Ultraviolet radiation (UVR) exposure is the major risk factor for melanoma. However, epidemiologic studies on UVR and noncutaneous cancers have reported inconsistent results, with some suggesting an inverse relationship potentially mediated by vitamin D. To address this, we examined 3 US prospective cohorts, the Health Professionals Follow-up Study (HPFS) (1986) and Nurses' Health Study (NHS) I and II (1976 and 1989), for associations between cumulative erythemal UVR and incident cancer risk, excluding nonmelanoma skin cancer. We used a validated spatiotemporal model to calculate erythemal UVR. Participants (47,714 men; 212,449 women) were stratified into quintiles by cumulative average erythemal UVR, using the first quintile as referent, for Cox proportional hazards regression analysis. In the multivariable-adjusted meta-analysis of all cohorts, compared with the lowest quintile, risk of any cancer was slightly increased across all other quintiles (highest quintile hazard ratio (HR) = 1.04, 95% confidence interval (CI): 1.01, 1.07; P for heterogeneity = 0.41). All UVR quintiles were associated with similarly increased risk of any cancer excluding melanoma. As expected, erythemal UVR was positively associated with risk of melanoma (highest quintile HR = 1.17, 95% CI: 1.04, 1.31; P for heterogeneity = 0.83). These findings suggest that elevated UVR is associated with increased risk of both melanoma and noncutaneous cancers. [ABSTRACT FROM AUTHOR]

We conducted a multi-stage genome-wide association study of natural hair color in more than 10,000 men and women of European ancestry from the United States and Australia. An initial analysis of 528,173 single nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified IRF4 and SLC24A4 as loci highly associated with hair color, along with three other regions encompassing known pigmentation genes. We confirmed these associations in 7,028 individuals from three additional studies. Across these four studies, SLC24A4 rs12896399 and IRF4 rs12203592 showed strong associations with hair color, with p = 6.0×10−62 and p = 7.46×10−127, respectively. The IRF4 SNP was also associated with skin color (p = 6.2×10−14), eye color (p = 6.1×10−13), and skin tanning response to sunlight (p = 3.9×10−89). A multivariable analysis pooling data from the initial GWAS and an additional 1,440 individuals suggested that the association between rs12203592 and hair color was independent of rs1540771, a SNP between the IRF4 and EXOC2 genes previously found to be associated with hair color. After adjustment for rs12203592, the association between rs1540771 and hair color was not significant (p = 0.52). One variant in the MATP gene was associated with hair color. A variant in the HERC2 gene upstream of the OCA2 gene showed the strongest and independent association with hair color compared with other SNPs in this region, including three previously reported SNPs. The signals detected in a region around the MC1R gene were explained by MC1R red hair color alleles. Our results suggest that the IRF4 and SLC24A4 loci are associated with human hair color and skin pigmentation. [ABSTRACT FROM AUTHOR]

Glycyrrhizae Radix et Rhizoma, a Chinese herb known as licorice, is frequently incorporated in traditional Chinese medicine (TCM) formulations, due to its significant medicinal value and sweet taste. Despite licorice's merits, no systematic scientometric study has yet been conducted to analyze licorice research trends over the past 25 years. We conducted this study with the aim to provide researchers with a comprehensive overview of research advances in the application of licorice as a TCM ingredient and to offer valuable insights to guide future endeavors in this research field. We selected licorice-related research papers published between 1997 and 2021 from the Web of Science Core Collection then conducted a scientometric analysis using VOSviewer and CiteSpace software tools. A total of 4883 licorice-related publications, including 4511 research papers, 372 review papers, and their cited references, were included in the analysis. Most of these articles were authored by researchers in China (36.8%), including major contributors Wang Ying, Ye Min, and Zhang Yu. The Journal of Ethnopharmacology (impact factor = 5.4) hosted the greatest number of papers (145 articles). Keyword cluster analysis revealed three keyword categories indicating that current licorice research is focused on licorice quality control and identification of licorice active ingredients and associated pharmacological mechanisms. This study provides a comprehensive overview of licorice-related research trends over the past 25 years as based on quantitative and qualitative analyses of published licorice-related articles. The results of this multi-level analysis of licorice research related to TCM formulations, chemical compositions, and pharmacological effects should provide valuable reference data and insights to guide future research endeavors in this field. [Display omitted] • The study uses a scientometric approach to explore the literature on Glycyrrhiza glabra (licorice). • VOSviewer and CiteSpace are used to analyze 25 years of research on licorice. • This study identifies the knowledge domain and emerging trends in licorice. • These findings will facilitate the development of the licorice field and assist researchers in conducting in-depth studies. [ABSTRACT FROM AUTHOR]

Cutaneous melanoma (CM) is the most lethal type of skin cancers. Nicotinamide adenine dinucleotide phosphate (NADPH) plays an important role in anabolic reactions and tumorigenesis, but many genes are involved in the NADPH system. We used 10,912 single-nucleotide polymorphisms (SNPs) (2018 genotyped and 8894 imputed) in 134 NADPH-related genes from a genome-wide association study (GWAS) of 858 patients from The University of Texas MD Anderson Cancer Center (MDACC) in a single-locus analysis to predict CM survival. We then replicated the results in another GWAS data set of 409 patients from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). There were 95 of 858 (11.1%) and 48 of 409 (11.7%) patients who died of CM, respectively. In multivariable Cox regression analyses, we identified two independent SNPs (TKT rs9864057 G > A and deoxyribose phosphate aldolase (DERA) rs12297652 A > G) to be significantly associated with CM-specific survival [hazards ratio (HR) of 1.52, 95% confidence interval (CI) = 1.18–1.96, P = 1.06 × 10−3 and 1.51 (1.19–1.91, 5.89 × 10−4)] in the meta-analysis, respectively. Furthermore, an increasing number of risk genotypes of these two SNPs was associated with a higher risk of death in the MDACC, the NHS/HPFS, and their combined data sets (P trend <0.001, = 0.004 and <0.001, respectively). In the expression quantitative trait loci analysis, TKT rs9864057 G > A and DERA rs12297652 A > G were also significantly associated with higher mRNA expression levels in sun-exposed lower-leg skin (P = 0.043 and 0.006, respectively). These results suggest that these two potentially functional SNPs may be valuable prognostic biomarkers for CM survival, but larger studies are needed to validate these findings. • Two variants (TKT rs9864057 and DERA rs12297652) found to be associated with melanoma survival. • The risk genotypes were associated with survival of the patients in an allele dose-response manner. • Their risk alleles were associated with higher mRNA expression levels in the sun-exposed skin. [ABSTRACT FROM AUTHOR]

Background: Poor lifestyles have been linked to insulin insensitivity/hyperinsulinemia, which may contribute to downstream changes such as inflammation and oxidative damage and the development of chronic diseases. As a biomarker of intracellular oxidative stress, leukocyte mitochondrial DNA copy number (mtDNA-CN) has been related to lifestyle factors including diet and weight. No epidemiologic study has examined the relation between combined insulinemic potential of lifestyle and mtDNA-CN.Objectives: Our aim was to examine the association between Empirical Lifestyle Index for Hyperinsulinemia (ELIH) and leukocyte mtDNA-CN in US men and women.Methods: This cross-sectional analysis included 2835 white adults without cancers, diabetes, or cardiovascular disease at blood collection, including 2160 women from the Nurses' Health Study and 675 men from the Health Professionals Follow-Up Study. ELIH is an index based on plasma C-peptide that characterizes the insulinemic potential of lifestyle (diet, body weight, and physical activity). Relative mtDNA-CN in peripheral blood leukocytes was measured by qPCR-based assay.Results: We found a significant inverse association between ELIH and mtDNA-CN. In multivariable-adjusted linear models, absolute least squares means ± SDs of mtDNA-CN z score across ELIH quintiles in women were as follows: Q1: 0.14 ± 0.05; Q2: 0.04 ± 0.06; Q3: 0.008 ± 0.05; Q4: 0.01 ± 0.05; and Q5: -0.06 ± 0.05 (P-trend = 0.006). Means ± SDs in men were as follows: Q1: 0.25 ± 0.09; Q2: 0.23 ± 0.09; Q3: 0.07 ± 0.09; Q4: 0.02 ± 0.09; and Q5: -0.04 ± 0.09 (P-trend = 0.007). Means ± SDs in all participants were as follows: Q1: 0.16 ± 0.05; Q2: 0.07 ± 0.05; Q3: 0.01 ± 0.05; Q4: 0.01 ± 0.05; and Q5: -0.05 ± 0.05 (P-trend = 0.0004).Conclusions: Hyperinsulinemic lifestyles (i.e., higher ELIH) were associated with lower leukocyte mtDNA-CN among subjects without major diseases, suggesting that the difference in lifestyle insulinemic potential may be related to excessive oxidative stress damage. [ABSTRACT FROM AUTHOR]

Background: In prior studies, higher citrus consumption was associated with higher risk of cutaneous malignant melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Furocoumarins, compounds with phototoxicity and photocarcinogenicity in citrus, may be responsible for the association.Objectives: The objective of the study was to investigate the association between furocoumarin intake and skin cancer risk.Methods: A total of 47,453 men from the Health Professionals Follow-Up Study (HPFS) and 75,291 women from the Nurses' Health Study (NHS) with diet data collected every 2-4 y in the 2 prospective cohort studies were included. A furocoumarin food composition database for 7 common furocoumarins [bergaptol, psoralen, 8-methoxypsoralen, bergapten, 6',7'-dihydroxybergamottin (6'7'-DHB), epoxybergamottin, and bergamottin] was developed and used to calculate participants' cumulative average and energy-adjusted furocoumarin intake. Multivariate HRs and 95% CIs of the associations between furocoumarin intake and skin cancer risk were estimated using Cox proportional hazards models. Analyses were performed separately in each cohort as well as pooled using a fixed-effects model.Results: Throughout follow-up (1984-2012 in the NHS and 1986-2012 in the HPFS), we identified 1593 melanoma, 4066 SCC, and 28,630 BCC cases. Higher intake of total furocoumarins was associated with an increased risk of BCC; the pooled HR comparing the top with the bottom quintile was 1.16 (95% CI: 1.11, 1.21; P-trend = 0.002). Higher intakes of bergaptol, bergapten, 6'7'-DHB, and bergamottin were also significantly associated with increased BCC risk. No significant associations were found between intake of total furocoumarins and the risks of SCC or melanoma.Conclusions: Intakes of total furocoumarins as well as some individual furocoumarins were associated with an increased risk of skin cancer, especially BCC, in 2 cohorts of US health professionals. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods: To improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. Results: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5). Conclusions: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk. [ABSTRACT FROM AUTHOR]

Citrus products are rich sources of furocoumarins, a class of photoactive compounds. Certain furocoumarins combined with ultraviolet radiation can induce skin cancer. We examined the relationship between citrus consumption and cutaneous melanoma risk among 56,205 Caucasian postmenopausal women in the Women's Health Initiative. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by citrus intake level. During a mean follow-up of 15.7 years, 956 incident melanoma cases were documented. In multivariable adjusted models, the HR (95% CI) for melanoma was 1.12 (0.91, 1.37) among the highest citrus consumers (1.5+ servings/day of fruit or juice) versus the lowest (<2 servings/week), 0.95 (0.76, 1.20) among the highest citrus fruit consumers (5+ servings/week) versus non-consumers, and was 1.13 (0.96, 1.32) for the highest citrus juice consumers (1+ servings/day) versus the lowest (<1 serving/week). In stratified analyses, an increased melanoma risk associated with citrus juice intake was observed among women who spent the most time outdoors in summer as adults; the HR for the highest versus lowest intake was 1.22 (1.02, 1.46) (p trend = 0.03). Further research is needed to explore the association of melanoma with citrus juices among women with high sun exposure. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) is susceptible to oxidative stress and mutation. Few epidemiological studies have assessed the relationship between mtDNA copy number (mtDNAcn) and risk of colorectal cancer (CRC), with inconsistent findings. In this study, we examined the association between pre-diagnostic leukocyte mtDNAcn and CRC risk in a case–control study of 324 female cases and 658 matched controls nested within the Nurses' Health Study (NHS). Relative mtDNAcn in peripheral blood leukocytes was measured by quantitative polymerase chain reaction-based assay. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association of interest. Results showed lower log-mtDNAcn was significantly associated with increased risk of CRC, in a dose-dependent relationship (P for trend < 0.0001). Compared to the fourth quartile, multivariable-adjusted OR [95% confidence interval (CI)] was 1.10 (0.69, 1.76) for the third quartile, 1.40 (0.89, 2.19) for the second quartile and 2.19 (1.43, 3.35) for the first quartile. In analysis by anatomic subsite of CRC, we found a significant inverse association for proximal colon cancer [lowest versus highest quartile, multivariable-adjusted OR (95% CI) = 3.31 (1.70, 6.45), P for trend = 0.0003]. Additionally, stratified analysis according to the follow-up time since blood collection showed that the inverse association between mtDNAcn and CRC remained significant among individuals with ≥ 5 years' follow-up, and marginally significant among those with ≥ 10 years' follow-up since mtDNAcn testing, suggesting that mtDNAcn may serve as a long-term predictor for risk of CRC. In conclusion, pre-diagnostic leukocyte mtDNAcn was inversely associated with CRC risk. Further basic experimental studies are needed to explore the underlying biological mechanisms linking mtDNAcn to CRC carcinogenesis. [ABSTRACT FROM AUTHOR]

Remodeling or deregulation of the calcium signaling pathway is a relevant hallmark of cancer including cutaneous melanoma (CM). In this study, using data from a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center, we assessed the role of 41,377 common single-nucleotide polymorphisms (SNPs) of 167 calcium signaling pathway genes in CM survival. We used another GWAS from Harvard University as the validation dataset. In the single-locus analysis, 1830 SNPs were found to be significantly associated with CM-specific survival (CMSS; P ≤ 0.050 and false-positive report probability ≤ 0.2), of which 9 SNPs were validated in the Harvard study (P ≤ 0.050). Among these, three independent SNPs (i.e. PDE1A rs6750552 T>C, ITPR1 rs6785564 A>G and RYR3 rs2596191 C>A) had a predictive role in CMSS, with a meta-analysis-derived hazards ratio of 1.52 (95% confidence interval = 1.19–1.94, P = 7.21 × 10−4), 0.49 (0.33–0.73, 3.94 × 10−4) and 0.67 (0.53–0.86, 0.0017), respectively. Patients with an increasing number of protective genotypes had remarkably improved CMSS. Additional expression quantitative trait loci analysis showed that these genotypes were also significantly associated with mRNA expression levels of the genes. Taken together, these results may help us to identify prospective biomarkers in the calcium signaling pathway for CM prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Accumulating evidence implies that long noncoding RNAs (lncRNAs) play a crucial role in predicting survival for Hepatocellular carcinoma (HCC) patients. This study aims to capture the current research hotspots of HCC, based on the analysis of publications related to HCC research from 2013 to 2017, and to identify a novel lncRNA signature for HCC prognosis through the data mining in The Cancer Genome Atlas (TCGA). “Prognosis” and “biomarker” were located in the core of the HCC research hotspot. Moreover, long noncoding RNA was the top one research frontier in HCC research. The associations between survival outcome and the expression of lncRNAs were evaluated by the univariate and multivariate Cox proportional hazards regression analyses. Four lncRNAs (LINC00261, TRELM3P, GBP1P1, and CDKN2B‐AS1) were identified as significantly correlated with overall survival (OS). These four lncRNAs were gathered as a single prognostic signature. There was a significant positive correlation between HCC patients with low‐risk scores and overall survival (HR = 1.802, 95%CI [1.224‐2.652], P = .003). Further analysis suggested that the prognostic value of this four‐lncRNA signature was independent in clinical features. The enrichment analysis of prognostic lncRNA‐related gene was performed to find out the related pathways. Our study indicates that this novel lncRNA expression signature may be a useful biomarker of the prognosis for HCC patients, based on bioinformatics analysis. [ABSTRACT FROM AUTHOR]

Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5, NEGR1, FLJ35779, ETV5, CADM2, and NUDT3 genes were nominally significantly associated with hair color among 5,876 individuals of European ancestry. The genetic score combining 35 independent obesity-risk loci was significantly associated with darker hair color (beta-coefficient per ten alleles = 0.12, P value = 4 × 10). However, single SNPs or genetic scores showed non-significant association with tanning ability. We further examined the SNPs at the FTO locus for their associations with pigmentation and risk of melanoma. Among the 783 SNPs in the FTO gene with imputation R quality metric >0.8 using the 1,000 genome data set, ten and three independent SNPs were significantly associated with hair color and tanning ability respectively. Moreover, five independent FTO SNPs showed nominally significant association with risk of melanoma in 1,804 cases and 1,026 controls. But none of them was associated with obesity or in linkage disequilibrium with obesity-related variants. FTO locus may confer variation in human pigmentation and risk of melanoma, which may be independent of its effect on obesity. [ABSTRACT FROM AUTHOR]

• Long-term exposure to ambient PM was associated with decreased leukocyte mtDNAcn. • MtDNAcn may be influenced by the concentration, duration and size of PM exposure. • Husband's education and season modified the association between PM 2.5 and mtDNAcn. Ambient particulate matter (PM) has been associated with mitochondrial damage and dysfunction caused by excessive oxidative stress, but the associations between long-term PM exposure and leukocyte mitochondrial DNA copy number (mtDNAcn), a biomarker of mitochondrial dysfunction due to oxidative stress, are less studied. To investigate the associations between short-, intermediate- and long-term exposure (1-, 3- and 12-months) to different size fractions of PM (PM 2.5 , PM 2.5-10 and PM 10) and leukocyte mtDNAcn in a cross-sectional study. The associations between each of the PM exposure metrics with z scores of log-transformed mtDNAcn were examined using generalized linear regression models in 2758 female participants from the Nurses' Health Study (NHS). Monthly exposures to PM were estimated from spatio-temporal prediction models matched to each participants' address history. Potential effect modification by selected covariates was examined using multiplicative interaction terms and subgroup analyses. In single-size fraction models, increases in all size fractions of PM were associated with decreases in mtDNAcn, although only models with longer averages of PM 2.5 reached statistical significance. For example, an interquartile range (IQR) increase in 12-month average ambient PM 2.5 (5.5 μg/m3) was associated with a 0.07 [95% confidence interval (95% CI): −0.13, −0.01; p -value = 0.02] decrease in mtDNAcn z score in both basic- and multivariable-adjusted models. Associations for PM 2.5 were stronger after controlling for PM 2.5-10 in two size-fraction models. Our study suggests that long-term exposure to ambient PM 2.5 is associated with decreased mtDNAcn in healthy women. [ABSTRACT FROM AUTHOR]

Because aberrant glycosylation is known to play a role in the progression of melanoma, we hypothesize that genetic variants of glycosylation pathway genes are associated with the survival of cutaneous melanoma (CM) patients. To test this hypothesis, we used a Cox proportional hazards regression model in a single-locus analysis to evaluate associations between 34,096 genetic variants of 227 glycosylation pathway genes and CM disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies. The discovery dataset included 858 CM patients with 95 deaths from The University of Texas MD Anderson Cancer Center, and the replication dataset included 409 CM patients with 48 deaths from Harvard University nurse/physician cohorts. In the multivariable Cox regression analysis, we found that two novel single-nucleotide polymorphisms (SNPs) (ALG6 rs10889417 G>A and GALNTL4 rs12270446 G>C) predicted CMSS, with an adjusted hazards ratios of 0.60 (95% confidence interval = 0.44–0.83 and p = 0.002) and 0.66 (0.52–0.84 and 0.004), respectively. Subsequent expression quantitative trait loci (eQTL) analysis revealed that ALG6 rs10889417 was associated with mRNA expression levels in the cultured skin fibroblasts and whole blood cells and that GALNTL4 rs12270446 was associated with mRNA expression levels in the skin tissues (all p < 0.05). Our findings suggest that, once validated by other large patient cohorts, these two novel SNPs in the glycosylation pathway genes may be useful prognostic biomarkers for CMSS, likely through modulating their gene expression. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have identified more than a dozen loci associated with colorectal cancer (CRC) risk. Here, we examined potential effect-modification between single- nucleotide polymorphisms (SNP) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23), rs6983267 at 8q24 (MYC), rs10795668 at 10p14 (FLJ3802842), rs3802842 at 11q23 (LOC120376), rs4444235 at 14q22.2 (BMP4), rs4779584 at 15q13 (GREM1), rs9929218 at 16q22.1 (CDH1), rs4939827 at 18q21 (SMAD7), rs10411210 at 19q13.1 (RHPN2), and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/nonsteroidal anti- inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal interaction - 1.3 x 10 ; adjusted P ~ 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS seems to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption. [ABSTRACT FROM AUTHOR]