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2.  Synaptic and Cognitive Improvements by Inhibition of 2-AG Metabolism Are through Upregulation of MicroRNA-188-3p in a Mouse Model of Alzheimer's Disease 
The Journal of Neuroscience  2014;34(45):14919-14933.
Abnormal accumulation of β-amyloid (Aβ) is the major neuropathological hallmark of Alzheimer's disease (AD). However, the mechanisms underlying aberrant Aβ formation in AD remain unclear. We showed previously that inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, robustly reduces Aβ by inhibiting β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme responsible for Aβ formation. However, the molecular mechanisms responsible for suppression of BACE1 by inhibition of 2-AG metabolism are largely unknown. We demonstrate here that expression of the noncoding small RNA miR-188-3p that targets BACE1 was significantly downregulated both in the brains of AD humans and APP transgenic (TG) mice, a mouse model of AD. The downregulated miR-188-3p expression was restored by MAGL inhibition. Overexpression of miR-188-3p in the hippocampus reduced BACE1, Aβ, and neuroinflammation and prevented deteriorations in hippocampal basal synaptic transmission, long-term potentiation, spatial learning, and memory in TG mice. 2-AG-induced suppression of BACE1 was prevented by miR-188-3p loss of function. Moreover, miR-188-3p expression was upregulated by 2-AG or peroxisome proliferator-activated receptor-γ (PPARγ) agonists and suppressed by PPARγ antagonism or NF-κB activation. Reducing Aβ and neuroinflammation by MAGL inhibition was occluded by PPARγ antagonism. In addition, BACE1 suppression by 2-AG and PPARγ activation was eliminated by knockdown of NF-κB. Our study provides a novel molecular mechanism underlying improved synaptic and cognitive function in TG mice by 2-AG signaling, which upregulates miR-188-3p expression through PPARγ and NF-κB signaling pathway, resulting in suppressions of BACE1 expression and Aβ formation.
doi:10.1523/JNEUROSCI.1165-14.2014
PMCID: PMC4220026  PMID: 25378159
endocannabinoids; miRNA sponge; monoacylglycerol lipase; NF-κB; noncoding small RNA; PPARγ
3.  (PS)2: protein structure prediction server version 3.0 
Nucleic Acids Research  2015;43(Web Server issue):W338-W342.
Protein complexes are involved in many biological processes. Examining coupling between subunits of a complex would be useful to understand the molecular basis of protein function. Here, our updated (PS)2 web server predicts the three-dimensional structures of protein complexes based on comparative modeling; furthermore, this server examines the coupling between subunits of the predicted complex by combining structural and evolutionary considerations. The predicted complex structure could be indicated and visualized by Java-based 3D graphics viewers and the structural and evolutionary profiles are shown and compared chain-by-chain. For each subunit, considerations with or without the packing contribution of other subunits cause the differences in similarities between structural and evolutionary profiles, and these differences imply which form, complex or monomeric, is preferred in the biological condition for the subunit. We believe that the (PS)2 server would be a useful tool for biologists who are interested not only in the structures of protein complexes but also in the coupling between subunits of the complexes. The (PS)2 is freely available at http://ps2v3.life.nctu.edu.tw/.
doi:10.1093/nar/gkv454
PMCID: PMC4489310  PMID: 25943546
4.  Homeostatic regulation of brain functions by endocannabinoid signaling 
Neural Regeneration Research  2015;10(5):691-692.
doi:10.4103/1673-5374.156947
PMCID: PMC4468750  PMID: 26109933
5.  Dihydroaustrasulfone Alcohol Inhibits PDGF-Induced Proliferation and Migration of Human Aortic Smooth Muscle Cells through Inhibition of the Cell Cycle 
Marine Drugs  2015;13(4):2390-2406.
Dihydroaustrasulfone alcohol is the synthetic precursor of austrasulfone, which is a marine natural product, isolated from the Taiwanese soft coral Cladiella australis. Dihydroaustrasulfone alcohol has anti-inflammatory, neuroprotective, antitumor and anti-atherogenic properties. Although dihydroaustrasulfone alcohol has been shown to inhibit neointima formation, its effect on human vascular smooth muscle cells (VSMCs) has not been elucidated. We examined the effects and the mechanisms of action of dihydroaustrasulfone alcohol on proliferation, migration and phenotypic modulation of human aortic smooth muscle cells (HASMCs). Dihydroaustrasulfone alcohol significantly inhibited proliferation, DNA synthesis and migration of HASMCs, without inducing cell death. Dihydroaustrasulfone alcohol also inhibited platelet-derived growth factor (PDGF)-induced expression of cyclin-dependent kinases (CDK) 2, CDK4, cyclin D1 and cyclin E. In addition, dihydroaustrasulfone alcohol inhibited PDGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas it had no effect on the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/(Akt). Moreover, treatment with PD98059, a highly selective ERK inhibitor, blocked PDGF-induced upregulation of cyclin D1 and cyclin E and downregulation of p27kip1. Furthermore, dihydroaustrasulfone alcohol also inhibits VSMC synthetic phenotype formation induced by PDGF. For in vivo studies, dihydroaustrasulfone alcohol decreased smooth muscle cell proliferation in a rat model of restenosis induced by balloon injury. Immunohistochemical staining showed that dihydroaustrasulfone alcohol noticeably decreased the expression of proliferating cell nuclear antigen (PCNA) and altered VSMC phenotype from a synthetic to contractile state. Our findings provide important insights into the mechanisms underlying the vasoprotective actions of dihydroaustrasulfone alcohol and suggest that it may be a useful therapeutic agent for the treatment of vascular occlusive disease.
doi:10.3390/md13042390
PMCID: PMC4413217  PMID: 25898413
dihydroaustrasulfone alcohol; vascular smooth muscle cell; proliferation; migration; phenotypic modulation; cell cycle; restenosis
6.  Interleukin-10 promotor -592A/C polymorphism is associated with slow coronary flow in Han Chinese 
An accumulating body of evidence suggests that slow coronary flow (SCF) phenomenon seems to be an early-form of atherosclerosis and low-grade inflammation plays a major role in the atherosclerotic vascular processes. Interleukin (IL)-10 is a multifunctional cytokine involved in both innate and adaptive immune response. The aim of the present study is to investigate the association of IL-10 gene -592A/C polymorphism with SCF in Han Chinese. 250 patients who underwent coronary angiography and had angiographically normal coronary arteries of varying coronary flow rates without any atherosclerotic lesion were enrolled in this study. Patients who had thrombolysis in myocardial infarction frame counts (TFC) above the normal cutoffs were considered to have SCF and those within normal limits were considered to have normal coronary flow (NCF). The PCR-based restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotypes frequencies. The distribution of the IL-10 -592A/C genotypes (AA, AC, and CC) was 46.34%, 41.46%, and 12.20% in the NCF group, and 66.51%, 28.71%, and 4.78% in SCF subjects, respectively (P = 0.0280). The frequency of the A allele in the SCF group was significantly higher than that in the NCF group (80.86% vs. 67.07%, P = 0.0054). Compared with the CC genotype, the AA genotype had increased risk of SCF in both unadjusted and adjusted analyses. In SCF patients, the average serum IL-10 levels in AA genotype were statistically lower than in AC + CC genotype (P = 0.0000). These findings suggest that IL-10 -592A/C polymorphism is associated with SCF and the A allele has increased risk for SCF in Han Chinese.
PMCID: PMC4466984  PMID: 26097597
Slow coronary flow; interleukin-10; genetic polymorphism; coronary artery disease; Chinese
7.  Let-7 microRNAs Regenerate Peripheral Nerve Regeneration by Targeting Nerve Growth Factor 
Molecular Therapy  2014;23(3):423-433.
Peripheral nerve injury is a common clinical problem. Nerve growth factor (NGF) promotes peripheral nerve regeneration, but its clinical applications are limited by several constraints. In this study, we found that the time-dependent expression profiles of eight let-7 family members in the injured nerve after sciatic nerve injury were roughly similar to each other. Let-7 microRNAs (miRNAs) significantly reduced cell proliferation and migration of primary Schwann cells (SCs) by directly targeting NGF and suppressing its protein translation. Following sciatic nerve injury, the temporal change in let-7 miRNA expression was negatively correlated with that in NGF expression. Inhibition of let-7 miRNAs increased NGF secretion by primary cultured SCs and enhanced axonal outgrowth from a coculture of primary SCs and dorsal root gangalion neurons. In vivo tests indicated that let-7 inhibition promoted SCs migration and axon outgrowth within a regenerative microenvironment. In addition, the inhibitory effect of let-7 miRNAs on SCs apoptosis might serve as an early stress response to nerve injury, but this effect seemed to be not mediated through a NGF-dependent pathway. Collectively, our results provide a new insight into let-7 miRNA regulation of peripheral nerve regeneration and suggest a potential therapy for repair of peripheral nerve injury.
doi:10.1038/mt.2014.220
PMCID: PMC4351454  PMID: 25394845
8.  Association of marijuana smoking with oropharyngeal and oral tongue cancers: Pooled analysis from the INHANCE Consortium 
Background
The incidence of oropharyngeal and oral tongue cancers have increased over the last twenty years which parallels increased use of marijuana among individuals born after 1950.
Methods
Pooled analysis of individual-level data from nine case-control studies from the U.S. and Latin America in the INHANCE consortium. Self-reported information on marijuana smoking, demographic, and behavioral factors was obtained from 1,921 oropharyngeal cases, 356 oral tongue cases, and 7,639 controls.
Results
Compared with never marijuana smokers, ever marijuana smokers had an elevated risk of oropharyngeal (adjusted odds ratio [aOR]: 1.24; 95% confidence interval [CI]: 1.06, 1.47) and a reduced risk of oral tongue cancer (aOR: 0.47; 95% CI: 0.29, 0.75). The risk of oropharyngeal cancer remained elevated among never tobacco and alcohol users. The risk of oral tongue cancer decreased with increasing frequency (ptrend=0.005), duration (ptrend=0.002), and joint-years of marijuana use (ptrend=0.004), and was reduced among never users tobacco and alcohol users. Sensitivity analysis adjusting for potential confounding by HPV exposure attenuated the association of marijuana use with oropharyngeal cancer (aOR: 0.99; 95% CI: 0.71, 1.25), but had no effect on the oral tongue cancer association.
Conclusions
These results suggest that the association of marijuana use with Head and Neck Carcinoma may differ by tumor site.
Impact
The associations of marijuana use with oropharyngeal and oral tongue cancer are consistent with both possible pro- and anti-carcinogenic effects of cannabinoids. Additional work is needed to rule out various sources of bias, including residual confounding by HPV infection and misclassification of marijuana exposure.
doi:10.1158/1055-9965.EPI-13-0181
PMCID: PMC3947141  PMID: 24351902
marijuana; oropharynx; oral tongue; INHANCE; human papillomavirus
9.  Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer 
Wang, Yufei | McKay, James D. | Rafnar, Thorunn | Wang, Zhaoming | Timofeeva, Maria | Broderick, Peter | Zong, Xuchen | Laplana, Marina | Wei, Yongyue | Han, Younghun | Lloyd, Amy | Delahaye-Sourdeix, Manon | Chubb, Daniel | Gaborieau, Valerie | Wheeler, William | Chatterjee, Nilanjan | Thorleifsson, Gudmar | Sulem, Patrick | Liu, Geoffrey | Kaaks, Rudolf | Henrion, Marc | Kinnersley, Ben | Vallée, Maxime | LeCalvez-Kelm, Florence | Stevens, Victoria L. | Gapstur, Susan M. | Chen, Wei V. | Zaridze, David | Szeszenia-Dabrowska, Neonilia | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Mates, Dana | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Krokan, Hans E. | Gabrielsen, Maiken Elvestad | Skorpen, Frank | Vatten, Lars | Njølstad, Inger | Chen, Chu | Goodman, Gary | Benhamou, Simone | Vooder, Tonu | Valk, Kristjan | Nelis, Mari | Metspalu, Andres | Lener, Marcin | Lubiński, Jan | Johansson, Mattias | Vineis, Paolo | Agudo, Antonio | Clavel-Chapelon, Francoise | Bueno-de-Mesquita, H.Bas | Trichopoulos, Dimitrios | Khaw, Kay-Tee | Johansson, Mikael | Weiderpass, Elisabete | Tjønneland, Anne | Riboli, Elio | Lathrop, Mark | Scelo, Ghislaine | Albanes, Demetrius | Caporaso, Neil E. | Ye, Yuanqing | Gu, Jian | Wu, Xifeng | Spitz, Margaret R. | Dienemann, Hendrik | Rosenberger, Albert | Su, Li | Matakidou, Athena | Eisen, Timothy | Stefansson, Kari | Risch, Angela | Chanock, Stephen J. | Christiani, David C. | Hung, Rayjean J. | Brennan, Paul | Landi, Maria Teresa | Houlston, Richard S. | Amos, Christopher I.
Nature genetics  2014;46(7):736-741.
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants of BRCA2-K3326X (rs11571833; odds ratio [OR]=2.47, P=4.74×10−20) and of CHEK2-I157T (rs17879961; OR=0.38 P=1.27×10−13). We also showed an association between common variation at 3q28 (TP63; rs13314271; OR=1.13, P=7.22×10−10) and lung adenocarcinoma previously only reported in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants having substantive effects on cancer risk from pre-existing GWAS data.
doi:10.1038/ng.3002
PMCID: PMC4074058  PMID: 24880342
10.  Biochemical and Functional Characterization of Charge-defined Subfractions of High-density Lipoprotein From Normal Adults 
Analytical chemistry  2013;85(23):11440-11448.
High-density lipoprotein (HDL) is regarded as atheroprotective because it provides antioxidant and anti-inflammatory benefits and plays an important role in reverse cholesterol transport. In this paper, we outline a novel methodology for studying the heterogeneity of HDL. Using anion-exchange chromatography, we separated HDL from 6 healthy individuals into 5 subfractions (H1 through H5) with increasing charge and evaluated the composition and biologic activities of each subfraction. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis showed that apolipoprotein (apo) AI and apoAII were present in all 5 subfractions; apoCI was present only in H1; and apoCIII and apoE were most abundantly present in H4 and H5. HDL-associated antioxidant enzymes such as lecithin-cholesterol acyltransferase, lipoprotein-associated phospholipase A2, and paraoxonase 1 were most abundant in H4 and H5. Lipoprotein isoforms were analyzed in each subfraction by using matrix-assisted laser desorption–time of flight mass spectrometry. To quantify other proteins in the HDL subfractions, we used the isobaric tags for relative and absolute quantitation approach followed by nanoflow liquid chromatography–tandem mass spectrometry analysis. Most antioxidant proteins detected were found in H4 and H5. The ability of each subfraction to induce cholesterol efflux from macrophages increased with increasing HDL electronegativity, with the exception of H5, which promoted the least efflux activity. In conclusion, anion-exchange chromatography is an attractive method for separating HDL into subfractions with distinct lipoprotein compositions and biologic activities. By comparing the properties of these subfractions, it may be possible to uncover HDL-specific proteins that play a role in disease.
doi:10.1021/ac402516u
PMCID: PMC3919464  PMID: 24171625
11.  Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling 
Cell  2013;155(5):1154-1165.
SUMMARY
Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.
doi:10.1016/j.cell.2013.10.042
PMCID: PMC3918429  PMID: 24267894
12.  Association of Interleukin-10 promotor polymorphisms with atrial fibrillation in Han Chinese 
There is an accumulating body of evidence indicating strong association between inflammation and the pathogenesis of atrial fibrillation (AF). IL-10 is a multifunctional anti-inflammatory cytokine that down-regulates cell-mediated immune responses and cytotoxic inflammatory responses. The aim of the present study is to investigate the association of IL-10 gene -592A/C polymorphism with AF in Han Chinese. 117 AF patients and 100 healthy volunteers were eligible for this study. The PCR-based restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotypes frequencies. The distribution of the IL-10 -592A/C genotypes (AA, AC, and CC) was 55.00%, 35.00%, and 10.00% in the controls, and 71.79%, 23.08%, and 5.13% in AF subjects, respectively (p = 0.0335). The frequency of the A allele in the AF group was significantly higher than that in the control group (83.33% vs 72.50%, p = 0.0063). Compared with the CC genotype, the AA genotype had increased risk of AF in both unadjusted and adjusted analyses. The average serum IL-10 levels in AA genotype were statistically lower than in AC + CC genotype (p = 0.0000). These findings suggest that IL-10 -592A/C polymorphism is associated with AF and the A allele has increased risk for AF in Han Chinese.
PMCID: PMC4276189  PMID: 25550931
Atrial fibrillation; interleukin-10; genetic polymorphism; Chinese
13.  Smoking and Diabetes: Does the Increased Risk Ever Go Away? 
American Journal of Epidemiology  2013;178(6):937-945.
Recent studies reported that smoking cessation leads to higher short-term risk of type 2 diabetes than continuing to smoke. However, the duration of increased diabetes risk following smoking cessation needs further investigation. We followed 135,906 postmenopausal women aged 50–79 years enrolled in the Women's Health Initiative between September 1, 1993, and December 31, 1998, over an average of 11 years to examine the association between smoking cessation and risk of diabetes using Cox proportional hazard multivariable-adjusted regression models. Compared with that for never smokers, the risk for diabetes was significantly elevated in current smokers (hazard ratio = 1.28, 95% confidence interval: 1.20, 1.36) but was even higher in women who quit smoking during the first 3 years of follow-up (hazard ratio = 1.43, 95% confidence interval: 1.26, 1.63). Among former smokers, the risk of diabetes decreased significantly as the time since quitting increased and was equal to that of never smokers following a cessation period of 10 years. In new quitters with low cumulative exposure (<20 pack-years), diabetes risk was not elevated following smoking cessation. In conclusion, the risk of diabetes in former smokers returns to that in never smokers 10 years after quitting, and even more quickly in lighter smokers.
doi:10.1093/aje/kwt071
PMCID: PMC3816526  PMID: 23817918
risk factors; smoking; smoking cessation; type 2 diabetes
14.  Interleukin-6 genotypes and serum levels in Chinese Hui population 
Interleukin-6 (IL-6) is a key pro-inflammatory cytokine involved in different physiologic and pathophysiologic processes, and circulating levels of IL-6 differ greatly between individuals. The Chinese Hui is one of the largest ethnic minorities, little is known about the distribution of IL-6 genetic variations and their effects on serum levels in Hui population. The aim of the present study is to determine the prevalence of -174G/C (rs1800795), -597G/A (rs1800797), and -634C/G (rs1800796) polymorphisms in the IL-6 gene promoter region and their association with IL-6 serum levels in the Ningxia Hui population. A total of 96 Hui subjects, (57 men and 39 women; mean age 49.65 ± 19.73 years) unrelated nationality residents in Ningxia Hui Autonomous Region were enrolled. Genotyping of the three polymorphisms were performed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) combined with gel electrophoresis and then confirmed by direct sequencing. The -174G/C (97.92% GG, 2.08% GC, and 0% CC) and -597G/A (98.96% GG, 1.04% GA, and 0% AA) polymorphisms were rare. The frequencies of -634C/G genotypes CC, CG, and GG were found to be 54.17%, 40.62%, and 5.21%, respectively in total studied subjects, the derived allele frequencies for the C and G alleles were 74.48% and 25.52%. Increased IL-6 levels were correlated with the IL-6 -634G allele carriers (CG+GG genotypes). The results suggest that IL-6 -174G/C and -597G/A are rare but -634C/G is common in the Ningxia Hui population, and the -634G allele is associated with circulating levels of IL-6.
PMCID: PMC4211798  PMID: 25356148
Interleukin-6; genetic polymorphism; Hui nationality; Chinese
15.  Low-Density Lipoprotein Electronegativity Is a Novel Cardiometabolic Risk Factor 
PLoS ONE  2014;9(9):e107340.
Background
Low-density lipoprotein (LDL) plays a central role in cardiovascular disease (CVD) development. In LDL chromatographically resolved according to charge, the most electronegative subfraction–L5–is the only subfraction that induces atherogenic responses in cultured vascular cells. Furthermore, increasing evidence has shown that plasma L5 levels are elevated in individuals with high cardiovascular risk. We hypothesized that LDL electronegativity is a novel index for predicting CVD.
Methods
In 30 asymptomatic individuals with metabolic syndrome (MetS) and 27 healthy control subjects, we examined correlations between plasma L5 levels and the number of MetS criteria fulfilled, CVD risk factors, and CVD risk according to the Framingham risk score.
Results
L5 levels were significantly higher in MetS subjects than in control subjects (21.9±18.7 mg/dL vs. 11.2±10.7 mg/dL, P:0.01). The Jonckheere trend test revealed that the percent L5 of total LDL (L5%) and L5 concentration increased with the number of MetS criteria (P<0.001). L5% correlated with classic CVD risk factors, including waist circumference, body mass index, waist-to-height ratio, smoking status, blood pressure, and levels of fasting plasma glucose, triglyceride, and high-density lipoprotein. Stepwise regression analysis revealed that fasting plasma glucose level and body mass index contributed to 28% of L5% variance. The L5 concentration was associated with CVD risk and contributed to 11% of 30-year general CVD risk variance when controlling the variance of waist circumference.
Conclusion
Our findings show that LDL electronegativity was associated with multiple CVD risk factors and CVD risk, suggesting that the LDL electronegativity index may have the potential to be a novel index for predicting CVD. Large-scale clinical trials are warranted to test the reliability of this hypothesis and the clinical importance of the LDL electronegativity index.
doi:10.1371/journal.pone.0107340
PMCID: PMC4159324  PMID: 25203525
16.  Cigarette, Cigar, and Pipe Smoking and the Risk of Head and Neck Cancers: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium 
American Journal of Epidemiology  2013;178(5):679-690.
Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend ≤ 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers.
doi:10.1093/aje/kwt029
PMCID: PMC3755640  PMID: 23817919
head and neck neoplasms; smoking
17.  Adult height and head and neck cancer: a pooled analysis within the INHANCE Consortium 
Background
Several epidemiological studies have shown a positive association between adult height and cancer incidence. The only study conducted among women on mouth and pharynx cancer risk, however, reported an inverse association. This study aims to investigate the association between height and the risk of head and neck cancer (HNC) within a large international consortium of HNC.
Methods
We analyzed pooled individual-level data from 24 case-control studies participating in the International Head and Neck Cancer Epidemiology Consortium. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) were estimated separately for men and women for associations between height and HNC risk. Educational level, tobacco smoking, and alcohol consumption were included in all regression models. Stratified analyses by HNC subsites were performed.
Results
This project included 17,666 cases and 28,198 controls. We found an inverse association between height and HNC (adjusted OR per 10 cm height =0.91, 95% CI 0.86–0.95 for men; adjusted OR=0.86, 95% CI 0.79–0.93 for women). In men, the estimated OR did vary by educational level, smoking status, geographic area, and control source. No differences by subsites were detected.
Conclusions
Adult height is inversely associated with HNC risk. As height can be considered a marker of childhood illness and low energy intake, the inverse association is consistent with prior studies showing that HNC occur more frequently among deprived individuals. Further studies designed to elucidate the mechanism of such association would be warranted.
doi:10.1007/s10654-013-9863-2
PMCID: PMC4122122  PMID: 24271556
18.  Type I and II Endometrial Cancers: Have They Different Risk Factors? 
Journal of Clinical Oncology  2013;31(20):2607-2618.
Purpose
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Patients and Methods
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Results
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
Conclusion
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
doi:10.1200/JCO.2012.48.2596
PMCID: PMC3699726  PMID: 23733771
19.  Exome-Wide Association Study of Endometrial Cancer in a Multiethnic Population 
PLoS ONE  2014;9(5):e97045.
Endometrial cancer (EC) contributes substantially to total burden of cancer morbidity and mortality in the United States. Family history is a known risk factor for EC, thus genetic factors may play a role in EC pathogenesis. Three previous genome-wide association studies (GWAS) have found only one locus associated with EC, suggesting that common variants with large effects may not contribute greatly to EC risk. Alternatively, we hypothesize that rare variants may contribute to EC risk. We conducted an exome-wide association study (EXWAS) of EC using the Infinium HumanExome BeadChip in order to identify rare variants associated with EC risk. We successfully genotyped 177,139 variants in a multiethnic population of 1,055 cases and 1,778 controls from four studies that were part of the Epidemiology of Endometrial Cancer Consortium (E2C2). No variants reached global significance in the study, suggesting that more power is needed to detect modest associations between rare genetic variants and risk of EC.
doi:10.1371/journal.pone.0097045
PMCID: PMC4014590  PMID: 24810602
20.  Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls 
Human genetics  2013;132(5):579-589.
Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10−6), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.
doi:10.1007/s00439-013-1270-y
PMCID: PMC3628758  PMID: 23370545
21.  Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study 
Background
In the Women’s Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied.
Methods
We identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n = 25 328) or estrogen and progestin users (n = 16 121). Multivariable-adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided.
Results
After a mean of 11.3 (SD = 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR = 1.55, 95% CI = 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR = 1.03, 95% CI = 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR = 1.32, 95% CI = 0.90 to 1.93, P = .15), and more all-cause deaths after breast cancer (HR = 1.65, 95% CI = 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers.
Conclusions
Consistent with WHI randomized trial findings, estrogen plus progestin use is associated with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected.
doi:10.1093/jnci/djt043
PMCID: PMC3691942  PMID: 23543779
22.  Estimation of the Exposure of the UK Population to the Bovine Spongiform Encephalopathy Agent through Dietary Intake During the Period 1980 to 1996 
PLoS ONE  2014;9(4):e94020.
Although the incidence of variant Creutzfeldt-Jakob disease (vCJD) has declined to 1 since 2012 in the UK, uncertainty remains regarding possible future cases and the size of the subclinical population that may cause secondary transmission of the disease through blood transfusion. Estimating the number of individuals who were exposed to the bovine spongiform encephalopathy (BSE) infectious agent and may be susceptible to vCJD will help to clarify related public health concerns and plan strategies. In this paper, we explore this estimate by describing the probability of potential exposure due to dietary intake throughout the BSE epidemic period from 1980 to 1996 as a stochastic Poisson process. We estimate the age- and gender-specific exposure intensities in food categories of beef and beef-containing dishes, burgers and kebabs, pies, and sausages, separating the two periods of 1980–1989 and 1990–1996 due to the specified bovine offal legislation of 1989. The estimated total number of (living) exposed individuals during each period is 5,089,027 (95% confidence interval [CI] 4,514,963–6,410,317), which was obtained by multiplying the population size of different birth cohorts by the probability of exposure via dietary intake and the probability of survival until the end of 2013. The estimated number is approximately doubled, assuming a contamination rate of . Among those individuals estimated, 31,855 (95% CI 26,849–42,541) are susceptible to infection. We also examined the threshold hypothesis by fitting an extreme-value distribution to the estimated infectious dose of the exposed individuals and obtained a threshold estimate of 13.7 bID50 (95% CI 6.6–26.2 bID50) (Weibull). The results provide useful information on potential carriers of prion disease who may pose a threat of infection via blood transfusion and thus provide insight into the likelihood of new incidents of vCJD occurring in the future.
doi:10.1371/journal.pone.0094020
PMCID: PMC3988046  PMID: 24736322
23.  Gender disparity in LDL-induced cardiovascular damage and the protective role of estrogens against electronegative LDL 
Background
Increased levels of the most electronegative type of LDL, L5, have been observed in the plasma of patients with metabolic syndrome (MetS) and ST-segment elevation myocardial infarction and can induce endothelial dysfunction. Because men have a higher predisposition to developing coronary artery disease than do premenopausal women, we hypothesized that LDL electronegativity is increased in men and promotes endothelial damage.
Methods
L5 levels were compared between middle-aged men and age-matched, premenopausal women with or without MetS. We further studied the effects of gender-influenced LDL electronegativity on aortic cellular senescence and DNA damage in leptin receptor–deficient (db/db) mice by using senescence-associated–β-galactosidase and γH2AX staining, respectively. We also studied the protective effects of 17β-estradiol and genistein against electronegative LDL–induced senescence in cultured bovine aortic endothelial cells (BAECs).
Results
L5 levels were higher in MetS patients than in healthy subjects (P < 0.001), particularly in men (P = 0.001). LDL isolated from male db/db mice was more electronegative than that from male or female wild-type mice. In addition, LDL from male db/db mice contained abundantly more apolipoprotein CIII and induced more BAEC senescence than did female db/db or wild-type LDL. In the aortas of db/db mice but not wild-type mice, we observed cellular senescence and DNA damage, and the effect was more significant in male than in female db/db mice. Pretreatment with 17β-estradiol or genistein inhibited BAEC senescence induced by male or female db/db LDL and downregulated the expression of lectin-like oxidized LDL receptor-1 and tumor necrosis factor-alpha protein.
Conclusion
The gender dichotomy of LDL-induced cardiovascular damage may underlie the increased propensity to coronary artery disease in men.
doi:10.1186/1475-2840-13-64
PMCID: PMC3974745  PMID: 24666525
Electronegative low-density lipoprotein; Metabolic syndrome; Cardiovascular disease; Aortic senescence; 17β-estradiol; Genistein
24.  A 13-gene signature prognostic of HPV-negative OSCC: discovery and external validation 
Purpose
To identify a prognostic gene signature for HPV-negative OSCC patients.
Experimental Design
Two gene expression datasets were used; a training dataset from the Fred Hutchinson Cancer Research Center (FHCRC) (n=97), and a validation dataset from the MD Anderson Cancer Center (MDACC) (n=71). We applied L1/L2-penalized Cox regression models to the FHCRC data on the 131–gene signature previously identified to be prognostic in OSCC patients to identify a prognostic model specific for high-risk HPV-negative OSCC patients. The models were tested with the MDACC dataset using a receiver operating characteristic analysis.
Results
A 13-gene model was identified as the best predictor of HPV-negative OSCC-specific survival in the training dataset. The risk score for each patient in the validation dataset was calculated from this model and dichotomized at the median. The estimated 2-year mortality (± SE) of patients with high risk scores was 47.1 (±9.24)% compared with 6.35 (± 4.42)% for patients with low risk scores. ROC analyses showed that the areas under the curve for the age, gender, and treatment modality-adjusted models with risk score (0.78, 95%CI: 0.74-0.86) and risk score plus tumor stage (0.79, 95%CI: 0.75-0.87) were substantially higher than for the model with tumor stage (0.54, 95%CI: 0.48-0.62).
Conclusions
We identified and validated a 13-gene signature that is considerably better than tumor stage in predicting survival of HPV-negative OSCC patients. Further evaluation of this gene signature as a prognostic marker in other populations of patients with HPV-negative OSCC is warranted.
doi:10.1158/1078-0432.CCR-12-2647
PMCID: PMC3593802  PMID: 23319825
gene signature; prognosis; HPV-negative; OSCC
25.  Malondialdehyde mediates oxidized LDL-induced coronary toxicity through the Akt-FGF2 pathway via DNA methylation 
Background
Oxidized LDL (oxLDL) is involved in the development of atherosclerotic heart disease through a mechanism that is not fully understood. In this study, we examined the role of malondialdehyde (MDA), an important oxidative stress epitope of oxLDL, in mediating coronary endothelial cytotoxicity.
Results
Human coronary artery endothelial cells (HCAECs) were treated with oxLDL in the presence or absence of antibody against MDA (anti-MDA) or apoB100 (anti-apoB100). In HCAECs treated with oxLDL (100 μg/ml) alone, DNA synthesis, cell viability, and expression of prosurvival fibroblast growth factor 2 (FGF2) were significantly reduced (P < 0.01 vs phosphate buffered saline–treated cells). These inhibitory effects of oxLDL were significantly attenuated in HCAECs cotreated with anti-MDA (0.15 μg/ml; P < 0.05 vs oxLDL-treated cells), but not in those cotreated with anti-apoB100. When we tested the effects of a panel of signal transduction modifiers on the signal transduction pathways of MDA in oxLDL-treated HCAECs, we found that MDA-induced cytotoxicity was mediated partly through the Akt pathway. Using a reporter gene assay, we identified an oxLDL-response element in the FGF2 promoter that was responsible for the transcriptional repression of FGF2 by oxLDL. The results of bisulfite genomic DNA sequencing showed that in HCAECs treated with oxLDL, the GC-rich promoter of FGF2 was heavily methylated at cytosine residues, whereas cotreatment with anti-MDA markedly reduced oxLDL-induced FGF2 promoter methylation.
Conclusion
OxLDL disrupts the growth and survival of HCAECs through an MDA-dependent pathway involving methylation of the FGF2 promoter and repression of FGF2 transcription. This novel epigenetic mechanism of oxLDL may underlie its atherogenicity in patients with atherosclerotic cardiovascular disease.
doi:10.1186/1423-0127-21-11
PMCID: PMC3931320  PMID: 24490960
DNA methylation; Epigenetics; Gene expression; Lipid oxidation; Lipoproteins; Malondialdehyde (MDA); Signal transduction

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