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Background: Most of the subjects eligible for annual low‐dose computed tomography (LDCT) lung screening will not develop lung cancer for their life. It is important to identify novel biomarkers that can help identify those at risk of developing lung cancer and improve the efficiency of LDCT screening programs. Objective: This study aims to investigate the association between the morphology of the pulmonary circulatory system (PCS) and lung cancer development using LDCT scans acquired in the screening setting. Methods: We analyzed the PLuSS cohort of 3635 lung screening patients from 2002 to 2016. Circulatory structures were segmented and quantified from LDCT scans. The time from the baseline CT scan to lung cancer diagnosis, accounting for death, was used to evaluate the prognostic ability (i.e., hazard ratio (HR)) of these structures independently and with demographic factors. Five‐fold cross‐validation was used to evaluate prognostic scores. Results: Intrapulmonary vein volume had the strongest association with future lung cancer (HR = 0.63, p < 0.001). The joint model of intrapulmonary vein volume, age, smoking status, and clinical emphysema provided the strongest prognostic ability (HR = 2.20, AUC = 0.74). The addition of circulatory structures improved risk stratification, identifying the top 10% with 28% risk of lung cancer within 15 years. Conclusion: PCS characteristics, particularly intrapulmonary vein volume, are important predictors of lung cancer development. These factors significantly improve prognostication based on demographic factors and noncirculatory patient characteristics, particularly in the long term. Approximately 10% of the population can be identified with risk several times greater than average. [ABSTRACT FROM AUTHOR]

We evaluated whether aflatoxin B1 (AFB1) exposure was associated with later risk of developing gallbladder cancer (GBC). We measured AFB1‐lysine albumin adducts in baseline samples from the Shanghai Cohort Study of 18 244 men aged 45 to 64 years (recruited 1986‐1989). We included 84 GBC cases with sufficient serum and 168 controls matched on age at sample collection, date of blood draw and residence. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for detectable vs non‐detectable AFB1‐lysine albumin adducts and gallbladder cancer. AFB1‐lysine albumin adducts were detected in 50.0% of GBC cases, and risk of GBC was twice as high in those with detectable vs undetectable levels (OR = 2.0, 95% CI = 1.0‐3.9). ORs ranged from 1.8 (95% CI = 0.75‐4.3) for 0.5 to <1.75 pg/mg vs undetectable adduct levels to 2.2 (95% CI = 0.91‐5.6) for >3.36 pg/mg vs undetectable, suggesting a dose‐response (Ptrend =.05). When restricted to cases diagnosed before the median time to diagnosis after blood draw (18.4 years), results were similar (OR = 2.2, 95% CI = 0.80‐5.8) to those for the entire follow‐up duration. The OR was 9.4 (95% CI = 1.7‐51.1) for individuals with detectable AFB1‐lysine albumin adducts and self‐reported gallstones compared to individuals with neither. Participants with detectable AFB1‐lysine albumin adducts at baseline had increased risk of developing GBC, replicating the previously observed association between AFB1 exposure and providing the first evidence of temporality. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) is a major contributor to the rising incidence of hepatocellular carcinoma (HCC). Magnesium is a major cation in cellular activities. Epidemiological data on magnesium level and its relation to HCC are sparse. This study aimed to examine the associations between serum levels of magnesium and the risk of HCC among patients with NAFLD. Methods: A total of 26,053 patients with NAFLD were identified in the University of Pittsburgh Medical Center Electronic Health Records from 2004 through 2018. After an average of 5.15 years of follow‐up, 395 patients developed HCC after the first measurement of serum magnesium. Cox proportional hazards regression model was used to calculate hazard ratios (HRs) and 95% CIs of HCC incidence associated with quartile levels of serum magnesium after adjustment for age, sex, race, body mass index, diuretics use, history of type 2 diabetes, history of hypertension, history of hyperlipidemia, and tobacco smoking. Results: Patients with NAFLD who developed HCC had a significantly lower mean (± standard deviation) serum magnesium (0.769 ± 0.131 mmol/L) than those who remained free of HCC (0.789 ± 0.125 mmol/L; p =.003). Compared with the lowest quartile, the HRs (95% CIs) of HCC second, third, and fourth quartiles of serum magnesium were 0.87 (0.67–1.12), 0.77 (0.57–1.04), and 0.73 (0.56–0.96), respectively, after adjustment for multiple potential confounders (Ptrend =.02). Conclusion: This finding suggests higher levels of serum magnesium were significantly associated with decreased risk of HCC among patients with NAFLD. Monitoring serum magnesium levels among those with nonalcoholic fatty liver disease may be beneficial in hepatocellular carcinoma primary prevention. [ABSTRACT FROM AUTHOR]

Background: Blood neutrophil to lymphocyte ratio (NLR) or lymphocyte count may be important markers for immune function. Previous work has shown higher NLR was associated with higher risk of hepatitis B‐related hepatocellular carcinoma (HCC). However, studies in non‐alcoholic fatty liver disease (NAFLD) patients are lacking. Methods: Utilizing the University of Pittsburgh Medical Center (UPMC) electronic health records, we created a retrospective cohort of 27,834 patients diagnosed with NAFLD from 2004 to 2018 with complete NLR data. After an average 5.5 years of follow‐up, 203 patients developed HCC. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of HCC incidence associated with different levels of NLR and lymphocyte count. Results: Compared with the lowest tertile of NLR (<1.97), the highest tertile of NLR (≥3.09) was statistically significantly associated with a 43% higher risk of HCC incidence (HR = 1.43, 95% CI: 1.01–2.03, ptrend = 0.031) after adjustment for age, sex, race, body mass index, smoking status, history of type 2 diabetes, hyperlipidemia, hypertension, and fibrosis‐4 score category. Conversely the highest tertile of lymphocyte count (≥2.15 K/ul) was significantly associated with a 36% lower risk of HCC (HR = 0.64, 95% CI: 0.43–0.94, ptrend = 0.028) compared to the lowest tertile (<1.55 K/ul). There was no association between neutrophil count and HCC risk. Conclusions: Higher NLR and lower lymphocyte count are associated with significantly higher risk of HCC among NAFLD patients. These findings warrant further investigation of immune response and surveillance in association with HCC development in NAFLD patients. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a major contributor to cancer death globally. Several studies showed some protections by certain individual dietary antioxidants against CRC development. Epidemiologic data on the composite dietary antioxidant index (CDAI) in relation to CRC risk are sparse. Using the Singapore Chinese Health Study, an ongoing prospective cohort consisting of 61 321 cancer‐free participants aged 45 to 74 years at baseline, a food‐based CDAI was calculated according to a previously established and validated method that included six food‐sourced antioxidants including vitamins A, C and E, manganese, selenium and zinc. Cox proportional hazard regression method was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for CRC associated with various levels of CDAI with adjustment for multiple potential confounders. After an average of 17.5 years of follow‐up, 2140 participants developed CRC. HRs (95% CIs) of CRC for quartiles 2, 3 and 4 of CDAI were 0.94 (0.83‐1.07), 0.86 (0.75‐1.00) and 0.80 (0.66‐0.98), respectively, compared to the lowest quartile (Ptrend =.02). This inverse association between CDAI and CRC risk was more apparent in women or those without a history of diabetes, without family history of CRC, never smokers or overweight/obese individuals. However, none of the heterogeneity tests for the CDAI‐CRC risk association reached statistical significance. Our findings suggest that food‐based antioxidants may be beneficial for reducing the risk of CRC in the general population. What's new? Epidemiological studies on individual dietary antioxidants such as vitamins and minerals and the risk of colorectal cancer have produced inconsistent results. In this large prospective Asian cohort study, the authors apply a recently developed composite dietary antioxidant index (CDAI) that includes vitamins A, C and E, manganese, selenium and zinc. The analysis shows that a higher CDAI is associated with a lower risk of developing CRC overall. These findings support the notion that food‐based antioxidants may offer a beneficial effect and provide a potential strategy for the primary prevention of colorectal cancer. [ABSTRACT FROM AUTHOR]

There is limited research on the effect of dietary quality on hepatocellular carcinoma (HCC) risk in populations with relatively high risk of HCC. Using data from Singapore Chinese Health Study, a prospective cohort study, of 63 257 Chinese aged 45 to 74, we assessed four diet‐quality index (DQI) scores: the Alternative Health Eating Index‐2010 (AHEI‐2010), Alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH) and Heathy Diet Indicator (HDI). We identified 561 incident HCC cases among the cohort participants after a mean of 17.6 years of follow‐up. Cox proportional hazard regression model was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for HCC in relation to these DQI scores. Unconditional logistic regression method was used to evaluate the associations between DQIs and HCC risk among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg). High scores of AHEI‐2010, aMED and DASH, representing higher dietary quality, were associated with lower risk of HCC (all Ptrend <.05). Compared with the lowest quartile, HRs (95% CIs) of HCC for the highest quartile of AHEI‐2010, aMED and DASH were 0.69 (0.53‐0.89), 0.70 (0.52‐0.95) and 0.67 (0.51‐0.87), respectively. No significant association between HDI and HCC risk was observed. Among HBsAg‐negative individuals, similar inverse associations were observed, and the strongest inverse association was for aMED (HRQ4vsQ1 = 0.46, 95% CI: 0.23‐0.94, Ptrend =.10). These findings support the notion that adherence to a healthier diet may lower the risk of HCC, suggesting that dietary modification may be an effective approach for primary prevention of HCC. What's new? Can improving the daily diet of high‐risk populations lower their risk of hepatocellular carcinoma (HCC)? In this large, prospective Asian study, the authors found that the answer is yes. Three different diet‐quality index (DQI) scores were associated with a significant drop in HCC risk, by as much as 30%. These included the AHEI‐2010, aMED, and DASH. These findings suggest that public‐health programs emphasizing dietary modification may offer an effective strategy for the prevention of HCC. [ABSTRACT FROM AUTHOR]

Background: Weight loss is recommended as the primary treatment for nonalcoholic fatty liver disease (NAFLD). However, the magnitude and velocity of hepatic steatosis resolution with weight loss is unclear, making it difficult to counsel patients seeking weight loss for treatment of NAFLD. The aim of this study was to determine the rate of hepatic steatosis improvement and stool microbiome changes associated with rapid diet‐induced weight loss in NAFLD. Methods: Fourteen NAFLD patients (mean ± standard deviation, body mass index [BMI] 36.4 ± 4 kg/m2) enrolled in a 12‐week meal replacement program underwent frequent measurement of Fibroscan‐controlled attenuation parameter (CAP). Magnetic resonance imaging (MRI‐Dixon method) for hepatic fat quantitation and stool microbiome analysis (16S rRNA gene sequencing) were completed in 11 subjects at baseline and Week 12. Results: At Week 12, mean (95% confidence interval) weight loss was −13.4 (−15.2, −11.5)% and CAP score −26.6 (−35.6, −17.6)% (both Ps < 0.001). CAP scores changed at a rate of −4.9 dB/m/kg (−30.1 dB/m per unit BMI) in Weeks 1–4 and −0.6 dB/m/kg (−2.4 dB/m per unit BMI) in Weeks 8–12. MRI‐determined hepatic fat fraction decreased by −74.1% (p < 0.001) at a rate of −0.51%/kg (−3.19% per unit BMI), with complete steatosis resolution in 90% patients. BMI change was associated with decreased stool microbial diversity (coefficient = 0.17; Shannon Index), increased abundance of Prevotella_9 (Bacteroidetes; coefficient = 0.96) and decreased abundance of Phascolarctobacterium (Firmicutes; coefficient = −0.42) (both Ps < 0.05). Conclusions: Diet‐induced intensive weight loss is associated with rapid improvement and complete resolution of hepatic steatosis and decreased stool microbial diversity. These findings highlight the dynamic nature of hepatic fat and may help clinicians to develop evidence‐based treatment goals for patients with NAFLD and obesity who undertake weight loss interventions. Further research is warranted to understand the effects of intensive weight loss and gut microbiome changes on long‐term NAFLD resolution. [ABSTRACT FROM AUTHOR]

Telomeres play a key role in chromosomal maintenance and stability. To date, few studies have investigated the association of leukocyte telomere length with risk of cancer incidence and all‐cause mortality in a large prospective cohort, particularly of the Asian population. Relative telomere lengths in genomic DNA from peripheral blood samples were quantified using a validated quantitative real‐time PCR among 26 540 middle‐aged or older Chinese adults. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer and deaths by quintiles of telomere length were calculated using the Cox proportional hazards regression method with adjustment for age, sex and other potential confounders. After baseline blood collection, 4353 persons developed cancer and 7609 died. Participants with the longest decile of telomeres had a 26% (95% CI: 11%‐44%) higher risk of total cancer incidence compared to the shortest decile after controlling for age, sex and other potential founders (Ptrend <.0001). In contrast, longer telomeres were associated with lower risk of all‐cause mortality (HR = 0.93; 95% CI: 0.84‐1.03), noncancer death (HR = 0.81; 95% CI: 0.71‐0.92), specifically, death from chronic obstructive pulmonary disease and pneumonia (HR = 0.79, 95% CI: 0.70‐0.89) and digestive diseases (HR = 0.60, 95% CI: 0.42‐0.88). Our findings demonstrated that longer telomeres are associated with increased risk of cancer development overall and several common cancer types including breast, rectal, prostate, pancreatic cancer and lung adenocarcinoma. Our study also confirmed that longer telomeres are associated with a reduced risk of noncancer related death. What's new? Telomere length is a promising biomarker for cancer risk, with longer‐ and shorter‐than‐expected telomeres variously linked to increased risk of malignancy. Among Asian populations, however, relationships between telomere length, cancer incidence, and cancer mortality remain understudied. Here, investigation of more than 26 500 Chinese adults with greater than 12 years of health follow‐up shows that longer telomere length is associated with significantly elevated risk of total and cancer‐specific incidence and mortality and with reduced risk of all‐cause and non‐cancer‐related mortality. The data highlight the relevance of longer telomere length in the development and outcome of specific cancer types and non‐cancerous diseases. [ABSTRACT FROM AUTHOR]

Deficiencies in methyl donor status may render DNA methylation changes and DNA damage, leading to carcinogenesis. Epidemiological studies reported that higher dietary intake of choline is associated with lower risk of pancreatic cancer, but no study has examined the association of serum choline and its metabolites with risk of pancreatic cancer. Two parallel case–control studies, one nested within the Shanghai Cohort Study (129 cases and 258 controls) and the other within the Singapore Chinese Health Study (58 cases and 104 controls), were conducted to evaluate the associations of baseline serum concentrations of choline, betaine, methionine, total methyl donors (i.e., sum of choline, betaine and methionine), dimethylglycine and trimethylamine N‐oxide (TMAO) with pancreatic cancer risk. In the Shanghai cohort, odds ratios and 95% confidence intervals of pancreatic cancer for the highest quartile of choline, betaine, methionine, total methyl donors and TMAO were 0.27 (0.11–0.69), 0.57 (0.31–1.05), 0.50 (0.26–0.96), 0.37 (0.19–0.73) and 2.81 (1.37–5.76), respectively, compared to the lowest quartile. The corresponding figures in the Singapore cohort were 0.85 (0.23–3.17), 0.50 (0.17–1.45), 0.17 (0.04–0.68), 0.33 (0.10–1.16) and 1.42 (0.50–4.04). The inverse associations of methionine and total methyl donors including choline, betaine and methionine with pancreatic cancer risk in both cohorts support that DNA repair and methylation play an important role against the development of pancreatic cancer. In the Shanghai cohort, TMAO, a gut microbiota‐derived metabolite of dietary phosphatidylcholine, may contribute to higher risk of pancreatic cancer, suggesting a modifying role of gut microbiota in the dietary choline‐pancreatic cancer risk association. What's new? Over half of all pancreatic cancers aren't associated with known risk factors. In this prospective study, the authors examined serum levels of three nutrients (choline, methionine, and betaine) that have been associated with reduced oxidative DNA damage and epigenetic changes such as methylation. They found that, as predicted, higher serum levels of these nutrients were correlated with lower pancreatic cancer risk. They also found that certain compounds associated with gut microbiota increased this risk. These results identify novel etiological factors that may guide future prevention strategies for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Cell‐mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking‐matched case–control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry‐based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20–30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15–1.75), 1.42 (1.14–1.76) and 1.45 (1.13–1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan–kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression. What's new? The kynurenine pathway, by which tryptophan is degraded and NAD+ is synthesized, plays a role in inflammation and immune response. It may also be involved in cancer development and progression. Here, the authors investigated the relationship between the metabolites of the kynurenine pathway and risk of lung cancer. They found that lower levels of tryptophan and higher levels of kynurenine and quinolinic acid were associated with increased risk of lung cancer, especially in smokers. These biomarkers may be signs that immune suppression in the tumor microenvironment may boost cancer progression. [ABSTRACT FROM AUTHOR]

Specific organochlorines (OCs) have been associated with non‐Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g., dichlorodiphenyltrichloroethane [DDT], hexachlorocyclohexane [HCH]) are different from Western populations. We evaluated NHL risk and prediagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl congeners in a case–control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid‐adjusted OC levels and NHL risk. Median levels of p,p′‐dichlorodiphenyldichloroethylene (p,p′‐DDE), the primary DDT metabolite, and β‐HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher β‐HCH levels both overall (3rd vs. 1st tertile OR = 1.8, 95%CI = 1.0–3.2; ptrend = 0.049) and after excluding cases diagnosed within 2 years of blood collection (3rd vs. 1st tertile OR = 2.0, 95%CI = 1.1–3.9; ptrend = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p′‐DDE. Our findings provide support for an association between β‐HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p′‐DDE do not support an association. What's new? Organochlorines (OC) are environmentally persistent organic pollutants that have been associated with cancer risk. Here the authors conducted a prospective study of blood OC levels and risk of non‐Hodgkin lymphoma (NHL) in Asia, where high exposures and historical environmental contamination of certain OC pesticides have been reported. They find an association between risk of NHL and higher levels of β‐hexachlorocyclohexane, median levels of which were up to 65‐times higher in the Asian samples than in samples from several Western populations. These results add to the weight of evidence that environmental exposure to HCH is carcinogenic. [ABSTRACT FROM AUTHOR]

Incidence rates of non‐Hodgkin lymphoma (NHL) and distributions of certain viruses differ between East Asian and Western populations. There are limited data on associations between serologic markers of multiple viral infections in pre‐diagnostic blood and NHL risk in East Asians. We conducted a nested case‐control study of 214 NHL cases and 214 matched controls from three population‐based prospective cohorts in Shanghai and Singapore. Antibodies against antigens from herpesviruses, Hepatitis B (HBV) and C (HCV) virus and polyomaviruses were measured in plasma or serum using fluorescent bead‐based multiplex assays. Conditional logistic regression was used to evaluate associations between antibody levels and NHL risk. An increased risk of NHL was observed for higher compared to lower EA‐D (Odds Ratio (OR) = 2.04, 95% Confidence Interval (CI) = 1.10‐3.81; ptrend = 0.005) and ZEBRA (OR = 2.17, 95% CI = 0.96‐4.89; ptrend = 0.008) Epstein‐Barr Virus (EBV) antibodies, as well as for antibody seropositivity against the IE1A human herpesvirus‐6 (HHV‐6) antigen (OR = 1.85, 95% CI = 1.04‐3.29). An increased NHL risk was also observed for higher compared to lower antibodies against the HBV‐HBc and HBe antigens. An increased risk of NHL in relation to EBV and HBV infection in East Asians is consistent with findings in several studies of Western populations, suggesting similar viral risk factors for NHL in these diverse populations with distinct patterns of NHL. The association between HHV‐6 antibodies and NHL has not previously been reported in a prospective study in this population and will require replication. [ABSTRACT FROM AUTHOR]

Telomeres are crucial in the maintenance of chromosome integrity and genomic stability. Critically short telomeres can trigger programed cell death while cells with longer telomeres may have increased likelihood of replicative errors, resulting in genetic mutations and chromosomal alterations, and ultimately promoting oncogenesis. Data on telomere length and lung cancer risk from large prospective cohort studies are spare. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiplex quantitative polymerase chain reaction (qPCR) method in 26,540 participants of the Singapore Chinese Health Study. After a follow‐up of 12 years, 654 participants developed lung cancer including 288 adenocarcinoma, 113 squamous cell carcinoma and 253 other/unknown histological type. The Cox proportional hazard regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI). HR of lung adenocarcinoma for individuals in the highest comparing the lowest 20 percentile of telomere length was 2.84 (95% CI 1.94–4.14, ptrend < 0.0001). This positive association was present in never smokers (ptrend < 0.0001), ever smokers (ptrend = 0.0010), men (ptrend = 0.0003), women (ptrend < 0.0001), and in shorter (ptrend = 0.0002) and longer (ptrend = 0.0001) duration of follow‐up. There was no association between telomere length and risk of squamous cell carcinoma or other histological type of lung cancer in all or subgroups of individuals. The agreement of results from this prospective cohort study with those of previous prospective studies and Mendelian randomization studies suggest a possible etiological role of telomere length in the development of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Our recent studies on tobacco smoke carcinogen and toxicant biomarkers and cancer risk among male smokers in the Shanghai Cohort Study showed that exposure to tobacco-specific nitrosamines (TSNA) and polycyclic aromatic hydrocarbons (PAH) is prospectively associated with the risk of cancer. These findings support the hypothesis that the smokers' cancer risk is a function of the dose of select tobacco carcinogens and highlight the importance of understanding the factors that affect the intake of these carcinogens by smokers. Given that tobacco constituent exposures are driven, at least in part, by the levels of these constituents in cigarette smoke, we measured mainstream smoke TSNA and PAH levels in 43 Chinese cigarette brands that participants of the Shanghai Cohort Study reported to smoke. In all brands analyzed here, mainstream smoke levels of NNN and NNK, the two carcinogenic TSNA, were generally relatively low, averaging (±SD) 16.8(±25.1) and 14.2(±9.5) ng/cigarette, respectively. The levels of PAH were comparable to those found in U.S. cigarettes, averaging 15(±9) ng/cigarette for benzo[ a]pyrene, 119(±66) ng/cigarette for phenanthrene and 37(±19) ng/cigarette for pyrene. Our findings indicate that the generally low levels of NNN and NNK are most likely responsible for the relatively low levels of the corresponding biomarkers in the urine of the Shanghai Cohort Study participants as compared to those found in the U.S. smokers, supporting the role of the levels of these constituents in cigarette smoke in smokers' exposures. Our findings also suggest that, in addition to smoking, other sources contribute to Chinese smokers' exposure to PAH. [ABSTRACT FROM AUTHOR]

Gastric cancer incidence varies greatly worldwide, but is consistently twice as high in men than in women. The hormone-related factors hypothesized to be associated with lower risk of gastric cancer in women have not been fully explored in populations with a high background risk of gastric cancer. The Singapore Chinese Health Study (SCHS) is a prospective cohort study in which 34,022 of the participants enrolled between 1993 and 1998 were women between 45 and 74 years of age. Information on reproductive histories, hormone replacement therapy (HRT) and oral contraceptive (OC) use was collected through in-person interviews at baseline. As of December 31, 2013, 269 incident gastric cancer cases were identified. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate gastric cancer risk associations. Older age at natural menopause (≥55 versus <45 years: HR = 0.50, 95% CI: 0.25-0.99), type of menopause (other versus natural: HR = 0.48, 95% CI: 0.27-0.87) and greater years of menstrual cycling (fourth versus first quartile: HR = 0.67, 95% CI: 0.46-0.96) were associated with a decreased risk of gastric cancer. Ever use of OCs and HRT was also associated with reduced risk of gastric cancer; the multivariable-adjusted HRs (95% CIs) were 0.40 (0.17-0.90) for use of HRT >3 years and 0.67 (0.47-0.94) for ever use of OCs, compared with never use. Reproductive factors associated with a longer window of fertility and the use of exogenous hormones were shown to reduce gastric cancer development in a cohort of Chinese women with a high background risk of gastric cancer. [ABSTRACT FROM AUTHOR]

Background & Aim Lipidomic signature of lipid metabolism suggests that omega-6 polyunsaturated fatty acids ( PUFA) may play a role in oncogenesis of hepatocellular carcinoma ( HCC). Hence, we examined the association between dietary fatty acids and risk of HCC. Methods We used data from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 Chinese men and women aged 45-74 years enrolled between 1993 and 1998. Information on current diet assessed via a validated semi-quantitative food frequency questionnaire, medical history and lifestyle factors were obtained through in-person interview, and incidence of HCC recorded through 31 Dec 2010. We also examined the association between dietary fatty acids and HCC risk using a case-control set of 92 cases and 274 controls with available serological biomarkers of chronic infections with hepatitis B virus ( HBV) and hepatitis C virus ( HCV) nested within this cohort. Results Among the dietary fat components examined, which included saturated, monounsaturated, omega-3 and omega-6 PUFA, only omega-6 PUFA intake displayed a dose-dependent, positive association with HCC risk (p for trend = 0.02). Compared to the lowest quartile, the hazard ratio for the highest quartile intake was 1.49 [(95% confidence interval ( CI):1.08-2.07)]. In the nested case-control study, only among individuals negative for serology markers of chronic infection with HBV or HCV, those who consumed above median levels of dietary omega-6 PUFA had increased HCC risk (odds ratio = 4.36, 95% CI = 1.59-11.94) compared to those with lower intake. Conclusion Dietary omega-6 PUFA may be implicated in the risk of non-viral hepatitis related HCC. [ABSTRACT FROM AUTHOR]

Cytochrome P450 2A6 (CYP2A6) catalyzes nicotine metabolism and contributes to the metabolism of the tobacco-specific lung carcinogen, NNK. Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 325 lung cancer cases and 356 controls was conducted within a prospective cohort of 18,244 Chinese men in Shanghai, China. Quantified were 4 allelic variants of CYP2A6 [ *1(+51A), *4, *7, and *9] and urinary total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC) and total NNAL (an NNK metabolite). Calculated were total nicotine equivalents (TNE), the sum of total nicotine, total cotinine and total 3HC and the total 3HC:total cotinine ratio as a measure of CYP2A6 activity. The nicotine metabolizer status (normal, intermediate, slow and poor) was determined by CYP2A6 genotypes. The smoking-adjusted odds ratios (95% confidence intervals) of lung cancer for the highest vs lowest quartile of total nicotine, total cotinine, total 3HC, TNE and total NNAL were 3.03 (1.80-5.10), 4.70 (2.61-8.46), 4.26 (2.37-7.68), 4.71 (2.61-8.52), and 3.15 (1.86-5.33) (all Ptrend < 0.001), respectively. Among controls CYP2A6 poor metabolizers had a 78% lower total 3HC:total cotinine ratio and 72% higher total nicotine ( Ptrend ≤ 0.002). Poor metabolizers had an odds ratio of 0.64 (95% confidence interval = 0.43-0.97) for lung cancer, which was statistically nonsignificant (odds ratio = 0.74, 95% confidence interval = 0.48-1.15) after adjustment for urinary TNE and smoking intensity and duration. The lower lung cancer risk observed in CYP2A6 poor metabolizers is partially explained by the strong influence of CYP2A6 genetic polymorphisms on nicotine uptake and metabolism. [ABSTRACT FROM AUTHOR]

Identifying risk factors for future change in sleep duration can clarify whether, and if so how, sleep and morbidity are bidirectionally related. To date, only limited longitudinal evidence exists characterizing changes to sleep duration among older adults. This study aimed to identify factors associated with change in sleep duration in a large sample of older adults (≥ 60 years) residing in Singapore ( n = 10 335). These adults were monitored as part of the Singapore Chinese Health Study, which collected information regarding daily sleep duration at baseline (assessed in 1993-1998) and at a follow-up wave conducted over a mean of 12.7 years later (assessed in 2006-2010). Among adults sleeping 6-8 h at baseline ( n = 8265), most participants (55.6%) remained 6-8 h sleepers at follow-up, while 8.4% became short (< 6 h) and 36.0% became long (> 8 h) sleepers. A history of stroke, diabetes, cancer, hip fracture and greater age all independently increased the odds of having long sleep duration at follow-up, while greater educational attainment and weekly physical activity were both associated with reduced odds of becoming a long sleeper. Other than greater baseline age, the only factor related to higher odds of becoming a short sleeper was concurrent stomach/duodenal ulcer at follow-up. Long sleep duration among older adults may therefore reflect longstanding disease processes, whereas the aetiology of short sleep may predominately involve factors other than those examined. Future research is needed to distinguish if/when long sleep duration serves the disease recovery process, and when long sleep duration complicates disease and requires sleep medicine interventions. [ABSTRACT FROM AUTHOR]

Prospective studies conducted in Western populations have suggested that alterations in soluble CD27 (sCD27) and soluble CD30 (sCD30), two markers indicative of B-cell activation, are associated with risk of non-Hodgkin lymphoma (NHL). Given that the characteristics of NHL in East Asia differ from the West and mechanistic commonalities between these populations with respect to the role of intermediate endpoint biomarkers in lymphomagenesis have not been explored, we conducted a pooled nested case-control study from three prospective studies of Chinese men and women including 218 NHL cases and 218 individually matched controls. Compared with the lowest quartile, ORs (95% CIs) for the second, third and fourth quartiles of sCD27 were 1.60 (0.83-3.09), 1.94 (0.98-3.83) and 4.45 (2.25-8.81), respectively ( ptrend = 0.000005). The corresponding ORs for sCD30 were 1.74 (0.85-3.58), 1.86 (0.94-3.67) and 5.15 (2.62-10.12; ptrend = 0.0000002). These associations remained statistically significant in individuals diagnosed with NHL 10 or more years after blood draw. Notably, the magnitude of the associations with NHL risk was very similar to those in Western populations in previous studies. These findings of the similar association between sCD27 or sCD30 and NHL risk across different populations support an important underlying mechanism of B-cell activation in lymphomagenesis. [ABSTRACT FROM AUTHOR]

The tobacco-specific nitrosamines N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are potent carcinogens for the rat esophagus and lung, respectively. Consistent with the animal carcinogenicity data, we previously reported a remarkably strong association between prospectively measured urinary total NNN, a biomarker of human NNN intake, and the risk of developing esophageal cancer among smokers in the Shanghai Cohort Study. We also demonstrated that urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a biomarker of exposure to the lung carcinogen NNK, is strongly associated with the risk of lung, but not esophageal cancer in smokers. In this study, we investigated the potential relationship between NNN intake and lung cancer risk in the same cohort. The prospectively collected urine samples from lung cancer cases and matching controls selected for this study, all current smokers, have been previously analyzed for total NNAL, cotinine (a biomarker of nicotine intake) and phenanthrene tetraol (PheT) (a biomarker of exposure to polycyclic aromatic hydrocarbons). Urinary levels of total NNN were not associated with the risk of lung cancer: odds ratios (95% confidence intervals) associated with the second and third tertiles of total NNN, relative to the lowest tertile, were 0.82 (0.36-1.88) and 1.02 (0.39-2.89), respectively ( p for trend = 0.959), after adjustment for self-reported smoking history, urinary cotinine and PheT. The results of this study reaffirm the previously reported specificity of urinary total NNN and total NNAL as predictors of esophageal and lung cancer risks, respectively, in smokers, and demonstrate remarkable coherence between rat target tissues of these carcinogens and susceptibility to cancer in smokers. [ABSTRACT FROM AUTHOR]

ABSTRACT Experimental and epidemiologic data suggest that carotenoids in vegetables and fruits may benefit bone health due to their antioxidant properties. The relationship between dietary total and specific carotenoids, as well as vegetables and fruits, and risk of hip fracture was examined among Chinese in Singapore. We used data from the Singapore Chinese Health Study, a prospective cohort of 63,257 men and women who were of ages 45 to 74 years between 1993 and 1998. At recruitment, subjects were interviewed on lifestyle factors and medical history. Usual diet was measured using a validated food frequency questionnaire. During a mean follow-up of 9.9 years, we identified 1630 hip fracture incident cases. Among men, consumption of vegetables was associated with lower hip fracture risk. Similarly, dietary total carotenoids and specific carotenoids, α-carotene, β-carotene, and lutein/zeaxanthin were inversely associated with hip fracture risk. Compared to men in the lowest quartile of nutrient density, men in the highest quartile had statistically significant 26% to 39% risk reduction (all p for trend <0.05). When stratified by body mass index (BMI), the greatest protective effects of total vegetables and carotenoids were found in men with BMI <20 kg/m2 ( p for trend ≤0.004). There was no association between dietary carotenoids or vegetables/fruits and hip fracture risk among women. This study suggests that adequate intake of vegetables may reduce risk of osteoporotic fractures among elderly men and that the antioxidant effects of carotenoids may counteract the mechanism of osteoporosis related to leanness. © 2014 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

We previously reported an inverse association between sleep duration and breast cancer risk in the prospective, population-based Singapore Chinese Health Study (SCHS) cohort (Wu et al., Carcinogenesis 2008;29:1244-8). Sleep duration was significantly positively associated with 6-sulfatoxymelatonin (aMT6s) levels determined in a spot urine, but aMT6s levels in breast cancer cases were lacking (Wu et al., Carcinogenesis 2008;29:1244-8). We updated the sleep duration-breast cancer association with 14 years of follow-up of 34,028 women in the SCHS. In a nested case-control study conducted within the SCHS, randomly timed, prediagnostic urinary aMT6s concentrations were compared between 248 incident breast cancer and 743 individually matched cohort controls. Three female controls were individually matched to each case on age at baseline interview (within 3 years), dialect group, menopausal status, date of baseline interview (within 2 years), date of urine sample collection (within 6 months) and timing of urine collection during the day (within 1 hr). Cox proportional hazards and conditional regression models with appropriate adjustment for confounders were used to examine the sleep- and aMT6s-breast cancer relationships. Breast cancer risk was not significantly associated with sleep duration; adjusted odds ratio (OR) for 9+ vs. ≤6 hr is 0.89 [95% confidence interval (95% CI) = 0.64-1.22]. Prediagnostic aMT6s levels did not differ between breast cancer cases and matched controls; adjusted OR for highest versus lowest quartiles is 1.00 (95% CI = 0.64-1.54). We conclude that sleep duration is not significantly associated with breast cancer risk reduction. Melatonin levels derived from randomly timed spot urine are unrelated to breast cancer. Randomly timed, spot urine-derived melatonin levels are noninformative as surrogates of nocturnal melatonin production. [ABSTRACT FROM AUTHOR]

Cytochrome P450 1A2 (CYP1A2) is hypothesized to catalyze the activation of arylamines, known human bladder carcinogens present in cigarette smoke. The relationship between CYP1A2 phenotype and bladder cancer risk was examined in a case-control study involving 519 patients and 514 controls in Shanghai, China. Both CYP1A2 and N-acetyltransferase 2 (NAT2) phenotypic status were determined by a caffeine-based urinary assay. Our study showed that among smokers at urine collection, patients with bladder cancer had statistically significantly higher CYP1A2 phenotype scores compared to control subjects ( p = 0.001). The odds ratios (95% confidence intervals) of bladder cancer for the second, third and fourth quartiles of the CYP1A2 score were 1.31 (0.53-3.28), 2.04 (0.90-4.60) and 2.82 (1.32-6.05), respectively, relative to the lowest quartile ( p for trend = 0.003). NAT2 slow acetylation phenotype was associated with a statistically significant 40% increased risk of bladder cancer, and the relationship was independent of subjects' smoking status. Subjects possessing the NAT2 slow acetylation phenotype and the highest tertile of CYP1A2 scores showed the highest risk for bladder cancer. Their odds ratios (95% confidence intervals) was 2.13 (1.24-3.68) relative to their counterparts possessing the NAT2 rapid acetylation phenotype and the lowest tertile of CYP1A2 scores. The findings of our study demonstrate that CYP1A2 phenotype may be an important contributing factor in the development of smoking-related bladder cancer in humans. [ABSTRACT FROM AUTHOR]

Background: Experimental studies suggest that sex hormones may induce or promote the development of hepatocellular carcinoma (HCC). Androgens are converted to estrogens by the CYP19 gene product, aromatase. Hepatic aromatase level and activity have been shown to be markedly elevated in HCC. Aromatase expression in liver tumors is driven by a promoter upstream of CYP19 exon I.6.Methods: First, the authors identified an A/C polymorphism in the exon I.6 promoter of the CYP19 gene. To determine whether allelic variants in the CYP19 I.6 promoter differ in their ability to drive gene expression, we carried out an in vitro reporter gene assay. Then, the authors studied the association between this polymorphism and HCC risk in 2 complementary case-control studies: 1 in high-risk southern Guangxi, China, and another in low-risk US non-Asians of Los Angeles County.Results: Transcriptional activity was 60% higher for promoter vectors carrying the rs10459592 C allele compared with those carrying an A allele (P = .007). In both study populations, among subjects negative for at-risk serologic markers of hepatitis B or C, there was a dose-dependent association between number of high activity C allele and risk of HCC (P(trend) = .014). Risk of HCC was significantly higher (odds ratio [OR], 2.25; 95% confidence interval (CI), 1.18-4.31) in subjects homozygous for the C allele compared with those homozygous for the A allele.Conclusions: This study provides epidemiologic evidence for the role of hepatic aromatization of androgen into estrogen in the development of nonviral hepatitis-related HCC. [ABSTRACT FROM AUTHOR]

Although viral loads are known to influence the development of hepatitis B virus-induced hepatocellular carcinoma in a number of populations, little information is available in the Black African population. Black African patients with hepatocellular carcinoma differ from those in other populations in having a lower frequency of e antigen-positivity and in other respects that might affect viral loads. Hepatitis B viral loads were measured using real-time polymerase chain reaction assay in 124 Black Africans with hepatocellular carcinoma and compared with those in 125 Black adult asymptomatic viral carriers. The geometric mean viral load in the cancer patients was 553,618 copies/ml (95% CI 301,953-1,015,033 copies/ml), with 62.1% having loads >1 × 105 copies/ml and 87.1% >1 × 104 copies/ml, whereas that in the carriers was 16,084 copies/ml (95% CI 9,184-28,168 copies/ml), with only 15.2% having values >1 × 105 copies/ml and 49.6% >1 × 104 copies/ml ( P < 0.001 in each instance). Mean viral load was significantly higher in e antigen-positive than e antigen-negative cancer patients (5,905,357 copies/ml [1,362,847-25,588,520] cf 238,173 copies/ml [97,200-685,730]: P < 0.001) after adjusting for age and sex. No statistically significant difference existed between patients in different age groups, in men and women, or in patients infected with genotype A or D after adjusting for the other variables. Conclusion: Black Africans with hepatocellular carcinoma have high hepatitis B viral loads in spite of the relative infrequency of e antigen-positivity. J. Med. Virol. 81:1525-1530, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Incense use is an integral part of daily life in large parts of Asia. The burning of incense is a powerful producer of particulate matter and the smoke contains a multitude of well-characterized carcinogens. However, to the authors' knowledge, no convincing association has been reported between exposure to incense smoke and the development of cancer. Therefore, the relation between incense use and the risk of respiratory tract carcinomas was analyzed in a prospective cohort study.Methods: Between 1993 and 1998, a population-based cohort of 61,320 Singapore Chinese who were free of cancer and ages 45 to 74 years completed a comprehensive interview regarding living conditions and dietary and lifestyle factors. Through linkage to population-based registries, the cohort was followed through 2005 and cancer occurrence determined. The relative risk for these cancers associated with incense use was estimated using a Cox proportional hazards model.Results: A total of 325 upper respiratory tract (UPT) carcinomas and 821 lung carcinomas were observed during follow-up. Incense use was associated with a significantly increased risk of UPT carcinomas other than nasopharyngeal, whereas no overall effect was observed on lung cancer. The duration and intensity of incense use were associated with an increased risk of squamous cell carcinomas in the entire respiratory tract (P for trend = .004), whereas there was no significant association noted between incense use and nonsquamous cell carcinomas. The relative risk of squamous cell carcinomas among long-term incense users was 1.8 (95% confidence interval [95% CI], 1.2-2.6; P = .004) in the entire respiratory tract.Conclusions: The results of the current study indicate that long-term use of incense is associated with an increased risk of squamous cell carcinoma of the respiratory tract. [ABSTRACT FROM AUTHOR]

The authors investigated the association of resting heart rate (RHR) with cardiovascular disease (CVD) risk factors and mortality among normal-weight individuals. Using data from our cohort (baseline examination in 1967–1973), individuals with a body mass index of 18.5 to 24.9 kg/m2 (men [n=3724] and women [n=4929] aged 18–39; men [n=1959] and women [n=3735] aged 40–59), were grouped by RHR: <75, 75–84, and ≥85 beats per minute (bpm). A lower RHR was associated with lower mean blood pressure (BP) and cigarette use in each subgroup and total cholesterol (TC) and diabetes in men (P <.05). After a 32-year follow-up, hazard ratios (95% confidence intervals) for CVD mortality for an RHR <75 compared with ≥85 bpm adjusted for age, race, education level, BP, cigarette use, diabetes, and TC were 0.58 (0.34–0.84), 0.73(0.56–0.95), and 0.77 (0.61–0.98) for men aged 18 to 39 and men and women aged 40 to 59, respectively. In women aged 18 to 39, the relationship was not significant. In general, normal-weight individuals with lower RHRs have lower levels of CVD risk factors and mortality. [ABSTRACT FROM AUTHOR]