A Study on Survival Analysis Methods Using Neural Network to Prevent Cancers.

Background: Cancer is one of the main global health threats. Early personalized prediction of cancer incidence is crucial for the population at risk. This study introduces a novel cancer prediction model based on modern recurrent survival deep learning algorithms. Methods: The study includes 160,407 participants from the blood-based cohort of the Korea Cancer Prevention Research-II Biobank, which has been ongoing since 2004. Data linkages were designed to ensure anonymity, and data collection was carried out through nationwide medical examinations. Predictive performance on ten cancer sites, evaluated using the concordance index (c-index), was compared among nDeep and its multitask variation, Cox proportional hazard (PH) regression, DeepSurv, and DeepHit. Results: Our models consistently achieved a c-index of over 0.8 for all ten cancers, with a peak of 0.8922 for lung cancer. They outperformed Cox PH regression and other survival deep neural networks. Conclusion: This study presents a survival deep learning model that demonstrates the highest predictive performance on censored health dataset, to the best of our knowledge. In the future, we plan to investigate the causal relationship between explanatory variables and cancer to reduce cancer incidence and mortality.

The Association between Blood Concentrations of PCDD/DFs, DL-PCBs and the Risk of Type 2 Diabetes Mellitus and Thyroid Cancer in South Korea.

BACKGROUND AND OBJECTIVES: Epidemiological studies have inconsistently shown an association between dioxin and risk of type 2 diabetes mellitus (T2DM) and cancer. This study aims to examine the effects of blood concentration of dioxin-like polychlorinated biphenyls (DL-PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/DFs) on T2DM and thyroid cancer. METHODS: We conducted a nested case-control study within the Korean cancer prevention study-II (KCPS-II) consisting of 15 thyroid cancer cases, 30 T2DM cases, and 55 controls. A total of 500 samples were used in 100 pooling samples. An average value of a pooled sample was calculated weighted by the blood volume of each sample. RESULTS: The study population included 100 participants from the KCPS-II (median (IQR) baseline age, 54.06 [21.04] years; 48 women). The toxic equivalents of PCDD/DFs showed a significant positive association with T2DM and thyroid cancer, after adjustments for potential confounders (T2DM ORs = 1.23; 95% CI = 1.05-1.43; thyroid cancer ORs = 1.34; 95% CI = 1.12-1.61). CONCLUSION: In this study, both T2DM and thyroid cancer were associated with the blood concentrations of PCDD/DFs. The association between PCDD/DFs and T2D was found among women but not among men. Our findings suggest that further biochemical in vivo research and epidemiologic studies are needed to clarify the association between dioxins concentrations and diseases.

Characterization of a Compound Heterozygous SLC2A9 Mutation That Causes Hypouricemia.

Renal hypouricemia is a rare genetic disorder. Hypouricemia can present as renal stones or exercise-induced acute renal failure, but most cases are asymptomatic. Our previous study showed that two recessive variants of SLC22A12 (p.Trp258*, pArg90His) were identified in 90% of the hypouricemia patients from two independent cohorts: the Korean genome and epidemiology study (KoGES) and the Korean Cancer Prevention Study (KCPS-II). In this work, we investigate the genetic causes of hypouricemia in the rest of the 10% of unsolved cases. We found a novel non-synonymous mutation of SLC2A9 (voltage-sensitive uric acid transporter) in the whole-exome sequencing (WES) results. Molecular dynamics prediction suggests that the novel mutation p.Met126Val in SLCA9b (p.Met155Val in SLC2A9a) hinders uric acid transport through a defect of the outward open geometry. Molecular analysis using Xenopus oocytes confirmed that the p.Met126Val mutation significantly reduced uric acid transport but does not affect the SLC2A9 protein expression level. Our results will shed light on a better understanding of SLC2A9-mediated uric acid transport and the development of a uric acid-lowering agent.

Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo.

Bisphenol A (BPA), a synthetic monomer commonly included in the daily products, has a structure similar to the estrogen receptor agonist. Therefore BPA has been anticipated to interfere with the hormone metabolisms and cause diverse pathological conditions. But the effects of BPA on the genetic landscapes of liver or hepatic cells have not been fully established. Gene expressional changes induced by low- or high-dose of BPA were evaluated in 3D cultured human hepatoma cells (HepG2 spheroids) in vitro at 0, 0.5, 5 and 200 µM and liver of rats exposed to BPA at 0, 0.5 and 250 mg/kg for 90 days in vivo. Functional enrichment analysis, pathway activity measurement and network analysis were performed using BPA-responsive genes. Treatment with BPA changed a lot of gene expressions in both HepG2 spheroids and rat livers depending on doses of BPA. Functional enrichment and pathway analysis show that lipid or steroid metabolism-related functions were altered by BPA in both HepG2 spheroids and livers of rats. Lipid metabolism-related functions altered by BPA formed a large cluster encompassing lipid biosynthesis, steroid metabolic process and cholesterol regulation process. It was also observed that distribution of pathway activities was correlated between HepG2 spheroids and rat livers at low-dose of BPA. Distance distribution in protein-protein interaction network also evidenced the closeness of BPA-responsive genes to metabolism pathways which include lipid metabolism. Collectively, we demonstrated that BPA greatly influenced overall gene expression and biological functions in both human hepatoma spheroids and rat liver, in which lipid- or steroid metabolism-associated genes were significantly altered by the exposure to BPA.

Di-2-ethylhexylphthalate promotes thyroid cell proliferation and DNA damage through activating thyrotropin-receptor-mediated pathways in vitro and in vivo.

Phthalates are being suggested to be associated with altered thyroid function and proliferative changes, but detailed mechanisms remain unclear. Here, we examined the effects of di-(2-ethylhexyl) phthalate (DEHP) on DNA damage and proliferation in thyroid using thyroid carcinoma cell line, 8505C, in vitro and the rats orally treated with DEHP at 0, 0.3, 3, 30 and 150 mg/kg for 90 days from post-natal day 9 in vivo. Exposure to DHEP (1-50 µM) induced cellular proliferation, as evidenced by increased cell viability and DNA synthesis. Activation of γH2AX, a sensitive biomarker for DNA damage was observed following the exposure to DHEP (from 5 to 50 µM) with increased comet tail moment (5-100 µM) in comet assay, reflecting that DNA damage also occurred. When upstream signaling was examined, both thyrotropin receptor (TSHR)-ERK1/2 axis and TSHR-AKT axis were activated with upregulation of Pax8, a master transcriptional factor for thyroid differentiation and proliferation. Thyroid tissue from juvenile rats orally exposed to DEHP also confirmed DNA damage responses and the activation of TSHR signaling, which was evident from 0.3 to 3 mg/kg respectively. Notably, deletion of TSHR through siRNA attenuated these DEHP-induced events in vitro. Collectively these results suggest that DEHP induces DNA damage and cellular proliferation in thyroid, which appears to be from TSHR activation, providing an important insight into endocrine disrupting activities of phthalates on thyroid.

ApoB/ApoA-I ratio is independently associated with carotid atherosclerosis in type 2 diabetes mellitus with well-controlled LDL cholesterol levels.

BACKGROUND/AIMS: This study aimed to investigate whether the apolipoprotein (Apo) B/ApoA-I ratio is associated with carotid intima-media thickness (CIMT) in type 2 diabetes mellitus (T2DM) subjects with low density lipoprotein cholesterol (LDL-C) levels less than 100 mg/dL. METHODS: This cross-sectional study included 845 subjects aged with T2DM 40 to 75 years who had visited Huh's Diabetes Center in Seoul, Republic of Korea for CIMT measurement. Traditional fasting lipid profiles, ApoB and ApoA-I levels were examined. CIMT was measured at three points on the far wall of 1 cm long section of the common carotid artery in the proximity of the carotid bulb. The mean value of six measurements from right and left carotid arteries were used as the mean CIMT. In this study, carotid atherosclerosis was defined as having a focal plaque or diffuse thickening of the carotid wall (mean CIMT ≥ 1.0 mm). RESULTS: The prevalence of carotid atherosclerosis increased with ApoB/ApoA-I ratio. The ApoB/ApoA-I ratio, expressed as both quartiles (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.21 to 3.79; p for trend = 0.014) and continuous values (OR, 10.05; 95% CI, 3.26 to 30.97; p < 0.001), was significantly associated with a higher risk for carotid atherosclerosis, regardless of conventional cardiovascular disease risk factors. The optimal ApoB/ApoA-I ratio cutoff value for detecting carotid atherosclerosis was 0.57, based on receiver operating characteristic curve analysis with a sensitivity of 58.0% and a specificity of 55.1%. CONCLUSIONS: A high ApoB/ApoA-I ratio was significantly associated with carotid atherosclerosis in T2DM patients with LDL-C levels less than 100 mg/dL.

Submicromolar bisphenol A induces proliferation and DNA damage in human hepatocyte cell lines in vitro and in juvenile rats in vivo.

An association between bisphenol A (BPA) exposure and hepatic tumors was suggested, but the employment of high-dose levels raises questions about its relevance to human health. Here, we demonstrate that submicromolar concentrations of BPA induce the proliferation and DNA damage in human hepatocyte cell lines. In HepG2 and NKNT-3, undifferentiated and differentiated hepatocyte cell lines, respectively, submicromolar BPA concentrations promoted the cell proliferation, as indicated by enhanced DNA synthesis and elevated expression of cell-cycle proteins. At concentrations higher than 10 µM, these effects disappeared, reflecting a non-monotonic dose-response relationship. Notably, histone H2AX was activated following exposure to BPA, which is a sensitive marker of DNA damage. Importantly, proliferative foci and DNA damage were also observed in liver tissue of rats orally exposed to BPA at 0.5 mg/kg for 90 days, from juvenile age (postnatal day 9) through adulthood. Reactive oxygen species appeared to play a role in the BPA-induced proliferation and DNA damage, as evidenced by a partial reversal of both processes upon pretreatment with an antioxidant, N-acetylcysteine. Collectively, these results demonstrate that submicromolar BPA concentrations induce the DNA damage and promote the cell proliferation in the liver, which may support its role as a risk factor for hepatocarcinogenicity.

Low-Dose Bisphenol A Increases Bile Duct Proliferation in Juvenile Rats: A Possible Evidence for Risk of Liver Cancer in the Exposed Population?

Increasing concern is being given to the association between risk of cancer and exposure to low-dose bisphenol A (BPA), especially in young-aged population. In this study, we investigated the effects of repeated oral treatment of low to high dose BPA in juvenile Sprague-Dawley rats. Exposing juvenile rats to BPA (0, 0.5, 5, 50, and 250 mg/kg oral gavage) from post-natal day 9 for 90 days resulted in higher food intakes and increased body weights in biphasic dose-effect relationship. Male mammary glands were atrophied at high dose, which coincided with sexual pre-maturation of females. Notably, proliferative changes with altered cell foci and focal inflammation were observed around bile ducts in the liver of all BPA-dosed groups in males, which achieved statistical significance from 0.5 mg/kg (ANOVA, Dunnett's test, p<0.05). Toxicokinetic analysis revealed that systemic exposure to BPA was greater at early age (e.g., 210-fold in Cmax, and 26-fold in AUC at 50 mg/kg in male on day 1 over day 90) and in females (e.g., 4-fold in Cmax and 1.6-fold in AUC at 50 mg/kg vs. male on day 1), which might have stemmed from either age- or gender-dependent differences in metabolic capacity. These results may serve as evidence for the association between risk of cancer and exposure to low-dose BPA, especially in young children, as well as for varying toxicity of xenobiotics in different age and gender groups.

Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians.

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.

Relationship between BMI, body image, and smoking in Korean women as determined by urine cotinine: results of a nationwide survey.

BACKGROUND: This study examined the influence of body mass index (BMI), subjective body perception (SBP), and the differences between BMI and SBP influence on smoking among women. METHODS: This study used the Korea National Health and Nutrition Examination Survey IV-2, 3 2008-2009. A urinary cotinine test was administered to 5485 women at least 19 years of age. Individuals whose cotinine level was at least 50 ng/mL were categorized as smokers. A multiple logistic regression analysis was performed to estimate the extent to which body-related variables affect female smoking. RESULTS: Women with a lower BMI who perceived themselves to be normal or very fat were 2.09 times (1.14-3.83) more likely to smoke than women with a normal BMI and SBP. Women who were never married with a low BMI and thin SBP were 3.11 times (1.47-6.55) more likely to smoke than women with a normal BMI and SBP. Married women with a high BMI who considered themselves very fat were 0.63 times (0.43-0.94) less likely to smoke than women with a normal BMI and SBP. In contrast, divorced and widowed women with a low or normal BMI who considered themselves very fat were 26.1 times (1.35-507.3) more likely to smoke. CONCLUSIONS: Discrepancies between the objective physical condition (BMI) and the subjective body image (SBP) influence the female smoking rate. To reduce the number of female smokers, public education on the association between smoking behavior and weight issues is needed, especially among women with low BMI and distorted weight perception.

A comparison of predictability of cardiovascular events between each metabolic component in patients with metabolic syndrome based on the revised National Cholesterol Education Program criteria.

PURPOSE: The prevalence of metabolic syndrome (MetS) generally varies depending on its diagnostic definition, and many different definitions inevitably lead to substantial confusion and lack of comparability between studies. Despite extensive research, there is still no gold standard for the definition of MetS, which continues to be a matter of debate. In this study, we investigate whether and to what extent its individual components are related to the risk of cardiovascular disease (CVD) in Korean population. MATERIALS AND METHODS: We used data from the 2005 Korea National Health and Nutrition Examination Survey, which is a nationally representative survey of the noninstitutionalized civilian population. The study sample consisted of 1,406 Korean adults (587 men, 819 women) who were diagnosed with MetS based on the revised National Cholesterol Education Program (NCEP) criteria. Central obesity is defined as a waist circumference cutoff point reported in Asia-Pacific criteria for obesity based on waist circumference by the World Health Organization. CVD was defined as presence of stroke, myocardial infarction, or angina pectoris on a medical history questionnaire. RESULTS: The CVD prevalence among the subjects was 6.8% for men and 8.6% for women. Besides age, the components of MetS showing a significant difference in the number of CVD events were high fasting glucose (FG) in men and high blood pressure (BP) and high FG in women. After adjusting for gender and age, high FG was shown to yield a significant difference (odds ratio: unadjusted 2.08, adjusted 1.81), alone among all MetS components. However, after adjusting for only age, no significant difference was found. CONCLUSION: Fasting glucose level is the highest predicting factor for CVD in Korean patients with MetS based on the revised NECP definition.

Relationship between HDL3 subclasses and waist circumferences on the prevalence of metabolic syndrome: KMSRI-Seoul Study.

OBJECTIVE: Limited information is available on the association of HDL subtypes and the risk of metabolic syndrome (MetSyn). The objective of the present study was to investigate the association of HDL subspecies with the prevalence of MetSyn in new outpatients. METHODS: Five hundred forty-one new outpatients (366 males and 175 females) were enrolled in two hospitals participating in the KMSRI-Seoul Study. The new criteria for the Korean MetSyn based on the 2005 KHANES were used. Medical questionnaires, anthropometric measurements, 3-day recall dietary assessments, and blood biomarker analyses were performed. Unconditional logistic regression models were used to estimate crude and odds ratios (ORs) and 95% confidence intervals (CIs) with multivariate adjustments. The proportions of HDL subtypes were measured after subtypes were identified by 4-30% gradient gel electrophoresis. RESULTS: Of the subjects, 50.8% were classified as MetSyn; blood pressure (BP) and fasting blood sugar (FBS) among the five criteria did not differ by gender. Increasing the HDL(2b) subtype significantly reduced the risk of MetSyn in males and females. The association of small size HDL(3b) with the risk of MetSyn was stronger in females than in males: adjusted ORs (95% CIs) for the 3rd tertile of HDL(3b) compared to the 1st tertile were 3.79 (CI, 2.00-7.18) in males and 11.2 (CI, 2.1-59.6) in females. However, a decreased waist circumference (WC), BP, and triglycerides (TG) were observed with increased large HDL particles in males. CONCLUSIONS: Small-sized HDL was associated with increased MetSyn risk factors and closely related to WC, BP, TG, and HOMA-IR, particularly in males.

White blood cell count and the risk of colon cancer.

Inflammation may be linked to the pathogenesis of colorectal cancer. However, two conflicting observational results were recently reported on the relationship between the inflammatory marker C-reactive protein (CRP) and the risk of colorectal cancer. Few epidemiologic studies have examined the association between inflammatory markers and the risk of colorectal cancer. We prospectively examined the mortality and incidence risk for colon and rectal cancers among 424,419 Koreans (108,907 men and 315,512 women). The subjects were 40 to 95 years of age and from the Korean Cancer Prevention Study (KCPS) cohort. All subjects received medical examination from the National Health Insurance Corporation in 1993 and 1995. The maximum follow-up period was 10 years, and the follow-up periods began in January 1, 1994 and ended in December 31, 2003. An elevated white blood cell count (WBC) was associated with a higher mortality risk of colon cancer (highest versus lowest quartile: men, 1.55, 95% CI 1.10-2.18, p for trend = 0.0014; women, 1.51, 95% CI 1.12- 2.03, p for trend = 0.0049). Similarly, an elevated WBC was associated with a higher incidence risk of colon cancer (highest versus lowest quartile: men, 1.38, 1.09-1.76, p for trend = 0.0017; women, 1.46, 95% CI 1.20-1.78, p for trend= 0.0003). A positive linear trend was also observed in non- smokers. There was no significant association between WBC and the risk of rectal cancer. Our findings demonstrate that an elevated WBC is associated with an increase in both the mortality and incidence rates of colon cancer. These results support our hypothesis that inflammation increases the risk of colon cancer.

[The relationship between socioeconomic position and the predicted risk of ischemic heart disease with using health risk appraisal].

OBJECTIVES: The object of this study is to assess the relationship between socioeconomic factors and the predicted 10-year risk of cardiovascular disease by using health risk appraisal of ischemic heart disease. METHODS: The study population was taken from The 2001 Korea National Health and Nutrition Survey, and it consisted of 1,566 men and 1,984 women aged 30-59. We calculated 10-year risk using the risk function of ischemic heart disease as developed by Jee. The educational level and equivalized household income were dichotomized by a 12 years education period and the median income level. Occupation was dichotomized into manual/non-manual work. We stratified the population by age (10 years) and sex, and then we rated the risk differences according to socioeconomic factors by performing t-tests for each strata. RESULTS: There were gradients of the predicted 10-year risk of ischemic heart disease with the educational level and the equivalized household income, and thet was an increasing tendency of risk differences with age. Manual workers didn't show significant risk difference from non-manual workers. CONCLUSIONS: There was definite relationship between low socioeconomic position and the predicted risk of ischemic heart disease in the future.