Mechanisms and functions of SUMOylation in health and disease: a review focusing on immune cells.

SUMOylation, which is a type of post-translational modification that involves covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to target substrates, regulates various important molecular and cellular processes, including transcription, the cell cycle, cell signaling, and DNA synthesis and repair. Newly synthesized SUMO is immature and cleaved by the SUMO-specific protease family, resulting in exposure of the C-terminal Gly-Gly motif to become the mature form. In the presence of ATP, mature SUMO is conjugated with the activating enzyme E1 through the cysteine residue of E1, followed by transfer to the cysteine residue of E2-conjugating enzyme Ubc9 in humans that recognizes and modifies the lysine residue of a substrate protein. E3 SUMO ligases promote SUMOylation. SUMOylation is a reversible modification and mediated by SUMO-specific proteases. Cumulative studies have indicated that SUMOylation affects the functions of protein substrates in various manners, including cellular localization and protein stability. Gene knockout studies in mice have revealed that several SUMO cycling machinery proteins are crucial for the development and differentiation of various cell lineages, including immune cells. Aberrant SUMOylation has been implicated in several types of diseases, including cancers, cardiovascular diseases, and autoimmune diseases. This review summarizes the biochemistry of SUMO modification and the general biological functions of proteins involved in SUMOylation. In particular, this review focuses on the molecular mechanisms by which SUMOylation regulates the development, maturation, and functions of immune cells, including T, B, dendritic, and myeloid cells. This review also discusses the underlying relevance of disruption of SUMO cycling and site-specific interruption of SUMOylation on target proteins in immune cells in diseases, including cancers and infectious diseases.

Significance of Hypermethylation of Tumor-Suppressor Genes PTGER4 and ZNF43 at CpG Sites in the Prognosis of Colorectal Cancer.

The status of DNA methylation in primary tumor tissue and adjacent tumor-free tissue is associated with the occurrence of aggressive colorectal cancer (CRC) and can aid personalized cancer treatments at early stages. Tumor tissue and matched adjacent nontumorous tissue were extracted from 208 patients with CRC, and the correlation between the methylation levels of PTGER4 and ZNF43 at certain CpG loci and the prognostic factors of CRC was determined using the MassARRAY System testing platform. The Wilcoxon signed-rank test, a Chi-square test, and McNemar's test were used for group comparisons, and Kaplan-Meier curves and a log-rank test were used for prediction. The hypermethylation of PTGER4 at the CpG_4, CpG_5, CpG_15, and CpG_17 tumor tissue sites was strongly correlated with shorter recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) [hazard ratio (HR) = 3.26, 95% confidence interval (CI) = 1.38-7.73 for RFS, HR = 2.35 and 95% CI = 1.17-4.71 for PFS, HR = 4.32 and 95% CI = 1.8-10.5 for OS]. By contrast, RFS and PFS were significantly longer in the case of increased methylation of ZNF43 at the CpG_5 site of normal tissue [HR = 2.33, 95% CI = 1.07-5.08 for RFS, HR = 2.42 and 95% CI = 1.19-4.91 for PFS]. Aberrant methylation at specific CpG sites indicates tissue with aggressive behavior. Therefore, the differential methylation of PTGER4 and ZNF43 at specific loci can be employed for the prognosis of patients with CRC.

Factors associated with insomnia in older adult outpatients vary by gender: a cross-sectional study.

BACKGROUND: Insomnia is a common sleep disturbance in older adults and is associated with many poor health outcomes. This study aimed to explore factors associated with insomnia in older adult outpatient clinics, and to further analyze the influence of gender on factors associated with insomnia. METHODS: This cross-sectional study was conducted in the outpatient clinics of a tertiary hospital in Southern Taiwan from July to September 2018. A total of 400 consecutive subjects aged 60 years or older were recruited. Insomnia was defined as a score of ≥6 points on the Athens Insomnia Scale (AIS). Socio-demographics, health behaviors and clinical data were collected by face-to-face interview. Multivariable logistic regression was adopted for statistical analysis of the entire sample and stratified by gender. RESULTS: Participants' mean age was 74.74 ± 8.54 years, and the majority (93%) had more than one chronic disease. The prevalence of insomnia accounted for 30% (120/400) of all subjects, with males 22.9% (46/201) and females 37.2% (74/199). Gender, appetite, exercise, depressive symptoms, and sleep-related conditions such as short sleep duration, sleeping pills usage, medium-high risk of obstructive sleep apnea (OSA) and restless leg syndrome (RLS) were factors associated with insomnia in older adults. Exercise, sleeping pills usage, and RLS were independently associated with insomnia only in men, while appetite and medium-high risk of OSA were associated with insomnia in women only. In addition, after further adjusting for covariates, prevalence of the insomnia-related symptoms such as sleep induction, total sleep duration, sleep quality and sleepiness during the day was significantly higher in females than in males. CONCLUSIONS: Insomnia symptoms are highly prevalent among older adults, predominantly females. Significant differences are found between genders in factors associated with insomnia and insomnia-related symptoms. Understanding gender differences may help clinicians to modify associated factors when managing older adults with insomnia.

Apolipoprotein B Level and the Apolipoprotein B/Apolipoprotein A-I Ratio as a Harbinger of Ischemic Stroke: A Prospective Observation in Taiwan.

AIM: Prospective studies indicate that apolipoprotein (apo) measurements predict coronary heart disease risk. However, few population-based follow-up studies have addressed the predictive value of apo measurements in stroke risk. The aims of the present study were to analyze the predictive ability of apo measurements in the risk of ischemic stroke. METHODS: Serum apo A-I and apo B levels and calculated apo B/apo A-I ratio were measured at baseline in 2002 in a cohort of 4,204 participants who were followed for a mean of 4.61 years for a stroke event. RESULTS: After adjustment for potential confounders, a significantly stepwise increase in the incidence rate of stroke across quartiles of both apo B and the apo B/apo A-I ratio was evident in both genders and across age-groups. The predictive ability of apo B to detect ischemic stroke was comparable with that of the apo B/apo A-I ratio. Furthermore, both apo B and the apo B/apo A-I ratio were better predictors of the risk of ischemic stroke than total cholesterol (TC), low-density lipoprotein cholesterol, and the TC/high-density lipoprotein cholesterol ratio. CONCLUSIONS: This cohort study demonstrates that apo B and the apo B/apo A-I ratio were a significant risk predictor of stroke. Furthermore, the predictive ability of apo B and the apo B/apo A-I ratio in stroke risk was better than routine clinical lipid measurements. Thus, measurements of apolipoproteins have superior clinical utility over traditional lipid measurements in identifying subjects at risk for ischemic stroke.

Automatic Detection Method for Cancer Cell Nucleus Image Based on Deep-Learning Analysis and Color Layer Signature Analysis Algorithm.

Exploring strategies to treat cancer has always been an aim of medical researchers. One of the available strategies is to use targeted therapy drugs to make the chromosomes in cancer cells unstable such that cell death can be induced, and the elimination of highly proliferative cancer cells can be achieved. Studies have reported that the mitotic defects and micronuclei in cancer cells can be used as biomarkers to evaluate the instability of the chromosomes. Researchers use these two biomarkers to assess the effects of drugs on eliminating cancer cells. However, manual work is required to count the number of cells exhibiting mitotic defects and micronuclei either directly from the viewing window of a microscope or from an image, which is tedious and creates errors. Therefore, this study aims to detect cells with mitotic defects and micronuclei by applying an approach that can automatically count the targets. This approach integrates the application of a convolutional neural network for normal cell identification and the proposed color layer signature analysis (CLSA) to spot cells with mitotic defects and micronuclei. This approach provides a method for researchers to detect colon cancer cells in an accurate and time-efficient manner, thereby decreasing errors and the processing time. The following sections will illustrate the methodology and workflow design of this study, as well as explain the practicality of the experimental comparisons and the results that were used to validate the practicality of this algorithm.

Metabolic syndrome and C-reactive protein concentration as independent correlates of chronic kidney disease.

Inflammation is a common phenotype for cardiometabolic disorders. In this study, we attempted to investigate inter-relationships between metabolic syndrome (MetS), C-reactive protein (an inflammatory biomarker) and chronic kidney disease (CKD). We performed a cross-sectional analysis of data from a representative sample of 4425 Chinese adults in Taiwan. The MetS was defined by a unified criteria set by several major organizations. A CKD event was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m(2). Additionly, a CRP cutpoint of 3 mg/L was used to differentiate high and low CRP levels. Overall, 1000 participants had MetS, resulting in a prevalence rate of 22.6%. High CRP level was noted in 782 (17.6%) subjects. In addition, a total of 508 (11.5%) persons qualified as having CKD. Subjects with the MetS had 1.55-fold [95% confidence interval (CI), 1.03-2.32] increased odds of CKD compared with their counterparts without the MetS after multiple adjustments. In addition, there was a significantly graded relationship between increasing levels of serum CRP and prevalent CKD (p for trend = 0.001). Participants in the highest category of serum CRP had a significantly elevated odds of CKD as compared with those in the lowest category [odds ratio (OR), 1.60; 95% CI, 1.21-2.12]. However, there was no interaction in excess of additive scale between the presence of MetS and high CRP level (p = 0.83). These findings suggest that MetS and high CRP were independently associated with increased prevalence of CKD in Chinese adults.

The effect of different patient education methods on quality of bowel cleanliness in outpatients receiving colonoscopy examination.

AIMS: To investigate the effectiveness of an educational film intervention on the quality of bowel cleanliness of outpatients receiving colonoscopy examinations and also to understand the related factors affecting bowel cleanliness. METHOD: This is a quasi-experimental design. One hundred four patients in the experimental group and 114 patients in the control group are the participants in this study. An 8-minute "Preparation for Bowel Cleanliness" educational film was made based on clinical experience and references to related literature. We adopted a valid Aronchick scale evaluate bowel cleanliness. RESULTS: The patients in the experimental group had significantly better bowel cleanliness compared to the control group (80.8% vs. 48.2%, p<.001). Logistic regression showed that the experimental group, gender, and experience with colonoscopy were potentially important factors that may affect bowel cleanliness. CONCLUSIONS: The "Preparation for Bowel Cleanliness" educational film provides simple and easy-to-follow methods for the preparation of cleaning the colon and related information.

Predicting the progress of colon cancer by DNA methylation markers of the p16 gene in feces - Evidence from an animal model.

A new noninvasive screening tool for colorectal neoplasia detects epigenetic alterations exhibited by gastrointestinal tumor cells shed into stool. There is insufficient existing data to determine temporal associations between colorectal cancer (CRC) progression and aberrant DNA methylation. To evaluate the feasibility of using fecal DNA methylation status to determine CRC progression, we collected stool samples from 14 male SD rats aged six weeks, and administered subcutaneous injections of either 1,2-dimethylhydrazine or saline weekly. p16 DNA methylation statuses in tumorous and normal colon tissue, and from stool samples were determined using methylation-specific PCR. Additionally, p16 methylation was detected in stool DNA from 85.7% of the CRC rats. The earliest change in p16 methylation status in the DMH-treated group stool samples occurred during week nine; repeatabilities were 57.1% in week 19 (p = 0.070) and 85.7% in week 34 (p = 0.005). A temporal correlation was evidenced between progression of CRC and p16 methylation status, as evidenced by DMH-induced rat feces. Using fecal DNA methylation status to determine colorectal tissue methylation status can reveal CRC progression. Our data suggests that p16 promoter methylation is a feasible epigenetic marker for the detection and may be useful for CRC screening.

Susceptibility to Colorectal Cancer Based on HSD17B4 rs721673 and rs721675 Polymorphisms and Alcohol Intake among Taiwan Biobank Participants: A Retrospective Case Control Study Using the Nationwide Claims Data.

Colorectal cancer (CRC) is a major public health issue, and there are limited studies on the association between 17ß-hydroxysteroid dehydrogenase type 4 (HSD17B4) polymorphism and CRC. We used two national databases from Taiwan to examine whether HSD17B4 rs721673, rs721675, and alcohol intake were independently and interactively correlated with CRC development. We linked the Taiwan Biobank (TWB) participants' health and lifestyle information and genotypic data from 2012 to 2018 to the National Health Insurance Database (NHIRD) to confirm their medical records. We performed a genome-wide association study (GWAS) using data from 145 new incident CRC cases and matched 1316 healthy, non-CRC individuals. We calculated the odds ratios (OR) and 95% confidence intervals (CI) for CRC based on multiple logistic regression analyses. HSD17B4 rs721673 and rs721675 on chromosome 5 were significantly and positively correlated with CRC (rs721673 A > G, aOR = 2.62, p = 2.90 × 10-8; rs721675 A > T, aOR = 2.61, p = 1.01 × 10-6). Within the high-risk genotypes, significantly higher ORs were observed among the alcohol intake group. Our results demonstrated that the rs721673 and rs721675 risk genotypes of HSD17B4 might increase the risk of CRC development in Taiwanese adults, especially those with alcohol consumption habits.

SENP2 restrains the generation of pathogenic Th17 cells in mouse models of colitis.

The molecular mechanisms contributing to the regulation of Th17-mediated inflammation remain underexplored. We here report a SUMO-specific protease (SENP)2-mediated pathway induced in pathogenic Th17 cells that restricts the pathogenesis of inflammatory colitis. SENP2 regulates the maturation of small ubiquitin-like modifiers (SUMO) and recycles SUMO from the substrate proteins. We find higher levels of SENP2 in pathogenic Th17 cells. By deleting Senp2 in T-cell lineages in mice, we demonstrate that the lack of Senp2 exacerbates the severity of experimental colitis, which is linked to elevated levels of GM-CSF+IL-17A+ pathogenic Th17 cells and more severe dysbiosis of the intestinal microbiome. Adoptive transfer experiments demonstrate the cell-autonomous effect of Senp2 in restraining Th17 differentiation and colitis. The enzymatic activity of SENP2 is important for deSUMOylation of Smad4, which reduces Smad4 nuclear entry and Rorc expression. Our findings reveal a SENP2-mediated regulatory axis in the pathogenicity of Th17 cells.

Albumin prevents reactive oxygen species-induced mitochondrial damage, autophagy, and apoptosis during serum starvation.

Aberrant levels of reactive oxygen species (ROS) rapidly generated from NADPH oxidase (NOX) activation can be cytotoxic due to activating pro-apoptotic signals. However, ROS also induce pro-survival autophagy through the engulfment of damaged mitochondria. This study is aimed at investigating the cytoprotective role of albumin against NOX/ROS-induced autophagy and apoptosis under serum starvation. Serum starvation induced apoptosis following a myeloid cell leukemia sequence 1 (Mcl-1)/Bax imbalance, loss of the mitochondrial transmembrane potential, and caspase activation accompanied by pro-survival autophagy following canonical inhibition of mammalian target of rapamycin complex 1 (mTORC1). Aberrant ROS generation, initially occurring through NOX, facilitated mitochondrial damage, autophagy, and apoptosis. Autophagy additionally regulated the accumulation of ROS-generating mitochondria. NOX/ROS permitted p38 mitogen-activated protein kinase (p38 MAPK)-regulated mitochondrial apoptosis, accompanied by non-canonical induction of autophagy. In addition, activation of glycogen synthase kinase (GSK)-3ß by NOX/ROS-inactivated Akt facilitated a decrease in Mcl-1, followed by mitochondrial apoptosis as well as autophagy. Restoring albumin conferred an anti-oxidative effect against serum starvation-deregulated NOX, p38 MAPK, and Akt/GSK-3ß/Mcl-1/caspase-3 signaling. Albumin also prevented autophagy by sustaining mTORC1. These results indicate an anti-oxidative role for albumin via preventing NOX/ROS-mediated mitochondrial signaling to stimulate apoptosis as well as autophagy. Autophagy, initially induced by canonical inhibition of mTORC1 and enhanced by non-canonical mitochondrial damage, acts physically as a pro-survival mechanism.

Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo.

An overdose and a prolonged treatment of propofol may cause cellular cytotoxicity in multiple organs and tissues such as brain, heart, kidney, skeletal muscle, and immune cells; however, the underlying mechanism remains undocumented, particularly in vascular endothelial cells. Our previous studies showed that the activation of glycogen synthase kinase (GSK)-3 is pro-apoptotic in phagocytes during overdose of propofol treatment. Regarding the intravascular administration of propofol, we therefore hypothesized that propofol overdose also induces endothelial cytotoxicity via GSK-3. Propofol overdose (100 µg/ml) inhibited growth in human arterial and microvascular endothelial cells. After treatment, most of the endothelial cells experienced caspase-independent necrosis-like cell death. The activation of cathepsin D following lysosomal membrane permeabilization (LMP) determined necrosis-like cell death. Furthermore, propofol overdose also induced caspase-dependent apoptosis, at least in part. Caspase-3 was activated and acted downstream of mitochondrial transmembrane potential (MTP) loss; however, lysosomal cathepsins were not required for endothelial cell apoptosis. Notably, activation of GSK-3 was essential for propofol overdose-induced mitochondrial damage and apoptosis, but not necrosis-like cell death. Intraperitoneal administration of a propofol overdose in BALB/c mice caused an increase in peritoneal vascular permeability. These results demonstrate the cytotoxic effects of propofol overdose, including cathepsin D-regulated necrosis-like cell death and GSK-3-regulated mitochondrial apoptosis, on endothelial cells in vitro and the endothelial barrier dysfunction by propofol in vivo.

Impact of metabolic syndrome on the incidence of chronic kidney disease: a Chinese cohort study.

AIM: Metabolic syndrome (MetS) is a major culprit in cardiovascular disease and chronic kidney disease (CKD) in Western populations. We studied the longitudinal association between MetS and incident CKD in Chinese adults. METHODS: A cohort study was conducted in a nationally representative sample of 4248 Chinese adults in Taiwan. The MetS was defined according to a unified criteria set by several major organizations and CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m(2). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for sex, age, body mass index (BMI) and serum levels of total cholesterol. RESULTS: The prevalence of MetS among participants at baseline recruitment was 15.0% (637/4248). During a median follow-up period of 5.40 years, 208 subjects (4.9%) developed CKD. The multivariate-adjusted HR of CKD in participants with MetS compared with those without was 1.42 (95% CI = 1.03, 1.73). Additionally, there was a significantly graded relationship between the number of the MetS components and risk of CKD. Further, the relation between MetS and incident CKD was more robust in subjects with BMI >27.5 kg/m(2) than in those with lower BMI. CONCLUSION: The results suggest that the presence of MetS was significantly associated with increased risk of incident CKD in a Chinese population. These findings warrant future studies to test the impact of preventing and treating MetS on the reduction of the occurrence of CKD.

Insomnia in older adult females is highly associated with metabolic syndrome.

PURPOSE: The aim of this study is to investigate the relationships between insomnia and metabolic syndrome among Taiwanese older adults. METHODS: This cross-sectional study enrolled participants aged over 60 years from outpatient clinics between July and September 2018. Demographic characteristics of all participants and questionnaire data for sleep duration, use of hypnotic agents, baseline activities of daily living, 5 items of the geriatric depression scale, comorbidities, medications, and risk of obstructive sleep apnea were obtained. Insomnia was defined by scores of questionnaires of the Chinese version of the Athens Insomnia Scale higher or equal to 6 points. Metabolic syndrome was diagnosed according to criteria of the National Cholesterol Education Program Adult Treatment Panel III. Multivariable forward stepwise logistic regression analysis was applied to investigate independent associations between insomnia and metabolic syndrome before and after stratifying by gender. RESULTS: Among the 336 participants (mean age 74.9 ± 8.5 years, female 49.1%), 63.1% participants had metabolic syndrome, with significantly higher prevalence among females than males (males 56.7%; females 69.7%). Participants with metabolic syndrome had higher rates of insomnia (34.0% vs. 21.8%, P = 0.018). The significant associations between insomnia and metabolic syndrome disappeared after adjusting for all covariates. However, insomnia was independently associated with metabolic syndrome in older females (adjusted OR 2.614, 95% CI 1.011-6.763, P = 0.048) after adjusting for all covariates. CONCLUSIONS: Insomnia is significantly associated with metabolic syndrome among older female adults. These findings suggest that gender may play a role in the pathogenesis of insomnia and metabolic syndrome in older adults.

Differential DNA methylation analysis of SUMF2, ADAMTS5, and PXDN provides novel insights into colorectal cancer prognosis prediction in Taiwan.

BACKGROUND: Patients with colorectal cancer (CRC) undergo surgery, as well as perioperative chemoradiation or adjuvant chemotherapy primarily based on the tumor-node- metastasis (TNM) cancer staging system. However, treatment responses and prognostic outcomes of patients within the same stage vary markedly. The potential use of novel biomarkers can improve prognostication and shared decision making before implementation into certain therapies. AIM: To investigate whether SUMF2, ADAMTS5, and PXDN methylation status could be associated with CRC prognosis. METHODS: We conducted a Taiwanese cohort study involving 208 patients with CRC recruited from Tri-Service General Hospital and applied the candidate gene approach to identify three genes involved in oncogenesis pathways. A methylation-specific polymerase chain reaction (MS-PCR) and EpiTYPER DNA methylation analysis were employed to detect methylation status and to quantify the methylation level of candidate genes in tumor tissue and adjacent normal tissue from participants. We evaluated SUMF2, ADAMTS5, and PXDN methylation as predictors of prognosis, including recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS), using a Cox regression model and Kaplan-Meier analysis. RESULTS: We revealed various outcomes related to methylation and prognosis. Significantly shorter PFS and OS were associated with the CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue compared with CpG_3+CpG_7 hypomethylation [hazard ratio (HR) = 2.24, 95% confidence interval (CI) = 1.03-4.85 for PFS, HR = 2.56 and 95%CI = 1.08-6.04 for OS]. By contrast, a significantly longer RFS was associated with CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue compared with CpG_2 and CpG_13 hypomethylation [HR (95%CI) = 0.15 (0.03-0.71) for CpG_2 and 0.20 (0.04-0.97) for CpG_13]. The relationship between the methylation status of PXDN and the prognosis of CRC did not reach statistical significance. CONCLUSION: Our study found that CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue was associated with significantly shorter PFS and OS compared with CpG_3+CpG_7 hypomethylation. CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue was associated with a significantly longer RFS compared with CpG_2 and CpG_13 hypomethylation. These methylation-related biomarkers which have implications for CRC prognosis prediction may aid physicians in clinical decision-making.

Joint effect of peroxisome proliferator-activated receptor γ genetic polymorphisms and estrogen-related risk factors on breast cancer risk: results from a case-control study in Taiwan.

Peroxisome proliferator-activated receptor γ (PPARγ) has been linked with possible antineoplastic effects in colorectal carcinogenesis. However, data for the possible link between PPARγ and breast cancer risk are sparse. We assessed the association of three polymorphisms in PPARγ (rs10865710 [C-681T], rs1805192 [Pro12Ala], and rs3856806 [C1431T]) with the risk of breast cancer in an ethnic Chinese female population in Taiwan. In addition, interactions with estrogen exposures were also explored. Genotypes for the PPARγ polymorphisms were determined on 291 incident breast cancer cases and 589 matched controls by fluorogenic 5'-nuclease assay. The at-risk haplotypes were defined according to the three polymorphisms in the following order: C-681T, Pro12Ala, and C1431T, which include CCT, GGT, and GGC. In addition, a critical period of estrogen exposure was estimated by the interval between age at menarche and age at first full-term pregnancy. Overall, there was no evidence of a significant impact of individual polymorphisms of PPARγ on breast cancer risk. However, the haplotype analysis revealed that women harboring at-risk haplotypes showed a significant 67% increase in breast cancer risk [adjusted odds ratio (OR) 1.67; 95% confidence interval (CI) 1.11-2.52]. Furthermore, there was a significant joint effect of estrogen exposure-related factors and at-risk haplotypes of PPARγ on breast cancer risk (adjusted OR 4.04; 95% CI 1.89-8.65), particularly in premenopausal women. The present study implicates a role for PPARγ in breast cancer risk. Mechanistic studies to fully elucidate the mechanisms underlying PPARγ's effects should be pursued in future investigations.

Dietary intake of vitamin B(6) and risk of breast cancer in Taiwanese women.

BACKGROUND: B vitamins, including vitamin B(6), are coenzymes that are important for DNA integrity and stability. Deficiencies in B vitamins may promote tumor carcinogenesis. METHODS: We examined the association of dietary vitamin B(6) intake with overall breast cancer risk and breast cancers stratified by hormone receptor status. This case-control study included 391 breast cancer cases and 782 control subjects enrolled at the Tri-Service General Hospital in Taipei, Taiwan. Energy-adjusted intake of vitamin B(6) was derived from a food frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: As compared with women in the lowest tertile, the multivariate-adjusted ORs for breast cancer among women in the second and highest tertiles of vitamin B(6) intake were 0.78 (95% CI, 0.64-2.52) and 0.64 (0.26-0.92), respectively. In addition, higher vitamin B(6) intake was associated with a significantly lower risk of developing ER-negative breast tumors. CONCLUSIONS: Our findings suggest that higher intake of vitamin B(6) is associated with a reduction in breast cancer risk, particularly ER-negative tumors.

The Related Risk Factors of Diabetic Retinopathy in Elderly Patients with Type 2 Diabetes Mellitus: A Hospital-Based Cohort Study in Taiwan.

Diabetic retinopathy (DR), caused by small vessel disease, is the main cause of blindness in persons with diabetes. Taiwan is one of the Asian countries with the highest prevalence rate of DR. The purpose was to investigate the related risk factors of DR in elderly patients with type 2 diabetes mellitus (T2DM), in Lee's Endocrinology Clinic. 792 T2DM patients over 60 years old were invited to have an outpatient visit at least every three months, and all of them were asked to undergo a standardized interview and collect their blood samples. Significant factors were being female (adjusted hazard ratio (HR): 1.287; 95% CI, 1.082-1.531), higher glycated hemoglobin (HbA1c) (HR: 1.067; 95% CI: 1.016-1.119), higher mean low density of lipoprotein cholesterol (LDL-c) (HR: 1.004; 95% CI: 1.001-1.006), and chewing betel nut (HR: 1.788; 95% CI: 1.362-2.347). This study showed that gender, the behavior of chewing betel nut, HbA1c, and LDL-c are important factors for the development of DR in elderly patients with T2DM. It is suggested that patients should control their HbA1c and LDL-c and quit chewing betel nut to prevent DR. This suggestion applies especially to female patients.

MTNR1B polymorphisms with CDKN2A and MGMT methylation status are associated with poor prognosis of colorectal cancer in Taiwan.

BACKGROUND: Identifying novel colorectal cancer (CRC) prognostic biomarkers is crucial to helping clinicians make appropriate therapy decisions. Melatonin plays a major role in managing the circadian rhythm and exerts oncostatic effects on different kinds of tumours. AIM: To explore the relationship between MTNR1B single-nucleotide polymorphism (SNPs) combined with gene hypermethylation and CRC prognosis. METHODS: A total of 94 CRC tumour tissues were investigated. Genotyping for the four MTNR1B SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) was performed using multiplex polymerase chain reaction. The relationships between the MTNR1B SNPs and CRC 5-year overall survival (OS) was assessed by calculating hazard ratios with 95%CIs. RESULTS: All SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) were correlated with decreased 5-year OS. In stratified analysis, rs1387153, rs10830963, and rs1447352 risk genotype combined with CDKN2A and MGMT methylation status were associated with 5-year OS. A strong cumulative effect of the four polymorphisms on CRC prognosis was observed. Four haplotypes of MTNR1B SNPs were also associated with the 5-year OS. MTNR1B SNPs combined with CDKN2A and MGMT gene methylation status could be used to predict shorter CRC survival. CONCLUSION: The novel genetic biomarkers combined with epigenetic biomarkers may be predictive tool for CRC prognosis and thus could be used to individualise treatment for patients with CRC.

Adipocytokine resistin and breast cancer risk.

Adipocytokine resistin is a member of the newly discovered family of cysteine-rich protein. Recent data suggest that macrophages are a major source of human resistin. Given the obesity-breast cancer link and convergence of adipocyte and macrophage function, resistin may provide unique insight into links between obesity, inflammation, and breast cancer risk in humans. We conducted a hospital-based case-control study to evaluate whether plasma resistin levels were associated with breast cancer risk in women. We also examined the modification effect of estrogen exposures on the resistin-breast cancer link. Questionnaire information, anthropometric measures, and blood samples were taken before treatment from 380 incident cases with breast cancer and 760 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2008. Plasma levels of resistin were measured by enzyme immunoassay. Cumulative exposure to estrogens were estimated according to the age at menarche and age at enrollment for premenopausal women and age at menarche and age at menopause for postmenopausal women. Cases with breast cancer had significantly elevated resistin concentrations as compared with control subjects. Compared with those in the lowest quartile, the adjusted odds ratios of breast cancer for women in the second, third, and highest quartiles were 1.48 [95% confidence interval (CI) = 0.65-3.38], 1.76 (95% CI = 1.00-4.73), and 2.08 (95% CI = 1.04-3.85), respectively. Furthermore, the biological gradient of breast cancer risk by plasma resistin levels remained after adjustment for measures of adiposity. The dose-dependent relationship of resistin levels with breast cancer risk was notably pronounced among women with excess exposure to estrogens. Adipocytokine resistin may have an adiposity-independent role in breast carcinogenesis. Mechanistic studies to fully elucidate the mechanisms underlying resistin's effects should be pursued in future investigations.