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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Author Correction: Multiple gene promoter methylation and clinical stage in adjacent normal tissues: Effect on prognosis of colorectal cancer in Taiwan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel methylation gene panel in adjacent normal tissues predicts poor prognosis of colorectal cancer in Taiwan.

BACKGROUND: It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis. Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer (CRC). AIM: To estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis. METHODS: We enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways. Patients were divided into two groups based on the methylation status of the six evaluated genes, namely, the < 3 aberrancy group and ≥ 3 aberrancy group. Various tumor stages were divided into two subgroups (local and advanced stages) on the basis of the pathological type of the following tissues: Tumor and adjacent normal tissues (matched normal). We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression (TTP) and overall survival. RESULTS: We observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue. The 5-year TTP survival curves showed a significant difference between the ≥ 3 aberrancy group and the < 3 aberrancy group. Compared with the < 3 aberrancy group, a significantly shorter TTP was observed in the ≥ 3 aberrancy group. We further analyzed the interaction between CRC prognosis and different cancer stages (local and advanced) according to the methylation status of the selected genes in both types of tissues. There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages. We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues. CONCLUSION: Our data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC. We recommend using these novel markers to assist in clinical decision-making.

Multiple gene promoter methylation and clinical stage in adjacent normal tissues: Effect on prognosis of colorectal cancer in Taiwan.

This study provide an insight that the panel genes methylation status in different clinical stage tended to reflect a different prognosis even in matched normal tissues, to clinical recommendation. We enrolled 153 colorectal cancer patients from a medical center in Taiwan and used the candidate gene approach to select five genes involved in carcinogenesis pathways. We analyzed the relationship between DNA methylation with different cancer stages and the prognostic outcome. There were significant trends of increasing risk of 5-year time to progression and event-free survival of subjects with raising number of hypermethylation genes both in normal tissue and tumor tissue. The group with two or more genes with aberrant methylation in the advanced cancer stages (Me/advanced) had lower 5-year event-free survival among patients with colorectal cancer in either normal or tumor tissue. The adjusted hazard ratios in the group with two or more genes with aberrant methylation with advanced cancer stages (Me/advanced) were 8.04 (95% CI, 2.80-23.1; P for trend <0.01) and 8.01 (95% CI, 1.92-33.4; P for trend <0.01) in normal and tumor tissue, respectively. DNA methylation status was significantly associated with poor prognosis outcome. This finding in the matched normal tissues of colorectal cancer patients could be an alternative source of prognostic markers to assist clinical decision making.

Blimp-1 Contributes to the Development and Function of Regulatory B Cells.

Regulatory B cells (Bregs) are a B cell subset that plays a suppressive role in immune responses. The CD19+CD1dhiCD5+ Bregs that can execute regulatory functions via secreting IL-10 are defined as B10 cells. Bregs suppress autoimmune and inflammatory diseases, whereas they exacerbate infectious diseases caused by bacteria, viruses, or parasites. Notably, the molecular mechanisms regulating the development and functions of Bregs are still largely unknown. Furthermore, the biological impact of Bregs in fungal infection has not yet been demonstrated. Here, we compared the gene expression profiles of IL-10-producing and -non-producing mouse splenic B cells stimulated with lipopolysaccharide (LPS) or anti-CD40 antibody. Blimp-1, a transcription factor known to be critical for plasma cell differentiation, was found to be enriched in the IL-10-producing B cells. The frequency of Blimp-1+ B10 cells was increased in LPS-treated mice and in isolated B10 cells that were stimulated with LPS. Surprisingly, B cell-specific Blimp-1 knockout (Cko) mice, generated by CD19 promoter driven Cre recombinase-dependent deletion of Prdm1 (gene encoding Blimp-1), showed higher frequencies of B10 cells both in the steady state and following injection with LPS, as compared with control littermates. However, B10 cells lacking Blimp-1 failed to efficiently suppress the proliferation of naïve CD4+ T cells primed with anti-CD3 and anti-CD28 antibodies. B10 cells can be stimulated for further differentiation into plasmablasts, and a subset of plasmablasts express IL-10. We found that B10 cells from Cko mice failed to generate both IL-10-non-producing and IL-10-producing plasmablasts. Mechanistically, we found that Blimp-1 can directly suppress Il-10, whereas, in the presence of activated STAT3, Blimp-1 works together with activated STAT3 to upregulate Il-10. Moreover, we also found that B10 cells improve the clearance of Candida albicans infection but worsen the infection mortality. Notably, a lack of Blimp-1 in B10 cells did not change these effects of adoptively transferred B10 cells on fungal infections. Together, our data show that Blimp-1 regulates the generation, differentiation, and IL-10 production of Bregs.

Long-term predictive models of risk factors for early chronic kidney disease: a longitudinal study.

BACKGROUND: The high incidence and prevalence of chronic kidney disease (CKD) in Taiwan have produced tremendous burdens on health care resources. The work environment of air force special operations personnel engenders high psychological stress, and the resulting increased blood pressure can lead to glomerular hypertension and accelerated glomerular injury in the long term. The aim of the study was to establish the predictive models to define the predictors of CKD. RESULTS: The results indicated that the prevalence of CKD over 4 consecutive years was 3.8%, 9.4%, 9.0%, and 9.4%. The capability of using occult blood in urine to predict the risk of CKD after 1, 2, and 3 years was statistically significant. The age-adjusted odds ratio (OR) and 95% confidence interval (CI) were 7.94 (95% CI: 2.61-24.14), 12.35 (95% CI: 4.02-37.94) and 4.25 (95% CI: 1.32-13.70), respectively. DISCUSSION: The predictive power of occult blood in urine for the risk of CKD in each model was statistically significant. Future investigations can explore the feasibility of implementing simple and accurate urine dipsticks for preliminary testing besides annual aircrew physical examinations to facilitate early detection and treatment. METHODS: This study was a longitudinal study, in which air force special operations personnel who received physical examinations at military hospitals between 2004 and 2010 were selected. CKD was determined based on the definition provided by the US National Kidney Foundation. Overall, 212 participants that could be followed continuously for 4 years were analyzed.

Clinical stage and risk of recurrence and mortality: interaction of DNA methylation factors in patients with colorectal cancer.

Aberrant DNA methylation plays a crucial role in cancer development; however, prospective evidence of an interaction between molecular biomarkers and cancer staging for predicting the prognosis of colorectal cancer (CRC) is still limited. We examined DNA methylation in tumors and adjacent normal tissues from patients who underwent CRC surgical resection, and evaluated the interaction between cancer staging (advanced vs local) and DNA methylation to predict the prognosis of CRC. We recruited 132 patients with CRC from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select 3 tumor suppressor genes involved in carcinogenesis pathways. ORs and 95% CIs were computed using logistic regression analyses while adjusting for potential covariates. Advanced cancer stage was correlated with cancer recurrence (OR 7.22, 95% CI 2.82 to 18.45; p<0.001). In addition, after stratification by promoter methylation in 3 combined genes in the matched normal tissues, we observed a joint effect after adjusting for sex, age at surgery, and adjuvant chemotherapy, yielding a significant OR of 20.35 (95% CI 4.16 to 99.57; p<0.001). DNA methylation status would significantly increase the recurrence risk of CRC with a significant impact on joint effect between DNA methylation and clinical stage, particularly in matched normal tissues. This was attributed to molecular changes that could not be examined on the basis of clinical pathology. Our interaction results may serve as a reference marker for evaluating the risk of recurrence in future studies.

The Link of Self-Reported Insomnia Symptoms and Sleep Duration with Metabolic Syndrome: A Chinese Population-Based Study.

STUDY OBJECTIVES: The aims of this study are to investigate the relationships of metabolic syndrome (MetS) with insomnia symptoms and sleep duration in a Chinese adult population. METHODS: Data from a nationwide epidemiological survey conducted on residents from randomly selected districts in Taiwan in 2007 were used for this cross-sectional population-based study. A total of 4,197 participants were included in this study. Insomnia symptoms, including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), were assessed using the Insomnia Self-Assessment Inventory questionnaire. Subjects were divided into 3 groups based upon their reported sleep duration (< 7, 7-8, and ≥ 9 h per night). Odds ratios (ORs) and 95% confidence intervals (CIs) derived from multivariable logistic regression were used to evaluate the study aims. RESULTS: The endorsement of DIS and DMS were cross-sectionally associated with the MetS after adjustment for sleep duration (OR [95% CI] was 1.24 [1.01-1.51] and 1.28 [1.02-1.61], respectively). In addition, short sleep duration was significantly associated with the prevalence of MetS independent of insomnia symptoms (OR [95% CI] was 1.54 [1.05-2.47]). However, there was no significant combined effect of insomnia symptoms and sleep duration on the prevalence of MetS. CONCLUSIONS: The current investigation shows that short sleep duration and insomnia symptoms, specifically DIS and DMS, were significant correlates of MetS. These findings should be replicated in prospective studies using both sleep duration and sleep quality measures.

A Study on the Effects of a Health Education Intervention on Anxiety and Pain During Colonoscopy Procedures.

BACKGROUND: Colonoscopy is currently considered the best screening tool in the diagnosis of colon diseases. However, this procedure often causes pain and discomfort in patients, thus reducing patient willingness to undergo and comply with this procedure. PURPOSE: This study explores the effects of providing procedure-related information to patients receiving colonoscopy in terms of anxiety and pain reduction and identifies factors that influence the pain and anxiety experienced by patients during this procedure. METHODS: This study adopted a quasi-experimental design that targeted colonoscopy patients in outpatient clinics. Two hundred thirteen patients were recruited, with 103 patients in the experimental group and 110 in the control group. Participants were recruited between January and April 2011. All of the participants received standard care, and only those participants who were assigned to the experimental group were asked to watch "A Guide to the Colonoscopy Procedure," a multimedia health informatics CD-ROM. RESULTS: Anxiety scores of the experimental group dropped from 48.7 ± 11.6 to 39.2 ± 8.7 after the intervention. The average pain score of the experimental group was significantly lower than that of the control group (3.8 ± 2.5 vs. 5.0 ± 2.7). Furthermore, trait anxiety, gender, and educational level were identified as the main predictors for state anxiety, and state anxiety was identified as an important predictor for pain during the colonoscopy examination. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This study found that using a multimedia health informatics CD-ROM to provide information on the colonoscopy procedure effectively reduced the examination-related anxiety and pain of patients.

Association between Hyperuricemia and Metabolic Syndrome: An Epidemiological Study of a Labor Force Population in Taiwan.

The increasing prevalence of metabolic syndrome (MetS) has become an important issue worldwide. Metabolic comorbidities of hypertension, obesity, and hyperlipidemia are shown as important risk factors for incident gout. The purpose of this study was to investigate the relationship between hyperuricemia and MetS. This is a cross-sectional study. The effective sample included 21,544 individuals who received worker health examinations at a local teaching hospital in Changhua County from 2008~2012. We used multiple logistic regression analysis to investigate the influences of hyperuricemia on MetS. The results showed that individuals with MetS had significantly higher blood pressure, fasting plasma glucose, triglycerides, waist circumference, and high-density lipoprotein cholesterol than those without MetS (P < 0.001). Multiple logistic regression analysis revealed hyperuricemia to be an important factor of MetS. The risk of developing MetS is higher with high levels of serum uric acid (SUA) and the odds ratio (OR) of having MetS is 4.98 times higher for Tertile 3 than for Tertile 1 (95% CI = 4.16-5.97) and 4 times higher for Quartile 4 than for Quartile 1 (95% CI = 3.59-4.46). In conclusion, males are more likely to develop MetS than females, and the risk of having MetS increases with age and SUA concentration.