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Summary Organoids mimic the physiologic and pathologic events of organs. However, no consensus on esophageal organoid (EO) culture methods has been reached. Moreover, organoid models reproducing esophageal squamous cell carcinoma (ESCC) initiation have been unavailable. Herein, we sought to develop an esophageal minimum essential organoid culture medium (E-MEOM) for culturing murine EOs and establishing an early ESCC model. We formulated E-MEOM to grow EOs from a single cell with clonal expansion, maintenance, and passage. We found that EOs cultured in E-MEOM were equivalent to the esophageal epithelium by histological analysis and transcriptomic study. Trp53 knockout and KrasG12D expression in EOs induced the development of esophageal squamous neoplasia, an early lesion of ESCC. Here we propose the new formula for EO culture with minimum components and the organoid model recapitulating ESCC initiation, laying the foundation for ESCC research and drug discovery., Graphical abstract, Highlights • Identification of minimal components for murine EO growth and maintenance • Mouse EOs morphologically and transcriptionally recapitulate the human esophagus • Trp53 KO and KrasG12D induced esophageal neoplasia mimicking early ESCC, Cancer; Biological sciences research methodologies; Methodology in biological science

It has not been adequately studied which biomarkers for cardiovascular risk indicate changes of atherosclerosis by aging process. The current study aimed to investigate the characteristics of metabolic factors related to arterial stiffness in young and old adults. Our cross-sectional study enrolled 851 healthy young adults and 719 old adults. Metabolic biomarkers included glucose, lipid profiles, and liver enzymes. In young adults, additional biomarkers such as C-reactive protein, apolipoproteins, lipoprotein(a), ferritin, and 25-hydroxycholecalciferol were measured. Arterial stiffness was evaluated by measuring brachial-ankle pulse wave velocity (baPWV). The mean age was 37.8 and 65.1 years old in the young and old groups, respectively. Without adjustment, most parameters were significantly correlated with baPWV in both young and old groups. Mean baPWV was significantly different according to metabolic syndrome (MetS) in both groups (13.1 and 12.1 m/s in the young subjects with and without MetS, respectively; 17.4 and 15.8 m/s, respectively, in the old group). After adjusting for age, sex, and hemodynamic factors, the difference in baPWV according to MetS was significant only in the old group. The relationship between most biomarkers and baPWV was influenced by metabolic disorders such as hypertension and diabetes in old adults. Total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), and apolipoprotein B were significant in young group. In conclusion, the metabolic biomarkers related to arterial stiffness were different between young and old adults. Contrary to old adults, TC, LDLC, and apolipoprotein B were independent biomarkers for arterial stiffness in healthy young adults.

Recent evidence suggests that cellular perturbations play an important role in the pathogenesis of cardiovascular diseases. Therefore, we analyzed the association between the levels of urinary metabolites and arterial stiffness. Our cross-sectional study included 330 Korean men and women. The brachial-ankle pulse wave velocity was measured as a marker of arterial stiffness. Urinary metabolites were evaluated using a high-performance liquid chromatograph-mass spectrometer. The brachial-ankle pulse wave velocity was found to be positively correlated with l-lactate, citrate, isocitrate, succinate, malate, hydroxymethylglutarate, α-ketoisovalerate, α-keto-β-methylvalerate, methylmalonate, and formiminoglutamate among men. Whereas, among women, the brachial-ankle pulse wave velocity was positively correlated with cis-aconitate, isocitrate, hydroxymethylglutarate, and formiminoglutamate. In the multivariable regression models adjusted for conventional cardiovascular risk factors, three metabolite concentrations (urine isocitrate, hydroxymethylglutarate, and formiminoglutamate) were independently and positively associated with brachial-ankle pulse wave velocity. Increased urine isocitrate, hydroxymethylglutarate, and formiminoglutamate concentrations were associated with brachial-ankle pulse wave velocity and independent of conventional cardiovascular risk factors. Our findings suggest that metabolic disturbances in cells may be related to arterial stiffness.

Summary The DREAM complex orchestrates cell quiescence and the cell cycle. However, how the DREAM complex is deregulated in cancer remains elusive. Here, we report that PAF (PCLAF/KIAA0101) drives cell quiescence exit to promote lung tumorigenesis by remodeling the DREAM complex. PAF is highly expressed in lung adenocarcinoma (LUAD) and is associated with poor prognosis. Importantly, Paf knockout markedly suppressed LUAD development in mouse models. PAF depletion induced LUAD cell quiescence and growth arrest. PAF is required for the global expression of cell-cycle genes controlled by the repressive DREAM complex. Mechanistically, PAF inhibits DREAM complex formation by binding to RBBP4, a core DREAM subunit, leading to transactivation of DREAM target genes. Furthermore, pharmacological mimicking of PAF-depleted transcriptomes inhibited LUAD tumor growth. Our results unveil how the PAF-remodeled DREAM complex bypasses cell quiescence to promote lung tumorigenesis and suggest that the PAF-DREAM axis may be a therapeutic vulnerability in lung cancer., Graphical abstract, Highlights • Paf KO suppresses lung adenocarcinoma (LUAD) development • PAF depletion induces cell quiescence and growth arrest of LUAD cells • PAF drives the global expression of cell-cycle genes by remodeling the DREAM complex • Pharmacological mimicking of PAF-depleted transcriptomes inhibits LUAD growth, Bypassing cell quiescence and cell-cycle arrest is a crucial step for tumorigenesis. Here, Kim et al. show that a PAF-remodeled DREAM complex induces the global expression of cell-cycle genes, thereby evading quiescence and promoting lung tumorigenesis.

Copper, an essential micronutrient, is required for lipid metabolism, mitochondrial function, iron metabolism, and antioxidant defense. Copper deficiency has been linked to alterations in lipid metabolism and various metabolic processes of the liver, including nonalcoholic fatty liver disease (NAFLD); however, most of these studies relied on copper measurements in the blood or tissues. In this study, we investigated the association between hair copper concentration and NAFLD in Korean adults, independent of metabolic syndrome status. Clinical and laboratory parameters, including factors of metabolic syndrome, were analyzed in 751 Korean adults divided into quintiles, according to hair copper concentration. Lower hair copper concentration was significantly correlated with higher body mass index, waist circumference, blood pressure, and lower levels of high-density lipoprotein cholesterol. Subjects with NAFLD showed significantly lower hair copper concentrations, and the risk of NAFLD was significantly higher for the lower hair copper quintile groups even after adjusting for metabolic syndrome-related factors. Overall, this study suggests that lower hair copper concentration could be associated with NAFLD, independent of metabolic syndrome factors.

Vesicular acidification and trafficking are associated with various cellular processes. However, their pathologic relevance to cancer remains elusive. We identified transmembrane protein 9 (TMEM9) as a vesicular acidification regulator. TMEM9 is highly upregulated in colorectal cancer. Proteomic and biochemical analyses show that TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking. TMEM9-v-ATPase hyperactivates Wnt/β-catenin signalling via lysosomal degradation of adenomatous polyposis coli (APC). Moreover, TMEM9 transactivated by β-catenin functions as a positive feedback regulator of Wnt signalling in colorectal cancer. Genetic ablation of TMEM9 inhibits colorectal cancer cell proliferation in vitro, ex vivo and in vivo mouse models. Moreover, administration of v-ATPase inhibitors suppresses intestinal tumorigenesis of APC mouse models and human patient-derived xenografts. Our results reveal the unexpected roles of TMEM9-controlled vesicular acidification in hyperactivating Wnt/β-catenin signalling through APC degradation, and propose the blockade of TMEM9-v-ATPase as a viable option for colorectal cancer treatment.

Epithelial integrity is maintained by the cytoskeleton and through cell adhesion. However, it is not yet known how a deregulated cytoskeleton is associated with cancer. We identified cancer-related regulator of actin dynamics (CRAD) as frequently mutated or transcriptionally downregulated in colorectal cancer. We found that CRAD stabilizes the cadherin–catenin–actin complex via capping protein inhibition. The loss of CRAD inhibits F-actin polymerization and subsequently disrupts the cadherin–catenin–actin complex, which leads to β-catenin release and Wnt signalling hyperactivation. In mice, CRAD knockout induces epithelial cell integrity loss and Wnt signalling activation, resulting in the development of intestinal mucinous adenoma. With APC mutation, CRAD knockout initiates and accelerates mucinous and invasive adenoma development in the colorectum. These results define CRAD as a tumour suppressor, the inactivation of which deregulates the cytoskeleton and hyperactivates Wnt signalling thus initiating mucinous colorectal cancer. Our study reveals the unexpected roles of an actin cytoskeletal regulator in maintaining epithelial cell integrity and suppressing tumorigenesis. Jung et al. demonstrate that loss of CRAD impairs F-actin polymerization and disrupts the cadherin–catenin–actin complex, thereby hyperactivating Wnt signalling and promoting mucinous intestinal tumorigenesis.

Background: Korean Red Ginseng (KRG) has been used in Asia for its various biological effects, but no studies have investigated the safety of its long-term intake. Therefore, the present study evaluated the safety of KRG intake for 24 weeks. Methods: We randomized 1,000 participants in a 1:1 ratio into two groups, which were treated daily with 2 g of KRG or a placebo for 24 weeks. The primary endpoint was all adverse events and adverse drug reactions (ADRs) that occurred after KRG or placebo administration, which were reported at week 4, 12, and 24 after the baseline visit. Results: In total, 192 and 211 participants experienced adverse events in the KRG and placebo groups (39.2% and 42.0%, respectively; p = 0.361), and 59 and 57 KRG- and placebo-treated individuals reported ADRs (12.0% and 11.4%, respectively; p = 0.737). The frequently occurring ADRs were pruritus (2.0%), headache (1.6%), diarrhea (1.4%), and dizziness (1.2%) in the KRG group and pruritus (2.0%), headache (1.8%), dizziness (1.6%), rash (1.4%), and diarrhea (1.2%) in the placebo group. Discontinuation of drug administration due to ADRs was reported in 13 participants, six (1.2%) and seven (1.4%) in the KRG and placebo groups, respectively (p = 0.814). No significant abnormal changes were revealed by anthropometric, laboratory, and vital sign measurements in the KRG group compared with those in the placebo group. Conclusion: The present study confirms the safety and tolerability of daily intake of 2 g of KRG for 24 weeks by healthy adults. Keywords: Adverse drug reaction, Adverse event, Korean Red Ginseng, Safety, Tolerability

Corticosterone (CORT)-induced oxidative stress and neurotoxicity can cause neuronal dysfunction and mental disorders. In the present study, we investigated the effects and mechanism of the HP-20 resin fraction of the water extract of Vaccinium bracteatum leaves (NET-D1602) and its bioactive compound p-coumaric acid on neuronal cell damage in SH-SY5Y cells and primary culture of rat cortical cells. NET-D1602 and p-coumaric acid significantly improved cell viability in CORT-induced neurotoxicity in SH-SY5Y cells and primary cultures of rat cortical cells, and increased the activities of antioxidant enzymes (superoxide dismutase and catalase) against CORT-induced neurotoxicity in SH-SY5Y cells. NET-D1602 and p-coumaric acid increased the phosphorylation levels of ERK1/2 and cAMP response element-binding protein (CREB) in cortical neurons. In addition, CREB phosphorylation by NET-D1602 and p-coumaric acid was dramatically reversed by PKA, c-Raf/ERK, PI3K, and mTOR inhibitors. Lastly, we demonstrated the neuroprotective effects of NET-D1602 (3 and 10 μg/mL) and p-coumaric acid (3 and 10 μM) via increased CREB phosphorylation in CORT-induced neurotoxicity mediated via the ERK1/2, Akt, and mTOR pathways. These results suggest that p-coumaric acid is a potential neuroprotective component of NET-D1602, with the ability to protect against CORT-induced neurotoxicity by regulating ERK1/2, Akt, and mTOR-mediated CREB phosphorylation.

Testosterone and insulin-like growth factor-1 (IGF-1) are essential factors for the maintenance of bone health in men. However, the results for the association of testosterone and IGF-1 with bone parameters were not consistent in prior studies. We evaluated the relationship of testosterone, sex hormone-binding globulin (SHBG), and IGF-1 with bone mineral density (BMD) and bone turnover markers (BTMs) in Korean men. We enrolled 1227 men aged ≥50 years in this cross-sectional study. Serum levels of total testosterone (TT), SHBG, IGF-1, osteocalcin, and C-terminal cross-linking telopeptide of type I collagen (CTX) were measured. Free testosterone (FT) was calculated using Vermeulen's method. BMD was measured by dual-energy X-ray absorptiometry. TT level was not related to BMD or BTMs in the unadjusted model; however, after adjusting for SHBG and IGF-1, the association between TT and BTMs was significant (β = -0.139 for osteocalcin and β = -0.204 for CTX). SHBG levels were negatively associated with lumbar BMD, and positively associated with BTMs in all models. As SHBG level increased, the prevalence of osteopenia or osteoporosis defined by BMD significantly increased (OR of 1SD change, 1.24). IGF-1 levels were significantly related with BMD, but not with BTMs. Meanwhile, FT levels were positively associated with BMD and negatively associated with BTMs. In conclusion, SHBG levels were independently related with bone parameters and osteopenia in men aged ≥50 years. IGF-1 levels were positively associated with BMD, but not with BTMs. SHBG may play a role in regulating age-related bone loss in men after middle-age.

ObjectiveTo examine the hypothesis that the association between vitamin D deficiency and depressive symptoms is dependent upon total cholesterol level in a representative national sample of the South Korean population.DesignThis was a population-based cross-sectional study.SettingThe Fifth Korean National Health and Nutrition Examination Survey (KNHANES V, 2010–2012).SubjectsWe included 7198 adults aged 20–88 years.ResultsThe incidence of depressive symptoms in individuals with vitamin D deficiency (serum 25-hydroxyvitamin DConclusionsThe association between vitamin D deficiency and depressive symptoms was weakened by high serum total cholesterol status. These findings suggest that both vitamin D and total cholesterol are important targets for the prevention and treatment of depression.

Objectives Emerging evidence suggests that intermuscular adipose tissue is a risk factor for insulin resistance, but the underlying mechanism still remains unclear. We investigated whether the levels of leptin, adiponectin, and monocyte chemoattractant protein-1 are associated with intermuscular adipose tissue in obese subjects. Design and methods A cross-sectional study was performed on 77 obese Korean women. Areas of visceral adipose tissue, subcutaneous adipose tissue, and intermuscular adipose tissue were measured by computed tomography scan, and serum concentrations of adipokines were measured by enzyme-linked immunosorbent assays. Correlation between the levels of adipokines and the fat areas was assessed using Pearson correlation and covariate-adjusted multivariable regression. Results Leptin was positively correlated with subcutaneous adipose tissue (r = 0.452, P

The relationship between bone turnover markers and atherosclerosis is controversial.The purpose of this study was to determine the association of arterial stiffness with the levels of osteocalcin and C-terminal telopeptide of type I collagen (CTx).This cross-sectional study included 1691 men and 1913 women who participated in the medical examination programs of a hospital from March 2008 to December 2011.Arterial stiffness was estimated by brachial-ankle pulse wave velocity (baPWV). Osteocalcin and CTx were assayed by chemiluminescence immunoassay. Bone mineral density was measured by dual-energy X-ray absorptiometry.The mean baPWV was elevated at both ends of the osteocalcin quintiles in both men and women. However, the adjusted mean was higher in the lowest quintile of osteocalcin than in the other quintiles in men and women. Before adjustment, negative and positive relationships of baPWV with the levels of osteocalcin and CTx were observed in men (β = -0.123 and -0.078 for osteocalcin and CTx, respectively) and women (β = 0.151 and 0.193), respectively. After adjustment for age and metabolic parameters, osteocalcin was negatively related with baPWV at lower osteocalcin levels (Q1-Q2) in both sexes (in the fully adjusted model, β = -0.090 for men and -0.053 for women). No significant relationship was observed at higher values. The osteocalcin level was fit for a quadratic model for baPWV showing an inverse J-shape.The level of serum osteocalcin showed an inverse J-shaped relationship with arterial stiffness in both men and women. However, the association between the CTx level and arterial stiffness was not significant.

Simple Summary Therapeutic targeting of Wnt has long been suggested for gastrointestinal (GI) cancer treatment because deregulation of Wnt signaling is associated with GI cancers. However, therapeutic targeting of Wnt is still challenging because of the pleiotropic roles of Wnt signaling in the human body. Thus, targeting strategies of Wnt signaling are continuously evolving. The current flows of targeting Wnt signaling for cancer treatment are focused on increasing the specificity of drugs and combinatory treatment with other cancer drugs that minimize side effects and increase efficacy. Additionally, increased knowledge about the β-catenin paradox has expanded the cases that can be treated with Wnt targeting therapy, not strictly considering Wnt upstream and downstream mutations. Here, we discuss these evolving views of targeting Wnt signaling and describe examples of current clinical trials. Abstract Wnt signaling governs tissue development, homeostasis, and regeneration. However, aberrant activation of Wnt promotes tumorigenesis. Despite the ongoing efforts to manipulate Wnt signaling, therapeutic targeting of Wnt signaling remains challenging. In this review, we provide an overview of current clinical trials to target Wnt signaling, with a major focus on gastrointestinal cancers. In addition, we discuss the caveats and alternative strategies for therapeutically targeting Wnt signaling for cancer treatment.

Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.

Objectives While weight gain is known as a predictor of non-alcoholic fatty liver disease (NAFLD) incidence, it remains controversial whether adipokine levels predict the development of NAFLD. We aimed to investigate the relationship of total adiponectin, high-molecular-weight (HMW) adiponectin, and leptin with the development and improvement of non-alcoholic fatty liver (NAFL) independent of sex and weight change over a maximum of 8.5 years. Methods This prospective study enrolled 2735 participants in a hospital health check-up setting. Adipokine levels were measured at baseline. NAFL was assessed with liver ultrasonography, and the development or improvement of NAFL was determined by repeated ultrasonography at follow-ups. Results Cross-sectional analyses revealed that total and HMW adiponectin levels were inversely associated with NAFL prevalence. In longitudinal analyses, the incidence of NAFL was 5.6 per 100-person-years during the observation period. The hazard ratios (HRs) per 1 μg/mL increase in the levels of total and HMW adiponectin were 0.900 (0.836–0.969) and 0.846 (0.754–0.948), respectively. Sex-stratified analyses showed that total and HMW adiponectin levels were significantly related to NAFL incidence only in women. In the subgroup of minimal weight change, only HMW adiponectin was a significant predictor for NAFL. Leptin predicted NAFL in the subgroup with weight gain. The improvement of NAFL was influenced by weight change, but not by adipokine levels. Conclusions Low levels of total and HMW adiponectin may predict the development of NAFL independent of pathophysiological factors including obesity and insulin resistance. This predictability was evident in women. Leptin was a significant predictor for NAFL in the subjects with weight gain.

This study investigated the effects of changes in metabolic syndrome (MS) status and each component on subsequent dementia occurrence. The study population was participants of a biennial National Health Screening Program in 2009&ndash, 2010 and 2011&ndash, 2012 in Korea. Participants were divided into four groups according to change in MS status during the two-year interval screening: sustained normal, worsened (normal to MS), improved (MS to normal), and sustained MS group. Risk of dementia among the groups was estimated from the second screening date to 31 December 2016 using a Cox proportional hazards model. A total of 4,106,590 participants were included. The mean follow-up was 4.9 years. Compared to the sustained normal group, adjusted hazard ratios (aHR) (95% confidence interval) were 1.11 (1.08&ndash, 1.13) for total dementia, 1.08 (1.05&ndash, 1.11) for Alzheimer&rsquo, s disease, and 1.20 (1.13&ndash, 1.28) for vascular dementia in the worsened group, 1.12 (1.10&ndash, 1.15), 1.10 (1.07&ndash, 1.13), and 1.19 (1.12&ndash, 1.27) for the improved group, and 1.18 (1.16&ndash, 1.20), 1.13 (1.11&ndash, 1.15), and 1.38 (1.32-1.44) for the sustained MS group. Normalization of MS lowered the risk of all dementia types, total dementia (aHR 1.18 versus 1.12), Alzheimer&rsquo, s disease (1.13 versus 1.10), and vascular dementia (1.38 versus 1.19). Among MS components, fasting glucose and blood pressure showed more impact. In conclusion, changes in MS status were associated with the risk of dementia. Strategies to improve MS, especially hyperglycemia and blood pressure, may help to prevent dementia.

Background and Aims The association between testosterone level and development of non-alcoholic fatty liver disease (NAFLD) is not well known. We examined the relationship of total testosterone level with development and regression of NAFLD. Methods Among the men who had undergone repeated liver ultrasonography in 2 years or more at a health promotion center, subjects with available serum testosterone level at baseline were included in the study. Alcohol consumers (> 20 g/day) were excluded from the study. Results Among the 1944 men, 44.3% of subjects were diagnosed with NAFLD. Higher level of testosterone significantly lowered the prevalence of fatty liver (odds ratios per SD increase, 0.686 and 0.795 at baseline and follow-up, respectively). During the median 4.2 years follow-up, 22.4% of subjects in the normal group developed fatty liver, and 21.0% of subjects in the NAFLD group recovered at the follow-up. In longitudinal analyses, higher level of testosterone was significantly associated with the development or regression of fatty liver, before adjustment for obesity and metabolic parameters. However, in the full-adjusted model, testosterone level did not influence the development or regression of fatty liver. Conclusions Although testosterone level was significantly low in the subjects with NAFLD in cross-sectional analyses, baseline testosterone level did not independently influence the development or regression of fatty liver at the median 4.2 years follow-up. Obesity and metabolic parameters may play key roles in the link between testosterone level and NAFLD.

The association between sex hormone-binding globulin (SHBG) and arterial stiffness in women is not conclusive. In addition, obesity might also be involved in the relationship between SHBG and atherosclerosis. The aim of this study was to determine the relationship between SHBG and arterial stiffness in association with central obesity in women. This cross-sectional study included 381 women who participated in the health checkup programs in one hospital. The brachial-ankle pulse wave velocity (baPWV) was measured as a marker for arterial stiffness. A negative correlation was observed between SHBG levels and baPWV (rho = −0.281). The relationship was significant even after adjusting for potential confounders (beta = −0.087 in fully adjusted model). After considering the interaction between central obesity and SHBG levels, the significant association was evident only in obese women (Pfor interaction = 0.025). Adjustment for a 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores, instead of each cardiovascular risk factor individually, did not affect the significance of the relationship between SHBG levels and baPWV. Serum levels of SHBG were negatively associated with arterial stiffness independent of cardiovascular risk factors or 10-year ASCVD risk scores in Korean women. The relationship may be potentiated by central obesity.

Although zinc was known to be associated with insulin metabolism and diabetes, the relationship of serum zinc concentration with insulin resistance (IR) and metabolic syndrome (MetS) was not well investigated in general population. The aim of this study is to evaluate the relationships of serum zinc concentration with IR and MetS in a nondiabetic adult population. This cross-sectional study included 656 men and 825 women who were nondiabetic adults from the fifth Korea National Health and Nutrition Examination Survey conducted in 2010. Serum zinc concentration and metabolic parameters were measured. IR was estimated by homeostatic model assessment (HOMA2). MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. Serum zinc concentration was negatively correlated with homeostasis model assessment for insulin resistance (HOMA2-IR) in men (r = -0.104, P = 0.008), but not in women. After adjusting for conventional cardiovascular risk factors, the inverse correlation was significant in both men and women (B = -0.262, SE = 0.060 for men, and B = -0.129, SE = 0.052 for women). However, serum zinc concentration was not different between the groups with and without MetS (P = 0.752 for men and P = 0.371 for women). In conclusion, serum zinc concentration was inversely associated with IR but not related to MetS in nondiabetic adult population.

Aims Our aim was to clarify the association between type 2 diabetes and the risk of low muscle mass in older adults. Methods In the present study, 414 adults aged 65 years or older (144 patients with type 2 diabetes and 270 control participants) were included. Body composition was measured by dual-energy X-ray absorptiometry. Low muscle mass was defined as the appendicular skeletal muscle mass/height2 (ASM/Ht2) or appendicular skeletal muscle mass/weight (ASM/Wt) of

Background: The purpose of this study was to compare clinical features of vitamin B-12 deficiency patients with a history of gastrectomy to those without a history of gastrectomy. Methods: Twenty-two patients with vitamin B-12 deficiency were included. Patients' chief complaints, oral manifestations, blood examination results, and past medical histories were reviewed. Results: Eleven patients had a history of gastrectomy and 11 did not. The chief complaint was glossodynia in all patients. No significant differences were observed between the two groups regarding age, sex, symptom duration, or plasma vitamin B-12 level. Erythema and depapillation of the tongue were the most common findings, however less common among patients without a history of gastrectomy. Two patients with a history of gastrectomy and 5 patients without a history of gastrectomy had normal oral mucosa. Patients with a history of gastrectomy were more anemic. Oral symptoms of the majority of patients responded to antifungals and vitamin B-12 replacement. The suggested etiologies for vitamin B-12 deficiency in the patients without a history of gastrectomy were gastritis, medications, diet, autoimmunity, and early gastric cancer. Conclusions: Vitamin B-12 deficiency and its associated etiological factors should be considered in patients with glossodynia, even those whose oral mucosa appears normal and who lack a history of gastrectomy.

Results regarding the association between adipokine levels and bone mineral density (BMD) have been inconsistent; the effects of sex, menopause, and central obesity remain unknown. We evaluated the association between serum leptin, adiponectin, and high-molecular-weight (HMW) adiponectin levels and BMD according to menopause and central obesity status in Korean women. This cross-sectional study comprised 255 women undergoing examinations at the CHA Bundang Medical Center. Participants were divided according to menopause, and central obesity status. We measured serum adipokine levels and BMD using an enzyme-linked immunosorbent assay and dual-energy X-ray absorptiometry, respectively. After adjusting for age, body mass index, alkaline phosphatase levels and the Homeostasis Model Assessment index, leptin levels were negatively associated with non-vertebral BMD (total hip, β = −0.576, P = 0.006; femoral neck, β = −0.608, P = 0.007) in postmenopausal women without central obesity. Among women without central obesity, HMW adiponectin levels were positively associated with total hip BMD (β = 0.240, P = 0.010) in premenopausal women but negatively associated with BMD (lumbar, β = −0.436, P = 0.012; femoral neck, β = −0.468, P = 0.007) in postmenopausal women. Thus, the association between adipokine levels and BMD varies according to the menopause and central obesity status.

Epithelial cell behavior and homeostasis are mainly modulated by the cytoskeleton and cell adhesion. However, much concerning epithelial cell deregulation in cancer remains unknown. We identified Cancer-related Regulator of Actin Dynamics (CRAD) as frequently mutated or transcriptionally downregulated in colorectal cancer. We found that CRAD is a capping protein inhibitor and stabilizes the cadherin-catenin-actin (CCA) complex. CRAD inactivation disrupts the CCA complex via inhibiting actin polymerization, liberating β-catenin and aberrantly activating Wnt pathway. In mice, CRAD knockout induces the loss of epithelial cell integrity and hyperactivates Wnt signaling, resulting in intestinal adenoma development. With APC mutation, CRAD knockout induces and accelerates mucinous and invasive adenoma development in the colorectum. These results define CRAD as a new tumor suppressor, of which inactivation deregulates the cytoskeleton and hyperactivates Wnt signaling, initiating mucinous intestinal tumorigenesis. Our study reveals the unexpected roles of an actin cytoskeletal regulator in maintaining epithelial cell integrity. Citation Format: Youn-Sang Jung, Wenqi Wang, Sohee Jun, Jie Zhang, Mrianl Srivastava, Moon Jong Kim, Esther M. Lien, Joan Shang, Pierre D. McCrea, Songlin Zhang, Junjie Chen, Jae-Il Park. Tumorigenesis by deregulation of CRAD-controlled cytoskeleton dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4473.

CONTEXT The association of low muscle mass with cardiometabolic risks is still controversial. OBJECTIVE The aim of this study was to investigate the relationship between low muscle mass and metabolic syndrome (MetS) according to the various muscle mass indices and to evaluate the influence of muscle mass on MetS independent of fat mass. DESIGN Cross-sectional study SUBJECTS About 841 men and 1106 women aged 70 or older from Korea National Health and Nutrition Examination Survey 2008-2010 MEASUREMENTS: We used various muscle mass indices: appendicular skeletal muscle mass (ASM) divided by height squared (ASM/Ht(2) ), ASM divided by body weight (ASM/Wt) and ASM adjusted for height and fat mass (residual). Low muscle mass is defined as ASM/Ht(2) and ASM/Wt below 2 SD of the sex-specific mean for healthy young adults. The sex-specific lowest quintile of the distribution of the residual was regarded as low muscle mass. RESULTS The prevalence of MetS was higher in the population with low muscle mass defined by ASM/Wt, but lower in those defined by ASM/Ht(2) . However, after stratification according to the central obesity, low muscle mass was barely related with MetS. Meanwhile, when both ASM and fat mass were included in a logistic regression model, the odds ratios of 1 SD change of ASM for MetS were 1·07 (0·85-1·34) for men and 1·24 (1·04-1·47) for women, respectively. CONCLUSIONS The relationship between low muscle mass and MetS was different according to the various muscle mass indices. After controlling the influence of fat mass, decreased muscle mass was not an independent risk factor for MetS.

Background: The relationship between serum homocysteine levels and non-alcoholic fatty liver disease is poorly understood. This study aims to investigate the sex-specific relationship between serum homocysteine level and non-alcoholic fatty liver disease in the Korean population. Methods: This cross-sectional study included 150 men and 132 women who participated in medical examination programs in Korea from January 2014 to December 2014. Patients were screened for fatty liver by abdominal ultrasound and patient blood samples were collected to measure homocysteine levels. Patients that consumed more than 20 grams of alcohol per day were excluded from this study. Results: The homocysteine level (11.56 vs. 8.05 nmol/L) and the proportion of non-alcoholic fatty liver disease (60.7% vs. 19.7%) were significantly higher in men than in women. In men, elevated serum homocysteine levels were associated with a greater prevalence of non-alcoholic fatty liver disease (quartile 1, 43.6%; quartile 4, 80.6%; P=0.01); however, in females, there was no significant association between serum homocysteine levels and the prevalence of non-alcoholic fatty liver disease. In the logistic regression model adjusted for age and potential confounding parameters, the odds ratio for men was significantly higher in the uppermost quartile (model 3, quartile 4: odds ratio, 6.78; 95% confidential interval, 1.67 to 27.56); however, serum homocysteine levels in women were not associated with non-alcoholic fatty liver disease in the crude model or in models adjusted for confounders. Conclusion: Serum homocysteine levels were associated with the prevalence of non-alcoholic fatty liver disease in men.

Weight loss in older persons is associated with a variety of deleterious effects, including hip fracture, pressure ulcers, decreasing immune function, decreased functional status, and death. There are 4 major causes of weight loss: anorexia, sarcopenia, cachexia, and dehydration. Many of the reasons for the development of these conditions are treatable. For example, depression is the most common cause of weight loss in the elderly. Early screening for anorexia can be undertaken in the physician's office utilizing the Simplified Nutritional Assessment Questionnaire. An algorithmic approach to the office management of weight loss is provided.

PURPOSE: To describe two cases of bacterial keratitis with atypical mycobacteria after laser in situ keratomileusis (IASIK). METHODS: Two cases of non-tuberculous mycobacterial keratitis occurred in the interface between the stromal bed and flap, 20 days and 14 days after LASIK. The keratitis progressed slowly and worsened after attempts were made to renio ve the colonies. Mycobacterium fortuitum was confirmed 2 months after initial presentation following culture of the excised flap tissue in one case, and Mycobacterium chelonae was identified by culture of removed material and by RT-PCR with primers in the other case. The patients were treated medically and by surgical flap removal. RESULTS: In the first case, the keratitis was controlled only after removal of the partially melted flap and intensive medical treatment. In the second case, the lesion cleared after 2 months of antibiotics, but after tapering of antibiotics, the infiltrate progressed. Eventually, the keratitis was controlled after removal of the flap. CONCLUSIONS: Non-tuberculous Mycobacterium should be considered as one of the causes of keratitis when presenting as white colonies in the lamellar bed after LASIK. Treatment for 2 months may not be enough to eradicate the infection and excision of the flap may be necessary. [J Refract Surg 2002;18?.81-85]

Our aim was to examine whether serum testosterone concentrations are in fact low in hospitalized men with poorly controlled type 2 diabetes compared with healthy men. In this study, 79 men aged 40 years or older (41 healthy men and 38 men with type 2 diabetes) were included. Total testosterone and sex hormone-binding globulin levels were measured. The average duration of diagnosed diabetes was 10.8 years and the mean glycated hemoglobin value was 10.8%. Total testosterone concentrations were lower in men with type 2 diabetes than in healthy men, after adjusting for age and body mass index (3.83±0.32 ng/mL vs. 5.63±0.31 ng/mL, P

BACKGROUND/AIMS Nonalcoholic fatty liver disease (NAFLD) is known to be closely associated with various metabolic abnormalities including metabolic syndrome. However, there are few data available on the association of metabolic syndrome with the sonographically fatty liver and normal range of liver function test. The purposes of this study were to find the incidence of ultrasonographic fatty liver with normal range of liver function test and to evaluate the association with metabolic syndrome in apparently healthy Korean adults. METHODS We examined 538 men and women, aged 30-80 years, who participated in a health screening test. Among the people with normal ALT level, we compared clinical characteristics and prevalence of metabolic disorders according to the presence of nonalcoholic sonographyally fatty liver, and then they were subdivided into upper normal range and lower normal range of ALT level. RESULTS Compared to the people without sonographic fatty liver, people with sonographic fatty liver and normal range of ALT level had odds ratios for metabolic syndrome of 4.53, insulin resistance 4.83, hypertension 2.69, dyslipidemia 6.90, and obesity 5.39, respectively. Furthermore, the prevalence of metabolic syndromes and other metabolic disorders were increased in both sonographically fatty liver group or ultrasonographically normal liver group with upper normal range of ALT level compared with lower normal ALT level (p

Background/Aims The proper treatment of subclinical hypothyroidism and the normal range of serum thyroid stimulating hormone (TSH) concentration are intensely debated. However, few reports have investigated TSH concentrations in Asian ethnic groups. Therefore, the present study was designed to define the TSH reference range in a Korean population and to investigate the metabolic significance of TSH concentration. Methods We enrolled patients who underwent medical examination at the CHA Bundang Medical Center. Anthropometric data were evaluated, and serum TSH, free T4, and lipid profiles were assayed. Results A total of 7,270 subjects were included. Mean TSH concentration of the study population was 1.82 ± 0.95 mU/L, and we observed a sex-related difference in TSH concentration (male, 1.67 ± 0.87 mU/L; female, 2.02 ± 1.01 mU/L; p < 0.01). When the 2.5 and 97.5 percentiles were calculated, 95% TSH reference limits were 0.52-4.29 mU/L. TSH concentration was higher in elderly subjects, during winter, in postmenopausal women, and in obese males. Moreover, TSH showed significantly positive correlations with serum total cholesterol, triglyceride, and low density lipoprotein cholesterol regardless of sex, age, season, obesity, or menopausal status (all p < 0.01). Finally, TSH concentration was positively related to the prevalence of metabolic syndrome. Conclusions We demonstrated the association between TSH concentration within the normal reference range and serum lipid levels. TSH concentration varies according to sex, age, season, and body mass index (only in males). Moreover, high normal TSH levels were significantly associated with an increased prevalence of metabolic syndrome, which may be of importance when evaluating subjects with high normal TSH concentration.