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Objective This study aimed to investigate clinical and demographic factors associated with oral health-related quality of life (OHRQoL) in patients with xerostomia. Methods Forty-one patients (55.2 ± 13.8 years) with xerostomia as a chief complaint participated in the study. Comprehensive information about clinical and demographic characteristics of the patients with xerostomia, xerostomia-related symptoms and behaviours, and xerostomia-associated complaints was investigated using a xerostomia questionnaire. Flow rates of unstimulated and stimulated whole saliva were measured. The Oral Health Impact Profile-14 (OHIP-14) score was used to assess the OHRQoL of patients. The relationships between various factors and the OHIP-14 score were assessed by simple and multiple linear regression analyses. Results The OHIP-14 score of patients with xerostomia was high (44.3 ± 13.2). Characteristics of the patients with xerostomia associated with high OHIP-14 score were the intensity of xerostomia-related symptoms, frequency of xerostomia-related behaviours and the presence of speaking difficulty. Results from multiple linear regressions found that self-reported amount of saliva in usual, everyday life (β = 0.622, p = 0.012) and the presence of a speaking difficulty (β = 0.348, p = 0.014) had significant adversely affected the OHRQoL in patients with xerostomia. Conclusions Subjective perceptions of the amount of saliva in the mouth and the experience of speaking difficulty affected the OHRQoL in patients with xerostomia.

Aberrant Wnt signaling activation is frequently observed in many cancers. The mutation acquisition of Wnt signaling leads to tumorigenesis, whereas the inhibition of Wnt signaling robustly suppresses tumor development in various in vivo models. Based on the excellent preclinical effect of targeting Wnt signaling, over the past 40 years, numerous Wnt-targeted therapies have been investigated for cancer treatment. However, Wnt signaling-targeting drugs are still not clinically available. A major obstacle to Wnt targeting is the concomitant side effects during treatment due to the pleiotropic role of Wnt signaling in development, tissue homeostasis, and stem cells. Additionally, the complexity of the Wnt signaling cascades across different cancer contexts hinders the development of optimized targeted therapies. Although the therapeutic targeting of Wnt signaling remains challenging, alternative strategies have been continuously developed alongside technological advances. In this review, we give an overview of current Wnt targeting strategies and discuss recent promising trials that have the potential to be clinically realized based on their mechanism of action. Furthermore, we highlight new waves of Wnt targeting that combine recently developed technologies such as PROTAC/molecular glue, antibody–drug conjugates (ADC), and anti-sense oligonucleotides (ASO), which may provide us with new opportunities to target ‘undruggable’ Wnt signaling.

In South Korea, popcorn consumption may have boomed in recent years but little has changed little for farmers or breeders. The majority of popcorn sold in the domestic market is derived from imported hybrids. The efforts are needed to identify parental lines and develop hybrids suitable for domestic conditions. However, the major constraint remains a narrow germplasm pool. Thus, knowledge of genetic variability among germplasm as well as among commercial hybrids is important to avoid genetic uniformity, thereby reducing the risk of vulnerability to stress and yield loss. Recently, the Maize Research Institute in Hongcheon developed valuable breeding material: ‘G-popcorn’, a new hybrid, together with ‘Oryun popcorn’, ‘Oryun popcorn2′, and ‘Gichan popcorn’. In this study, we assessed the genetic relationships among domestic and imported hybrids using 55 k single-nucleotide polymorphism (SNP) markers. Approximately 80% of the SNP markers were highly informative for future routine and low-cost genotyping. Considerable polymorphism among the SNP markers was observed with regard to reproducibility, ease of scoring, and minor allele frequency. Broad genetic diversity was detected among the germplasm analyzed; cluster analysis revealed the presence of two distinct groups of hybrids and generally agreed with pedigree information. In addition, we demonstrated the conversion of bead-chip SNP alleles into species-specific primers and used the ARMS-PCR technique to differentiate imported and domestic popcorn hybrids. The developed method will be useful for rapid and cost-effective identification of genetic purity among popcorn hybrids.

Objectives To evaluate the treatment outcomes of medication therapies in patients with burning mouth syndrome (BMS) and to identify the clinical characteristics that may affect the efficacy of prescribed medications. Methods This is a retrospective study of 769 patients with oral burning sensations. Of these patients, 420 patients diagnosed as the primary BMS received an "Initial Approach" that involved a detailed explanation about its etiopathophysiology, self-care instruction, and use of an oral lubricant. Neuropathic medications were prescribed for 277 patients who did not respond to the initial approach. Clinical characteristics, prescribed medications, and changes in intensity of oral symptoms were reviewed. Results Clonazepam was administered as the first-line medication. Alpha-lipoic acid (ALA), gabapentin, and nortriptyline were commonly administered in combination with clonazepam. More than two-thirds of the patients reported a marked improvement in oral symptoms after treatments with combination of neuropathic medications and ALA. The efficacies of the initial approach and clonazepam had significant positive associations with the initial intensity of oral symptoms and significant negative associations with depression. Conclusions Clonazepam therapy in combination with appropriate medications was effective for managing patients with BMS. The initial intensity of oral symptoms and psychological status were significantly associated with treatment outcomes.

Although chemotherapy is a key cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/β-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of β-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated β-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1β in DRG. PAC also upregulated rAxin2 in mice. Furthermore, β-catenin was expressed in neurons, including calcitonin gene–related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and β-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-020-00956-w.

The purpose of this study was to assess oral health-related quality of life (OHRQoL) in patients with burning mouth syndrome (BMS) and to identify clinical factors associated with OHRQoL.Fifty-seven patients with BMS (56.4 ± 10.7 years) participated in the study. Patients underwent oral examination, laboratory tests, psychological evaluation, measurement of salivary flow rates and evaluation of clinical characteristics using a BMS questionnaire. The OHRQoL of patients was assessed using the Oral Health Impact Profile-14 (OHIP-14).The OHIP-14 score for patients with BMS was 38.6 ± 12.8. Patients had higher scores for the psychological discomfort and physical pain dimensions of the OHIP-14. The intensity of taste disturbance or xerostomia symptoms (β = 0.464, P .001), worry about symptoms (β = 0.307, P = .020), and results of psychological evaluation (β = 0.311, P = .026) were significantly associated with OHIP-14 score. Multiple linear regression showed that the intensity of taste disturbance or xerostomia symptoms was significantly associated with decreased OHRQoL (β = 0.637, P = .026).This study suggests that severity of taste disturbance or xerostomia is an important factor that influences OHRQoL in patients with BMS.

Objective The amount of online medical information available is rapidly growing and YouTube is considered as the most popular source of healthcare information nowadays. However, no study has been conducted to comprehensively evaluate YouTube videos related to temporomandibular disorders (TMD). So this study aimed to evaluate the content and quality of YouTube videos as a source of medical information on TMD. Method A total of 237 YouTube videos that were systematically searched using five keywords (temporomandibular disorders, tmd, temporomandibular joint, tmj, and jaw joint) were included. Included videos were categorized by purpose and source for analysis. The quality (DISCERN, Health on the Net (HON), Ensuring Quality Information for Patients (EQIP), and Global Quality Scale (GQS)) and scientific accuracy of video contents were evaluated. Results Total content, DISCERN, HON, EQIP, and GQS scores were 7.5%, 38.9%, 35.2%, 53.0%, and 48.6% of the maximum possible score, respectively. Only 69 videos (29.1%) were considered as “useful” for patients. News media, physician, and medical source videos showed higher evaluation scores than others. Quality evaluation scores were not significantly correlated or negatively correlated with public preference indices. In the ROC curve analysis, content and DISCERN score showed above excellent discrimination ability for high-quality videos based on GQS ( P Conclusions YouTube videos related to TMD contained low quality and scientifically inaccurate information that could negatively influence patients with TMD.

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

The expression of TERT (telomerase reverse transcriptase) has been implicated in stem and progenitor cells, which are essential for tissue homeostasis and regeneration. However, the roles of TERT-expressing cells in the pancreas remain elusive. Employing genetically engineered Tert knock-in mouse model, herein, we located a rare population of Tert+ acinar cells. While Tert+ cells are quiescent in normal conditions, acinar cell injury leads to mitotic activation of Tert+ cells and subsequent generation of new acinar cells. Moreover, the genetic ablation of Tert+ cells impairs pancreatic regeneration. We further found that Yap/Taz activation is required for the expansion of Tert+ acinar cells. Our results identified Tert+ acinar cells as a distinct subset of acinar cells, which contributes to pancreatic regeneration via Yap/Taz activation.

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.

The purpose of this study is to apply a machine learning approach to predict whether patients with burning mouth syndrome (BMS) respond to the initial approach and clonazepam therapy based on clinical data. Among the patients with the primary type of BMS who visited the clinic from 2006 to 2015, those treated with the initial approach of detailed explanation regarding home care instruction and use of oral topical lubricants, or who were prescribed clonazepam for a minimum of 1 month were included in this study. The clinical data and treatment outcomes were collected from medical records. Extreme Gradient-Boosted Decision Trees was used for machine learning algorithms to construct prediction models. Accuracy of the prediction models was evaluated and feature importance calculated. The accuracy of the prediction models for the initial approach and clonazepam therapy was 67.6% and 67.4%, respectively. Aggravating factors and psychological distress were important features in the prediction model for the initial approach, and intensity of symptoms before administration was the important feature in the prediction model for clonazepam therapy. In conclusion, the analysis of treatment outcomes in patients with BMS using a machine learning approach showed meaningful results of clinical applicability.

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

Objectives To investigate the effects of the molecular weight of hyaluronic acid on its viscosity and enzymatic activities of lysozyme and peroxidase in solution and on the hydroxyapatite surface. Design Hyaluronic acids of four different molecular weights (10 kDa, 100 kDa, 1 MDa, and 2 MDa), hen egg-white lysozyme, bovine lactoperoxidase, and human whole saliva were used. Viscosity values of hyaluronic acids were measured using a cone-and-plate viscometer at six different concentrations (0.1–5.0 mg/mL). Enzymatic activities of lysozyme and peroxidase were examined by hydrolysis of fluorescein-labeled Micrococcus lysodeikticus and oxidation of fluorogenic 2′,7′-dichlorofluorescein to fluorescing 2′,7′-dichlorofluorescein, respectively. Results In solution assays, only 2 MDa-hyaluronic acid significantly inhibited lysozyme activities in saliva. In surface assays, hyaluronic acids inhibited lysozyme and peroxidase activities; the inhibitory activities were more apparent with high-molecular-weight ones in saliva than in purified enzymes. The 100 kDa-hyaluronic acid at 5.0 mg/mL, 1 MDa-one at 0.5 mg/mL, and 2 MDa-one at 0.2 mg/mL showed viscosity values similar to those of human whole saliva at a shear rate range required for normal oral functions. The differences among the influences of the three conditions on the enzymatic activities were not statistically significant. Conclusions High-molecular-weight hyaluronic acids at low concentration and low-molecular-weight ones at high concentration showed viscosity values similar to those of human whole saliva. Inhibitory effects of hyaluronic acids on lysozyme and peroxidase activities were more significant with high-molecular-weight ones on the surface and in saliva compared with in solution and on purified enzymes.

Introduction. A nonspecific symptom, fatigue accompanies a variety of diseases, including cancer, and can have a grave impact on patients’ quality of life. As for multidimensional instruments, one of the most widely used is the Multidimensional Fatigue Inventory (MFI). This study aims to verify the reliability and validity of the MFI Korean (MFI-K) version. Materials and Method. This study was performed at four university hospitals in the Republic of Korea. Among outpatients visiting the Department of Family Medicine, those complaining of fatigue or visiting a chronic care clinic were enrolled in this study. A total of 595 participants were included, and the mean age was 42.2 years. Results. The Cronbach’s alpha coefficient of the MFI-K was 0.88. The MFI-K had good convergent validity. Most subscales of the MFI-K were significantly correlated with the Visual Analogue Scale (VAS) and Fatigue Severity Scale (FSS). In particular, general and physical fatigue had the greatest correlation with the VAS and FSS. Although the English version of MFI had five subscales, the factor analysis led to four subscales in the Korean version. Conclusion. This study demonstrated the clinical usefulness of MFI-K instrument, particularly in assessing the degree of fatigue and performing a multidimensional assessment of fatigue.

Fine control of stem cell maintenance and activation is crucial for tissue homeostasis and regeneration. However, the mechanism of quiescence exit of Tert+ intestinal stem cells (ISCs) remains unknown. Employing a Tert knockin (TertTCE/+) mouse model, we found that Tert+ cells are long-term label-retaining self-renewing cells, which are partially distinguished from the previously identified +4 ISCs. Tert+ cells become mitotic upon irradiation (IR) injury. Conditional ablation of Tert+ cells impairs IR-induced intestinal regeneration but not intestinal homeostasis. Upon IR injury, Wnt signaling is specifically activated in Tert+ cells via the ROS-HIFs-transactivated Wnt2b signaling axis. Importantly, conditional knockout of β-catenin/Ctnnb1 in Tert+ cells undermines IR-induced quiescence exit of Tert+ cells, which subsequently impedes intestinal regeneration. Our results that Wnt-signaling-induced activation of Tert+ ISCs is indispensable for intestinal regeneration unveil the underlying mechanism for how Tert+ stem cells undergo quiescence exit upon tissue injury.

Background and aims How Wnt signaling is orchestrated in liver regeneration and tumorigenesis remains elusive. Recently, we identified transmembrane protein 9 (TMEM9) as a Wnt signaling amplifier. Approach and results TMEM9 facilitates v-ATPase assembly for vesicular acidification and lysosomal protein degradation. TMEM9 is highly expressed in regenerating liver and hepatocellular carcinoma (HCC) cells. TMEM9 expression is enriched in the hepatocytes around the central vein and acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased adenomatosis polyposis coli (Apc) and reduced Wnt signaling. Mechanistically, TMEM9 down-regulates APC through lysosomal protein degradation through v-ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain β-catenin hyperactivation. TMEM9-up-regulated APC binds to and inhibits nuclear translocation of β-catenin, independent of HCC-associated β-catenin mutations. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation suppresses Wnt/β-catenin through APC stabilization and β-catenin cytosolic retention. Conclusions Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis through lysosomal degradation of APC.

Although colonoscopy is commonly conducted for medical check-ups in Korea, investigations for the influence of bowel preparation on various health conditions are insufficient. This cross-sectional study investigated whether bowel preparation has an influence on serum levels of testosterone. A total of 1114 men were divided into the bowel preparation group and control groups. The median total and free testosterone levels were significantly lower in the bowel preparation group (14.89 and 0.26 nmol/L, respectively) than in the control groups (15.72 and 0.28 nmol/L, respectively). The level of total testosterone significantly increased with age in the bowel preparation group (r = 0.103). The differences in the levels of total and free testosterone between the 2 groups were more prominent in younger men than in older men. In multivariate regression models, bowel preparation was independently associated with the levels of total and free testosterone. In these models, the interaction between age and bowel preparation was significant for the levels of total and free testosterone. In conclusion, bowel preparation may independently decrease the serum levels of total and free testosterone. The decline in testosterone was more evident in younger men than in older men.

Long-noncodingRNAs (lncRNAs) have been proposed as a critical regulator of various cellularprocesses including cell fate decision and cell proliferation (1,2).Mechanistically, lncRNAs control various gene expressions by recruiting thechromatin modifiers in cis and trans modes (1). Transcription oflncRNAs itself also can activate or suppress the neighboring gene expression bythe transcriptional interference through regulatory sequences (1,3). lncRNAsare also involved in a wide range of protein and RNA regulatory functions, suchas scaffoldings of proteins and RNAs, protein and RNA decoys, and functionalmicro-peptides production (1). Aberrant regulation of lncRNA-mediated cellularprocesses is implicated in human disease including cancer (4,5). The recenttechnologic advance including the single-cell RNA sequencing (scRNA-seq), andgene editing, genetically engineered mouse (GEM) models has made it feasible toelucidate the various roles of lncRNAs in the normal tissue physiology and thepathologic conditions including tumorigenesis and metastasis (2,6).

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.

Objectives The purpose of this study was to examine the relationships between subjective taste sensations and electrogustometry (EGM) results in patients with taste disorders according to the presence of burning mouth symptoms. Methods Forty-six patients (11 men, 53.5 ± 19.5 years; 35 women, 52.9 ± 12.9 years) with taste disturbances as a chief complaint were included. They were asked to complete a questionnaire including subjective taste sensations of 4 basic taste qualities and the pattern of taste disorders such as ageusia, hypogeusia, and dysgeusia. EGM was performed to measure detection thresholds of the chorda tympani, glossopharyngeal, and greater petrosal nerve areas in both sides. To examine the influence of burning mouth symptoms, they were divided into 2 groups: patients with (20 patients; 2 men and 18 women) and without (26 patients; 9 men and 17 women) burning mouth symptoms. The Mann-Whitney U or Kruskal-Wallis test was used to compare variables between the groups. The chi-square test or Fisher exact test for categorical variables and the Spearman correlation analysis for continuous variables were used to investigate associations. Results There were no significant differences in age and sex distribution according to the presence of burning mouth symptoms. Compared with the patients with burning mouth symptoms, those without burning mouth symptoms reported significantly lower levels of subjective taste sensations in all taste qualities and showed higher correlation levels between subjective taste sensations and EGM thresholds. Hypogeusia was the most common in both groups. Dysgeusia was more common than ageusia in the patients with burning mouth symptoms and vice versa in those without burning mouth symptoms. The pattern of taste disorders also showed more significant associations with the levels of subjective taste sensations in the patients without burning mouth symptoms than those with burning mouth symptoms. Conclusions Patients with taste disorder without burning mouth symptoms had a more severe level of taste disturbances than those with burning mouth symptoms. The pathophysiology of taste disturbances could differ according to the presence of burning mouth symptoms.

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.

Posterior disk displacement (PDD) of the temporomandibular joint (TMJ) is a rare condition and most descriptions of TMJ PDD are about the adhesion of superior TMJ in which the position of disk is relatively posterior to anteriorly translated condyle in open mouth position. However, there have been reports about truly posteriorly positioned disk to the condyle in closed mouth position. This type of PDD has been classified into three subtypes—thin flat disk type, grossly posterior displaced disk type, and perforated disk type. Here, we report two rare cases of TMJ PDD, one with thin flat disk and one with perforated disk. Its possible etiology, pathogenetic mechanisms, related signs and symptoms, differential diagnoses, and treatments were reviewed and discussed.

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.

Background: Fatigue is a common symptom both in diseases status and in healthy subjects. Various supplements and nutraceuticals for relieving of fatigue have been used. However, there are a few studies to evaluate the efficacy and the safety of the drug for fatigue alleviation, we conducted using URSA Complex to evaluate the efficacy on physical fatigue via score changes in the checklist individual strength (CIS). Methods: The study was designed as a multicenter, randomized, double-blind, placebo-controlled trial, with subjects randomized to one of the two arms, receiving either placebo or URSA Complex administered as identical capsules. The primary efficacy endpoints of this clinical trials are the ratio of improving CIS scores < 76 points in patients at the end (4 weeks). Secondary efficacy variables are as follows one is an improvement of fatigue and the other is an improvement of the liver enzyme. Results: The fatigue recovery rate in who had improved CIS scores of < 76 points were 70.0%, 50.9% in the therapy group and placebo group, respectively (P = 0.019). The fatigue recovery rate in CIS score was higher in URSA Complex therapy group than placebo group. The difference between therapy group and placebo group was statistically significant at 4 weeks later, but not 2 weeks. Conclusions: Our results provided that the URSA Complex was effective in alleviating physical fatigue. The adverse event frequency in the therapy groups was similar to that in the placebo group.

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.