Saururus chinensis (Lour.) Baill. extract promotes skeletal muscle cell differentiation by positively regulating mitochondrial biogenesis and AKT/mTOR signaling in vitro.

Promotion of myoblast differentiation by activating mitochondrial biogenesis and protein synthesis signaling pathways provides a potential alternative strategy to balance energy and overcome muscle loss and muscle disorders. Saururus chinensis (Lour.) Baill. extract (SCE) has been used extensively as a traditional herbal medicine and has several physiological activities, including anti­asthmatic, anti­oxidant, anti­inflammatory, anti­atopic, anticancer and hepatoprotective properties. However, the effects and mechanisms of action of SCE on muscle differentiation have not yet been clarified. In the present study, it was investigated whether SCE affects skeletal muscle cell differentiation through the regulation of mitochondrial biogenesis and protein synthesis in murine C2C12 myoblasts. The XTT colorimetric assay was used to determine cell viability, and myosin heavy chain (MyHC) levels were determined using immunocytochemistry. SCE was applied to C2C12 myotube at different concentrations (1, 5, or 10 ng/ml) and times (1,3, or 5 days). Reverse transcription­quantitative PCR and western blotting were used to analyze the mRNA and protein expression change of factors related to differentiation, mitochondrial biogenesis and protein synthesis. Treatment of C2C12 cells with SCE at 1,5, and 10 ng/ml did not affect cell viability. SCE promoted C2C12 myotube formation and significantly increased MyHC expression in a concentration­ and time­dependent manner. SCE significantly increased the mRNA and protein expression of muscle differentiation­specific markers, such as MyHC, myogenic differentiation 1, myogenin, Myogenic Factor 5, and ß­catenin, mitochondrial biosynthesis­related factors, such as peroxisome proliferator­activated receptor­gamma coactivator­1α, nuclear respirator factor­1, AMP­activated protein kinase phosphorylation, and histone deacetylase 5 and AKT/mTOR signaling factors related to protein synthesis. SCE may prevent skeletal muscle dysfunction by enhancing myoblast differentiation through the promotion of mitochondrial biogenesis and protein synthesis.

Comparison of endoscopic healing and durability between infliximab originator and CT-P13 in pediatric patients with inflammatory bowel disease.

Background and aims: Favourable clinical data were published on the efficacy of CT-P13, the first biosimilar of infliximab (IFX), in pediatric inflammatory bowel disease (IBD); however, few studies have compared the effect on endoscopic healing (EH) and drug retention rate between the IFX originator and CT-P13. Therefore, we aimed to compare EH and the drug retention rate between the IFX originator and CT-P13. Methods: Children with Crohn's disease (CD) and ulcerative colitis (UC)/IBD-unclassified (IBD-U) at 22 medical centers were enrolled, with a retrospective review conducted at 1-year and last follow-up. Clinical remission, EH and drug retention rate were evaluated. Results: We studied 416 pediatric patients with IBD: 77.4% had CD and 22.6% had UC/IBD-U. Among them, 255 (61.3%) received the IFX originator and 161 (38.7%) received CT-P13. No statistically significant differences were found between the IFX originator and CT-P13 in terms of corticosteroid-free remission and adverse events. At 1-year follow-up, EH rates were comparable between them (CD: P=0.902, UC: P=0.860). The estimated cumulative cessation rates were not significantly different between the two groups. In patients with CD, the drug retention rates were 66.1% in the IFX originator and 71.6% in the CT-P13 group at the maximum follow-up period (P >0.05). In patients with UC, the drug retention rates were 49.8% in the IFX originator and 56.3% in the CT-P13 group at the maximum follow-up period (P >0.05). Conclusions: The IFX originator and CT-P13 demonstrated comparable therapeutic response including EH, clinical remission, drug retention rate and safety in pediatric IBD.

Discovery of a Novel Potent EGFR Inhibitor Against EGFR Activating Mutations and On-Target Resistance in NSCLC.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) serve as the standard first-line therapy for EGFR-mutated non-small cell lung cancer (NSCLC). Despite the sustained clinical benefits achieved through optimal EGFR-TKI treatments, including the third-generation EGFR-TKI osimertinib, resistance inevitably develops. Currently, there are no targeted therapeutic options available postprogression on osimertinib. Here, we assessed the preclinical efficacy of BI-4732, a novel fourth-generation EGFR-TKI, using patient-derived preclinical models reflecting various clinical scenarios. EXPERIMENTAL DESIGN: The antitumor activity of BI-4732 was evaluated using Ba/F3 cells and patient-derived cell/organoid/xenograft models with diverse EGFR mutations. Intracranial antitumor activity of BI-4732 was evaluated in a brain-metastasis mouse model. RESULTS: We demonstrated the remarkable antitumor efficacy of BI-4732 as a single agent in various patient-derived models with EGFR_C797S-mediated osimertinib resistance. Moreover, BI-4732 exhibited activity comparable to osimertinib in inhibiting EGFR-activating (E19del and L858R) and T790M mutations. In a combination treatment strategy with osimertinib, BI-4732 exhibited a synergistic effect at significantly lower concentrations than those used in monotherapy. Importantly, BI-4732 displayed potent antitumor activity in an intracranial model, with low efflux at the blood-brain barrier. CONCLUSIONS: Our findings highlight the potential of BI-4732, a selective EGFR-TKI with high blood-brain barrier penetration, targeting a broad range of EGFR mutations, including C797S, warranting clinical development.

Inhibition of receptor activator of nuclear factor kappa-B ligand-mediated osteoclast differentiation and bone resorption by Gryllus bimaculatus extract: An in vitro study.

Excessive bone-resorbing osteoclast activity during bone remodeling is a major feature of bone diseases, such as osteoporosis. Therefore, the inhibition of osteoclast formation and bone resorption can be an effective therapeutic target for various bone diseases. Gryllus biomaculatus (GB) has recently been approved as an alternative food source because of its high nutritional value and environmental sustainability. Traditionally, GB has been known to have various pharmacological properties, including antipyretic and blood pressure-lowering activity, and it has recently been reported to have various biological activities, including protective effects against inflammation, oxidative stress, insulin resistance, and alcohol-induced liver injury. However, the effect of GB on osteoclast differentiation and bone metabolism has not yet been demonstrated. In this study, we confirmed the inhibitory effect of GB extract (GBE) on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. To determine the effect of GBE on RANKL-induced osteoclast differentiation and function, we performed TRAP and F-actin staining, as well as a bone-resorbing assay. The intracellular mechanisms of GBE responsible for the regulation of osteoclastogenesis were revealed by Western blot analysis and quantitative real-time polymerase chain reaction. We investigated the relationship between GBE and expression of osteoclast-specific molecules to further elucidate the underlying mechanisms. It was found that GBE significantly suppressed osteoclastogenesis by decreasing the phosphorylation of Akt, p38, JNK, and ERK, as well as Btk-PLCγ2 signaling, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos, NFATc1, and osteoclastogenesis-specific marker genes. Additionally, GBE inhibited the formation of F-actin ring-positive osteoclasts and bone resorption activity of mature osteoclasts. Our findings suggest that GBE is a potential functional food and therapeutic candidate for bone diseases involving osteoclasts.

Staphylococcal Enterotoxin-Specific IgE Sensitization: A Potential Predictor of Fixed Airflow Obstruction in Elderly Asthma.

PURPOSE: Staphylococcus aureus enterotoxin-specific immunoglobulin E (SE-sIgE) sensitization tends to increase with age and is known to be associated with asthma and severity in older adults. However, the long-term impact of SE-sIgE in the elderly remains unknown. This study aimed to examine the relationships between SE-sIgE and fixed airflow obstruction (FAO) in a cohort of elderly asthmatics. METHODS: A total of 223 elderly asthmatics and 89 controls were analyzed. Patients were assessed for demographics, history of chronic rhinosinusitis (CRS), asthma duration, acute exacerbation frequency, and lung function at baseline and then were prospectively followed up for 2 years. Serum total IgE and SE-sIgE levels were measured at baseline. Airflow obstruction was defined as forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio < 0.7 at baseline and FAO was defined as FEV1/FVC ratio < 0.7 over the 2-year follow-up. RESULTS: At baseline, the prevalence of airflow obstruction was 29.1%. Patients with airflow obstruction were significantly more likely to be male, and have a positive smoking history, comorbid CRS, and higher levels of SE-sIgE than those without airflow obstruction. Multivariate logistic regression analysis showed that airflow obstruction was significantly associated with current smoking and SE-sIgE sensitization at baseline. After the 2-year follow-up, baseline SE-sIgE sensitization was consistently related to FAO. Meanwhile, the number of exacerbations per year was significantly correlated with SE-sIgE levels. CONCLUSIONS: Baseline SE-sIgE sensitization was significantly associated with the number of asthma exacerbations and FAO after the 2-year follow-up in elderly asthmatics. These findings warrant further investigation of the direct and mediating roles of SE-sIgE sensitization on airway remodeling.

Effectiveness and Safety of Recombinant Human Follicle-Stimulating Hormone (Follitrope™) in Inducing Controlled Ovarian Stimulation in Infertile Women in Real-World Practice: a Prospective Cohort Study.

To evaluate the safety and effectiveness of recombinant human follicle-stimulating hormone (rhFSH [Follitrope™]) in infertile women undergoing in vitro fertilization (IVF). To identify predictors of ovarian response that induce optimal clinical outcomes. This multicenter prospective study enrolled infertile women who were scheduled to undergo IVF after ovarian stimulation with rhFSH (Follitrope™) following the gonadotropin-releasing hormone (GnRH) agonist or GnRH antagonist protocol. Predictive factors for ovarian response were identified in the GnRH antagonist group based on the number of oocytes retrieved. A total of 516 infertile women were enrolled, among whom 136 (except one who withdrew before administration) received rhFSH using the GnRH agonist protocol and 379 using the antagonist protocol. The mean number of oocytes retrieved was 13.4 in the GnRH agonist group and 13.6 in the GnRH antagonist group. The clinical pregnancy rates were 32.3% (30/93) and 39.9% (115/288) in the GnRH agonist and antagonist groups, respectively. The incidence of ovarian hyperstimulation syndrome was 1.8% and 3.4% in the GnRH agonist and antagonist groups, respectively. No other significant safety risks associated with rhFSH administration were identified. Body mass index, basal serum FSH and anti-Müllerian hormone levels, and antral follicle count were identified as predictors of ovarian response by multiple regression with backward elimination, and the final regression model accounted for 26.5% of the response variability. In real-world practice, rhFSH (Follitrope™) is safe and effective in inducing ovarian stimulation in infertile women. Patient characteristics identified as predictors can be considered to be highly related to optimal clinical outcomes.

Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs.

BACKGROUND: Although vasospastic angina (VSA) is known to be caused by coronary artery spasm, no study has fully elucidated the exact underlying mechanism. Moreover, in order to confirm VSA, patients should undergo invasive coronary angiography with spasm provocation test. Herein, we investigated the pathophysiology of VSA using peripheral blood-derived induced pluripotent stem cells (iPSCs) and developed an ex vivo diagnostic method for VSA. METHODS AND RESULTS: With 10 mL of peripheral blood from patients with VSA, we generated iPSCs and differentiated these iPSCs into target cells. As compared with vascular smooth muscle cells (VSMCs) differentiated from iPSCs of normal subjects with negative provocation test, VSA patient-specific iPSCs-derived VSMCs showed very strong contraction in response to stimulants. Moreover, VSA patient-specific VSMCs exhibited a significant increase in stimulation-induced intracellular calcium efflux (Changes in the relative fluorescence unit [ΔF/F]; Control group vs. VSA group, 2.89 ± 0.34 vs. 10.32 ± 0.51, p < 0.01), and exclusively induced a secondary or tertiary peak of calcium efflux, suggesting that those findings could be diagnostic cut-off values for VSA. The observed hyperreactivity of VSA patient-specific VSMCs were caused by the upregulation of sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) due to its enhanced small ubiquitin-related modifier (SUMO)ylation. This increased activity of SERCA2a was reversed by treatment with ginkgolic acid, an inhibitor of SUMOylated E1 molecules (pi/µg protein; VSA group vs. VSA + ginkgolic acid, 52.36 ± 0.71 vs. 31.93 ± 1.13, p < 0.01). CONCLUSIONS: Our findings showed that abnormal calcium handling in sarco/endoplasmic reticulum could be induced by the enhanced SERCA2a activity in patients with VSA, leading to spasm. Such novel mechanisms of coronary artery spasm could be useful for drug development and diagnosis of VSA.

Fecal Calprotectin Levels Significantly Correlate with Polyp Size in Children and Adolescents with Juvenile Colorectal Polyps.

Purpose: We aimed to investigate factors that correlate with fecal calprotectin (FC) levels in children and adolescents with colorectal polyps. Methods: Pediatric patients aged <19 years who underwent colonoscopic polypectomy for a juvenile polyps (JPs) and FC tests were simultaneously conducted in a multicenter, retrospective study. Baseline demographics, colonoscopic and histological findings, and laboratory tests, including FC levels, were investigated. Correlations between the factors were investigated, and linear regression analysis revealed factors that correlated with FC levels. FC levels measured after polypectomies were investigated and the FC levels pre- and post-polypectomies were compared. Results: A total of 33 patients were included in the study. According to Pearson correlation analysis, the polyp size was the only factor that showed a statistically significant correlation with FC levels (r=0.75, p<0.001). Furthermore, according to the multivariate linear regression analysis, polyp size was the only factor that showed a statistically significant correlation with FC levels (adjusted R2 =0.5718, ß=73.62, p<0.001). The median FC level was 400 mg/kg (interquartile range [IQR], 141.6-1,000 mg/kg), and the median polyp size was 14 mm (IQR, 9-20 mm). Nineteen patients underwent post-polypectomy FC tests. FC levels showed a significant decrease after polypectomy from a median of 445.2 mg/kg (IQR, 225-1,000) to 26.5 mg/kg (11.5-51) (p<0.001). Conclusion: FC levels significantly correlated with polyp size in children and adolescents with JPs.

Preparation of inhalable N-acetylcysteine-loaded magnetite chitosan microparticles for nitrate adsorption in particulate matter.

Airborne particulate matter has been designated as a class 1 carcinogen by the World Health Organization. Nitrate is a toxic substance that accounts for a large proportion of particulate matter, and nitrate toxicity has long been reported. In this study, we aimed to optimize the adsorption and removal of particulate matter containing nitrate for effective elimination by the lungs. To this end, particles were designed to optimize the inhalation and removal efficiencies. These particles were prepared as chitosan-based particles containing N-acetylcysteine by using emulsion diffusion methods. Chitosan adsorbs nitrate, while N-acetylcysteine dissolves mucus. This removal mechanism has been found to occur in various in vitro models that mimic respiratory environments and in vivo models. In particular, the removal of exogenous substances, such as particulate matter, by the motility of respiratory cilia through mucolytic effect was investigated. This new approach for the adsorption and elimination of toxic substances entering the lungs represents an alternative defense mechanism against exposure to nitrates from air pollution.

Associations of Polyp Characteristics in Children and Adolescents Presenting with Less Than Five Colorectal Polyps: A Full Colonoscopy Is Still Required.

Background/Aims: A full colonoscopy is currently required in children and adolescents with colorectal polyps, because of their potential of neoplastic transformation and complications such as intussusception. We aimed to analyze the associations of polyp characteristics in children and adolescents with colorectal polyps. Based on these findings, we also aimed to reevaluate the necessity of conducting a full colonoscopy. Methods: Pediatric patients <18 years of age who had undergone a colonoscopic polypectomy and those with <5 colorectal polyps were included in this multicenter, retrospective study. Baseline clinicodemographics, colonoscopic and histologic findings were investigated. Results: A total of 91 patients were included. Multivariate logistic regression analysis showed that polyp size was the only factor associated with the presence of any polyps located proximal to the splenic flexure (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.28 to 4.28; p=0.007). Furthermore, polyp location proximal to the splenic flexure and sessile morphology were associated with the presence of any adenomatous polyp (OR, 8.51; 95% CI, 1.43 to 68.65; p=0.023; OR, 18.41; 95% CI, 3.45 to 173.81; p=0.002, respectively). Conclusions: In children and adolescents presenting with <5 colorectal polyps, polyp size and the presence of any adenomatous polyp were positively associated with polyp location proximal to the splenic flexure. This finding supports the necessity of a full colonoscopic exam in pediatric patients with colorectal polyps for the detection of polyps before the occurrence of complications such as intussusception or neoplastic transformation.

Resistin impairs mitochondrial homeostasis via cyclase-associated protein 1-mediated fission, leading to obesity-induced metabolic diseases.

OBJECTIVE: One of the suggested mechanisms of obesity-induced insulin resistance is mitochondrial dysfunction in target tissues such as skeletal muscle. In our study, we examined whether resistin, an adipokine associated with obesity-mediated insulin resistance, induced metabolic disorders by impairing mitochondrial homeostasis. METHODS: The morphology and function of mitochondria of skeletal muscle were examined in resistin-knockout and humanized resistin mice that were subjected to high-fat diet for 3 months. Morphology was examined by transmission electron microscopy. Mitochondria bioenergetics of skeletal muscle were evaluated using a Seahorse XF96 analyzer. Human skeletal myoblasts were used for in vitro studies on signaling mechanisms in responses to resistin. RESULTS: A high-fat diet in humanized resistin mice increased fragmented and shorter mitochondria in the skeletal muscle, whereas resistin-knockout mice had healthy normal mitochondria. In vitro studies showed that human resistin treatment impaired mitochondrial homeostasis by inducing mitochondrial fission, leading to a decrease in ATP production and mitochondrial dysfunction. Induction of mitochondrial fission by resistin was accompanied by increased formation of mitochondria-associated ER membranes (MAM). At the same time, resistin induced up-regulation of the protein kinase A (PKA) pathway. This activation of PKA induced phosphorylation of Drp1 at serine 616, leading to Drp1 activation and subsequent induction of mitochondrial fission. The key molecule that mediated human resistin-induced mitochondrial fission was adenylyl cyclase-associated protein 1 (CAP1), which was reported as a bona fide receptor for human resistin. Moreover, our newly developed biomimetic selective blocking peptide could repress human resistin-mediated mitochondrial dysfunction. High-fat diet-fed mice showed lower exercise capacity and higher insulin resistance, which was prevented by a novel peptide to block the binding of resistin to CAP1 or in the CAP1-knockdown mice. CONCLUSIONS: Our study demonstrated that human resistin induces mitochondrial dysfunction by inducing abnormal mitochondrial fission. This result suggests that the resistin-CAP1 complex could be a potential therapeutic target for the treatment of obesity-related metabolic diseases such as diabetes and cardiometabolic diseases.

The Changes in Trends of Lower Gastrointestinal Endoscopy Conducted in Children and Adolescents after the COVID-19 Outbreak in Korea.

Background and Objectives: The coronavirus disease 2019 (COVID-19) pandemic has affected medical practice in diverse ways. We aimed to investigate the change in trends of lower gastrointestinal (LGI) endoscopy conducted in children and adolescents after the COVID-19 outbreak in Korea. Material and Methods: This was a multicenter, retrospective study conducted in Korea. We included children and adolescents aged <19 years who had undergone their first LGI endoscopy between 2016 and 2020. We compared clinicodemographic and endoscopic factors between groups divided according to the pre- and postCOVID-19 era in Korea. Results: We included 1307 patients in this study. Colonoscopies, instead of sigmoidoscopies, were conducted in most patients in the postCOVID-19 era compared to those in the preCOVID-19 era (86.9% vs. 78.5%, p = 0.007). The diagnosis of inflammatory bowel disease (IBD) was also significantly higher in the postCOVID-19 era compared to the preCOVID-19 era (47.2% vs. 28.5%, p < 0.001). According to multivariate logistic regression analysis, age at LGI endoscopy, LGI bleeding indication, and IBD diagnosis were independently associated with the use of a colonoscopy over a sigmoidoscopy (odds ratio (OR) 1.19, 95% confidence interval (CI) 1.12−1.27, p < 0.001; OR 0.56, 95% CI 0.37−0.83, p = 0.005; OR 1.80, 95% CI 1.20−2.77, p = 0.006, respectively). Conclusions: The COVID-19 pandemic has changed LGI endoscopy practice trends of pediatric gastroenterologists in Korea, who tended to perform lesser LGI endoscopies compared to previous years while conducting significantly more colonoscopies than sigmoidoscopies in the postCOVID-19 era. Furthermore, these colonoscopies were significantly associated with the diagnosis of IBD, as well as a significant increase in IBD diagnosis in the postCOVID-19 era.

Harpagoside attenuates local bone Erosion and systemic osteoporosis in collagen-induced arthritis in mice.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes local bone erosion and systemic osteoporosis. Harpagoside (HAR), an iridoid glycoside, has various pharmacological effects on pain, arthritis, and inflammation. Our previous study suggests that HAR is more deeply involved in the mechanism of bone loss caused by inflammatory stimuli than hormonal changes. Here, we identified the local and systemic bone loss inhibitory effects of HAR on RA and its intracellular mechanisms using a type 2 collagen-induced arthritis (CIA) mouse model. METHODS: The anti-osteoporosis and anti-arthritic effects of HAR were evaluated on bone marrow macrophage in vitro and CIA in mice in vivo by obtaining clinical scores, measuring hind paw thickness and inflammatory cytokine levels, micro-CT and histopathological assessments, and cell-based assay. RESULTS: HAR markedly reduced the clinical score and incidence rate of CIA in both the prevention and therapy groups. Histological analysis demonstrated that HAR locally ameliorated the destruction of bone and cartilage and the formation of pannus. In this process, HAR decreased the expression of inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß in the serum of CIA mice. Additionally, HAR downregulated the expression of receptor activator of nuclear factor-κB ligand and upregulated that of osteoprotegerin. HAR suppressed systemic bone loss by inhibiting osteoclast differentiation and osteoclast marker gene expression in a CIA mouse model. CONCLUSIONS: Taken together, these findings show the beneficial effect of HAR on local symptoms and systemic bone erosion triggered by inflammatory arthritis.

Effects of anxiety on sedation among pediatric patients undergoing esophagogastroduodenoscopy.

We investigated whether the severity of anxiety among children undergoing endoscopy could affect sedation. We prospectively recruited patients under 18 years of age who were scheduled to undergo esophagogastroduodenoscopy (EGD). Baseline anxiety was evaluated using the Spence Children's Anxiety Scale (SCAS). Our analysis considered the type and dose of sedative drugs, degree of sedation, and complications associated with sedation according to the scale score. The mean total SCAS T-scores and each subscale score were significantly higher in the 6-12-year age group. The mean T-score among patients who exhibited irritability during EGD was higher than that among other patients, with significant differences in the Total, Obsessive Disorder, Panic Agoraphobia and General Anxiety subscales. The midazolam doses of children exhibiting irritability were more likely to need higher (p = 0.006). Other sedation-related complications were not associated with the T-scores in each subscale. Total sleep time was not associated with any T-score subscales. Anxiety levels were significantly higher among 6-12-year-olds and children exhibiting irritability. Anxiety was often associated with irritability, difficulties achieving adequate sedation during EGD, and additional sedative drug administration. We recommend higher doses or more potent drugs to facilitate endoscopy for children with high anxiety levels.

Potential Utility of Fecal Calprotectin in Discriminating Colorectal Polyps From Other Major Etiologies in Children Presenting With Isolated Hematochezia.

BACKGROUND: Colorectal polyps are the most common cause of isolated hematochezia in children, which requires a colonoscopy for diagnosis. We aimed to investigate the potential utility of fecal calprotectin (FC) in assessing colorectal polyps detected by colonoscopy among children presenting with isolated hematochezia. METHODS: Pediatric patients of the age of < 18 years who had undergone both colonoscopy and FC tests for isolated hematochezia from June 2016 to May 2020 were included in the present multicenter, retrospective, cross-sectional study. Comparative analysis was conducted between major causes of isolated hematochezia and FC cut-offs for discriminating colorectal polyps were explored. RESULTS: A total 127 patients were included. Thirty-five patients (27.6%) had colorectal polyps, followed by anal fissure (14.2%), ulcerative colitis (UC; 12.6%), and others. A significant difference in FC levels was observed between patients with colorectal polyps (median, 278.7 mg/kg), anal fissures (median, 42.2 mg/kg), and UC (median, 981 mg/kg) (P < 0.001). According to receiver operating characteristic curve analysis, among patients diagnosed with colorectal polyp or anal fissure, the most accurate FC cut-off for discriminating colorectal polyps from anal fissures on colonoscopy was 225 mg/kg (sensitivity, 59.4%; specificity, 94.4%; positive predictive value [PPV], 95.0%; negative predictive value [NPV], 56.7%; area under the curve [AUC], 0.8; 95% confidence interval [CI], 0.678-0.923; P < 0.001), while among patients diagnosed with colorectal polyp or UC, the most accurate FC cut-off for discriminating colorectal polyps from UC on colonoscopy was 879 mg/kg (sensitivity, 81.2%; specificity, 56.2%; PPV, 78.8%; NPV, 60.0%; AUC, 0.687; 95% CI, 0.521-0.852; P < 0.001). CONCLUSION: FC may assist in assessing the cause of lower gastrointestinal tract bleeding in children who present with isolated hematochezia.

A novel function of HRP-3 in regulating cell cycle progression via the HDAC-E2F1-Cyclin E pathway in lung cancer.

To improve the poor survival rate of lung cancer patients, we investigated the role of HDGF-related protein 3 (HRP-3) as a potential biomarker for lung cancer. The expression of endogenous HRP-3 in human lung cancer tissues and xenograft tumor models is indicative of its clinical relevance in lung cancer. Additionally, we demonstrated that HRP-3 directly binds to the E2F1 promoter on chromatin. Interestingly, HRP-3 depletion in A549 cells impedes the binding of HRP-3 to the E2F1 promoter; this in turn hampers the interaction between Histone H3/H4 and HDAC1/2 on the E2F1 promoter, while concomitantly inducing Histone H3/H4 acetylation around the E2F1 promoter. The enhanced Histone H3/H4 acetylation on the E2F1 promoter through HRP-3 depletion increases the transcription level of E2F1. Furthermore, the increased E2F1 transcription levels lead to the enhanced transcription of Cyclin E, known as the E2F1-responsive gene, thus inducing S-phase accumulation. Therefore, our study provides evidence for the utility of HRP-3 as a biomarker for the prognosis and treatment of lung cancer. Furthermore, we delineated the capacity of HRP-3 to regulate the E2F1 transcription level via histone deacetylation.

Anti-Osteoporosis Effects of the Eleutherococcus senticosus, Achyranthes japonica, and Atractylodes japonica Mixed Extract Fermented with Nuruk.

Vigeo is a mixture of fermented extracts of Eleutherococcus senticosus Maxim (ESM), Achyranthes japonica (Miq.) Nakai (AJN), and Atractylodes japonica Koidzumi (AJK) manufactured using the traditional Korean nuruk fermentation method. Although the bioactive effects of ESM, AJN, and AJK have already been reported, the pharmacological effects of Vigeo have not been proven. Therefore, in this study, we investigated whether Vigeo had inhivitory effects on lipopolysaccharide (LPS)-induced inflammatory bone loss in vivo and receptor activator of nuclear factor-B ligand (RANKL)-induced osteoclastogenesis and the related mechanism in vitro. Vigeo administration conferred effective protection against bone loss induced by excessive inflammatory response and activity of osteoclasts in LPS-induced inflammatory osteoporosis mouse model. In addition, Vigeo significantly suppressed the formation of tartrate-resistant acid phosphatase-positive osteoclasts induced by RANKL and inhibited F-actin formation and bone resorbing activity without any cytotoxicity. Moreover, Vigeo significantly inhibited RANKL-induced phosphorylation of p38, ERK, JNK, IκB, and AKT and degradation of IkB. Additionally, Vigeo strongly inhibited the mRNA and protein expression of c-FOS and NFATc1 and subsequently attenuated the expression of osteoclast specific marker genes induced by RANKL. We demonstrated for the first time the anti-osteoporosis effect of Vigeo, suggesting that it could be a potential therapeutic candidate for the treatment of osteoclast-mediated inflammatory bone diseases.

Clinical Analysis of Hospitalized Patients with Hemophilia A: Single-hemophilia Treatment Center Experience in Korea over 10 years.

BACKGROUND: There is lack of data on admitted hemophilia patients in Korea. For this reason, this study was intended to analyze the hospitalization data of hemophilia patients in a regional Hemophilia Treatment Center (HTC) for the first time in Korea. METHODS: In this retrospective study, we surveyed hospitalized patients with Hemophilia A (HA) in a HTC for 14 years. Medical records of these hemophiliacs were reviewed and data regarding demographic characteristics, cause of admissions and their outcomes in each patient were obtained. In addition, the data of admitted days, type and amount of Coagulation factor concentrate (CFC) used, treatments other than CFC infusion during the admission days were also obtained from the medical record of each patient. RESULTS: A total 107 patients with hemophilia A were admitted during 14 years. Annual rate of admission of patients with HA was 8%. Mean age on admission was 29.63±19.51 years old and mean admission days were 11.28±5.46 days. Most admissions were occurred in severe and moderate hemophilia patients. The most common cause of admission was bleed control followed by surgery and other reasons. With modified WFH CFC supplementation guideline, all the bleeds were successfully controlled and all surgeries were also successfully conducted with less total CFC consumption compared to the consumed dose of other reports. CONCLUSION: These results suggest that it is necessary to develop more specified regimens different from WFH.

Methyltransferase-like protein 7A (METTL7A) promotes cell survival and osteogenic differentiation under metabolic stress.

While bone has an inherent capacity to heal itself, it is very difficult to reconstitute large bone defects. Regenerative medicine, including stem cell implantation, has been studied as a novel solution to treat these conditions. However, when the local vascularity is impaired, even the transplanted cells undergo rapid necrosis before differentiating into osteoblasts and regenerating bone. Thus, to increase the effectiveness of stem cell transplantation, it is quintessential to improve the viability of the implanted stem cells. In this study, given that the regulation of glucose may hold the key to stem cell survival and osteogenic differentiation, we investigated the molecules that can replace the effect of glucose under ischemic microenvironment of stem cell transplantation in large bone defects. By analyzing differentially expressed genes under glucose-supplemented and glucose-free conditions, we explored markers such as methyltransferase-like protein 7A (METTL7A) that are potentially related to cell survival and osteogenic differentiation. Overexpression of METTL7A gene enhanced the osteogenic differentiation and viability of human bone marrow stem cells (hBMSCs) in glucose-free conditions. When the in vivo effectiveness of METTL7A-transfected cells in bone regeneration was explored in a rat model of critical-size segmental long-bone defect, METTL7A-transfected hBMSCs showed significantly better regenerative potential than the control vector-transfected hBMSCs. DNA methylation profiles showed a large difference in methylation status of genes related to osteogenesis and cell survival between hBMSCs cultured in glucose-supplemented condition and those cultured in glucose-free condition. Interestingly, METTL7A overexpression altered the methylation status of related genes to favor osteogenic differentiation and cell survival. In conclusion, it is suggested that a novel factor METTL7A enhances osteogenic differentiation and viability of hBMSCs by regulating the methylation status of genes related to osteogenesis or survival.

ANGPTL4 accelerates KRASG12D-Induced acinar to ductal metaplasia and pancreatic carcinogenesis.

Oncogenic KRASG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), and drives pancreatic ductal adenocarcinoma (PDAC). Angiopoietin-like 4 (ANGPTL4) is known to be involved in the regulation of cancer growth and metastasis. However, whether ANGPTL4 affects KRASG12D-mediated ADM and early PDAC intervention remains unknown. In the current study, we investigated the role of ANGPTL4 in KRASG12D-induced ADM, PanIN formation, and PDAC maintenance. We found that ANGPTL4 was highly expressed in human and mouse ADM lesions and contributed to the promotion of KRASG12D-driven ADM in mice. Consistently, ANGPTL4 rapidly induced ADM in three-dimensional culture of acinar cells with KRAS mutation and formed ductal cysts that silenced acinar genes and activated ductal genes, which are characteristic of in vivo ADM/PanIN lesions. We also found that periostin works as a downstream regulator of ANGPTL4-mediated ADM/PDAC. Genetic ablation of periostin diminished the ADM/PanIN phenotype induced by ANGPTL4. A high correlation between ANGPTL4 and periostin was confirmed in human samples. These results demonstrate that ANGPTL4 is critical for ADM/PanIN initiation and PDAC progression through the regulation of periostin. Thus, the ANGPTL4/periostin axis is considered a potential target for ADM-derived PDAC.