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Chen-Lin Yu,1,2,* Hsiang-Lin Lee,3,4,* Shun-Fa Yang,2,5 Shih-Wei Wang,1,6 Ching-Pin Lin,4,7 Yi-Hsien Hsieh,2,5 Hui-Ling Chiou8,9 1Institute of Biomedical Science, Mackay Medical College, New Taipei City, Taiwan; 2Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 3Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan; 4School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 5Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan; 6Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 8School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan; 9Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Yi-Hsien Hsieh; Hui-Ling Chiou, Tel +886-4-2473-0022, Fax +886-4- 2472-3229, Email hyhsien@csmu.edu.tw; hlchiou@csmu.edu.twObjective: Protodioscin (PD), a steroidal saponin, has a diverse pharmacological activity including neuroprotection, male fertility improvement, and cytotoxicity against various cancers cell lines of different origins. However, the effect of PD on hepatocellular carcinoma (HCC) is still unclear.Methods: Cell viability, colony formation and flow cytometry analysis for apoptosis profile, mitochondrial membrane potential endoplasmic reticulum (ER) expansion were employed to determine the effect of PD against HCC cells. Transient transfection of siRNA, immunofluorescent imaging and immunoprecipitation were used to elucidate the anti-cancer mechanism of PD. The in vivo toxicity and efficacy of PD were assessed by a xenograft mouse model.Results: PD induced apoptosis, loss of mitochondrial membrane potential and ER expansion in HCC cells. Either downregulation of Mfn1 or Bak reversed PD-induced apoptosis and loss of mitochondrial membrane potential. Further analysis revealed that Mfn1 and Bak will form a complex with IP3R to facilitate the transfer of Ca2+ from ER to mitochondria and apoptosis. In addition, our tumour xenograft model further verifies the in vivo anti-tumour effect of PD.Conclusion: Our study sheds light on the understanding of the anti-HCC effects of PD and may open new aspects for the development of novel treatment for human hepatocellular carcinoma.Graphical Abstract: Keywords: hepatocellular carcinoma, protodioscin, mitochondrial, apoptosis, endoplasmic reticulum

Background/Purpose Inflammatory bowel disease (IBD) is a chronic gastrointestinal (GI) disorder that causes relapsing inflammation and severe mucosal damage in the intestine. Crohn’s disease (CD)-related stricturing complications are a major cause of surgery, disability, and reduced quality of life. Endoscopic balloon dilation (EBD) has been shown to reliably delay or prevent surgery in patients with stricturing CD. However, cases of EBD performed for stricture in CD in Taiwan are rare. In this study, we want to evaluate the experiences regarding EBD for stricturing CD in Taiwan. Methods We conducted a retrospective analysis of 9 medical centers in Taiwan. Patients with CD-related strictures who were treated with EBD were included and analyzed. Results In nine medical centers, a total of 26 CD patients (19 male, 7 female, mean disease duration 75.4 ± 65.2 months) underwent 42 EBD procedures during the study period. Among the subjects, an 83.3% (35/42) EBD success rate was seen, but 26.9% (7/26) patients underwent surgery after ineffective EBD. In the surgery group, the the small bowel strictures was high compared with the non-surgery group (p = 0.01). There were no significant differences in disease phenotype, disease duration or history of fistulizing disease. In the surgery group, immunosuppressant use was high, and 5-aminosalicylic acid (5-ASA) use was low compared with the non-surgery group. After EBD, the physicians tended to change the drugs, especially increasing the use of biologic agents. Conclusion EBD is a safe and effective procedure for CD-related stricture, with a 83.3% success rate in Taiwan.

IntroductionFinding the risk factors for thromboembolic (TE) disease and preventing its development in pregnant women is important. Asthma is a common chronic disease in pregnant women. The aim of the study is to find the risk factors.Material and methodsFrom 2004 to 2011, 55,057 pregnant women were recruited from a Taiwan database. They were grouped into AS and non-AS groups. AS subjects were divided into three groups. Group 1: with AS before pregnancy or during pregnancy; without AS after childbirth. Group 2: without AS before pregnancy, with AS during pregnancy or after childbirth. Group 3: with AS before, during pregnancy and after childbirth. The rate of TE (during pregnancy and 60 days after childbirth) was compared between different groups.ResultsIn pregnant women, TE rate was 2.47‰ in AS and 0.71‰ in non-AS subjects. The rate was higher in AS subjects (OR 3.47, adjust p 0.005). In group 2, the rate was 3.97‰, higher than that in non-AS subjects (OR 5.44, p 0.013). The TE rate in groups 1 and 3 was similar to non-AS subjects.ConclusionsThe rate of TE increases if pregnant women have AS. Physicians need to be alert to the occurrence of TE as early as possible in pregnant women with AS. If AS was re-appeared or worsened during pregnancy (group 2), the rate of TE increased. Pregnant women and physicians should prevent the re-appear of AS or control AS properly during pregnancy to prevent the occurrence of TE.

Background and Aims. Patients with Meckel’s diverticulum (MD) are difficult to preoperatively diagnose because of its endoscopic inaccessibility. Balloon-assisted enteroscopy (BAE) allows endoscopic access to the entire small intestine. The aim of the current study was to investigate patients with MD diagnosed by BAE in Taiwan. Methods. We conducted a retrospective, multicenter study of patients with MD who were diagnosed by BAE in Taiwan. The clinical characteristics, endoscopic features, histopathological findings, treatment methods, and outcomes were analyzed. Results. A total of 55 patients with MD were enrolled (46 males and 9 females). The mean age at diagnosis was 34.1 years. Overt gastrointestinal bleeding (87.3%) was the primary indication for BAE, followed by abdominal pain (9.1%), suspected small bowel tumor (1.8%), and Crohn’s disease follow-up (1.8%). The mean distance between the ileocecal valve and MD was 71.6 cm (regarding diagnostic yields: BAE—100%, capsule endoscopy—40%, Meckel’s scan—35.7%, computed tomography—14.6%, small bowel series—12.5%, and angiography—11.1%; regarding endoscopic features of MD: a large ostium—89.1%, a small ostium—7.3%, and a polypoid mass—3.6%). Surgical treatment was performed in 76.4% patients, and conservative treatment was performed in 23.6% patients. The mean length of MD in 42 patients who underwent surgical resection was 5.2 cm (in 43 patients of MD with available histopathology: heterotopic gastric tissue, 42.4%, heterotopic gastric and pancreatic tissues, 7%; heterotopic pancreatic tissue, 4.7%; heterotopic colonic tissue, 2.3%; and a neuroendocrine tumor, 2.3%). Conclusions. The current study showed BAE is a very useful modality for detecting MD compared with other conventional modalities.

Accumulating evidence suggests that there is a link between the host microbiome and pancreatic carcinogenesis, and that Porphyromonas gingivalis (P. gingivalis) increases the risk of developing pancreatic cancer. The aim of the current study was to clarify the role of P. gingivalis in the pathogenesis of pancreatic cancer and the potential immune modulatory effects of probiotics. The six-week-old LSL-K-rasG12D, Pdx-1-cre (KC) mice smeared P. gingivalis on the gums, causing pancreatic intraepithelial neoplasia (PanIN) after four weeks to be similar to the extent of lesions in untreated KC mice at 24 weeks. The oral inoculation of P. gingivalis of six-week-old LSL-K-rasG12D, Pdx-1-cre (KC) mice caused significantly pancreatic intraepithelial neoplasia (PanIN) after treatment four weeks is similar to the extent of lesions in untreated KC mice at 24 weeks. The pancreas weights of P. gingivalis plus probiotic-treated mice were significantly lower than the mice treated with P. gingivalis alone (P = 0.0028). The histological expressions of Snail-1, ZEB-1, collagen fibers, Galectin-3, and PD-L1 staining in the pancreas were also notably lower. In addition, probiotic administration reduced the histological expression of Smad3 and phosphorylated Smad3 in P. gingivalis treated KC mice. We demonstrated that oral exposure to P. gingivalis can accelerate the development of PanIN lesions. Probiotics are likely to have a beneficial effect by reducing cancer cell proliferation and viability, inhibiting PanIN progression, and cancer cell metastasis (Epithelial&ndash, mesenchymal transition, EMT). The transforming growth factor-&beta, signaling pathway may be involved in the tumor suppressive effects of probiotics.

Objective Bronchopulmonary dysplasia (BPD) is a complex chronic lung disease that primarily affects premature or critically ill infants. This pilot study investigated early changes in gut microbiota composition in BPD patients and explored the potential risk factors associated with these changes.Study Design Preterm infants admitted to our neonatal intensive care unit with a gestational age of 26 to 32 weeks were prospectively surveyed and eligible for stool collection on days 7 and 28 of postnatal age between February 2016 and June 2017. A 16S rRNA sequencing approach was applied to compare the gut microbiota composition between the BPD group and controls. Multiple linear regression analysis was used to identify the predictor variables.Results Eight subjects in the BPD group and 10 subjects in the preterm group were analyzed during the observation period. Actinobacteria, Proteobacteria, Bacteroidetes, and Firmicutes were the four dominant bacteria phyla of intestinal microflora. A significantly lower diversity of gut microbiota was observed in the BPD group compared with the preterm group on day 28 (number of observed operational taxonomic units, p = 0.034; abundance-based coverage estimator, p = 0.022; Shannon index, p = 0.028). Multiple linear regression analysis revealed that high Neonatal Therapeutic Intervention Scoring System score (≧19) at 24 hours was statistically significant in predicting the proportion of aerobic with facultative anaerobic bacteria on day 28 (p = 0.002).Conclusion Infants with BPD are prone to develop gut dysbiosis in early life. A higher severity of illness and treatment intensity may indicate a higher risk of disrupting an anaerobic environment in the gut during the first month of life.Key Points

Bergapten is a natural compound and has potent anticancer activities. In this study, we explored the cytotoxicity of bergapten on colorectal cancer (CRC) cell DLD-1 and LoVo and its underlying mechanisms. We observed that bergapten (30 and 50 μM) decreased the viability of the CRC cells and induced the G0/G1 and sub-G1 phase arrest. Furthermore, immunoblotting results indicated that bergapten increased p53, phospho-p53(Ser-46), p21, PUMA, Bax, PTEN, and the caspase-9 and caspase-3 cleavage, but decreased cyclin E, CDK2, and phosphor-AKT(Ser-473) in the CRC cells. Inhibition of p53 by pifithrin-α reversed the bergapten-induced p53-mediated apoptotic cascade and restored the survival signaling and cell viability. Collectively, our findings reveal that bergapten decrease the cell viability and induce cell cycle arrest in the CRC cells, which may be attributed to p53-mediated apoptotic cascade, upregulation of p21 and PTEN, and inhibition of AKT.

OBJECTIVES: Helicobacter pylori (H. pylori) is the leading cause of chronic gastritis and gastric ulcers and significantly increases the risk of developing gastric cancer. Even though many therapeutic improvements in H. pylori eradication rate, it is still associated with the high prevalence of infection. Several studies have verified that probiotics treatment were beneficial to gastrointestinal tract infections is increasingly documented as an alternative to antibiotics. This study aimed to investigate the efficacy of novelty probiotic complex on H. pylori infection in patients. METHODS: Between October 2018 and August 2019, all subjects with a clinical of Chung Shan Medical University Hospital in Taiwan, subjects who confirmed H. pylori infection (n = 20) were randomized to receive probiotic complex or placebo for 3 weeks. The probiotic complex contained Lactobacillus johnsonii No.1088 (HK-LJ88) 10(10) CFU/mL, Bacillus subtilis 10(12) CFU/mL, green tea extract and sake lees. Primary outcome of this study was The amounts of change of (13)C urea breath test ((13)C UBT) that was assessed 3 weeks after the end of supplementation. The hematological results, dietary records, anthropogenic indicators were measured/assessed at the 0 and 3(th) week. RESULTS: Subjects in the probiotic group had significantly lower (13)C UBT (39.6%) at the 3(th) week when compared to the value at week 0. In contrast with subjects in the placebo group had higher 50% (13)C UBT. The levels of anthropometric indices, blood glucose and lipid profiles had no significant changes during the intervention study period in both groups. After adjusting for age and gender, supplement had significant effect on reducing the change of (13)C UBT (β = -13.64, p = 0.047) and diastolic blood pressure (β = -6.91, p = 0.03). CONCLUSIONS: These results suggest that supplement with the combination of probiotic Lactobacillus johnsonii and Bacillus subtilis for 3 weeks may have a favorable effect on H. pylori infection in humans. The probiotics intervention also resulted in improved blood pressure. FUNDING SOURCES: Yang Ming Biomed Co., Ltd.

Background An association between allergic rhinitis (AR) and digestive diseases (DDs) has been reported; however, studies have only focused on the prevalence of DDs in populations of patients with AR. In individuals with specific DDs, the impact of AR on the frequency of clinical visits for each DD has not been studied. Moreover, the association between topical steroid usage for AR and DDs has not been investigated. Methods Data from 16 526 men and 18 438 women, aged 21 to 30 years, were collected from a national database. Individuals were separated into the AR and non-AR groups. Eight common DDs were studied: (1) gastroesophageal reflux disease (GERD), (2) gastritis and duodenitis, (3) peptic ulcers, (4) irritable bowel syndrome, (5) gastric functional disease, (6) intestinal functional disease, (7) gastroenteritis and colitis, and (8) constipation. The rate of each DD was compared between groups. In individuals with specific DDs, the frequency of clinical visits for each DD was also compared between groups. Between users and nonusers of topical steroids in the AR group, the rate of DDs was compared. Results Significant associations were observed between all eight DDs and AR in both sexes. In comparison to the non-AR group, women with AR visited clinics more frequently for gastritis/duodenitis, gastric and intestinal functional disease, gastroenteritis/colitis, and constipation, while men with AR visited clinics more frequently for gastritis/duodenitis, gastric functional disease, gastroenteritis/colitis, and constipation. Female topical-steroid users with AR had higher rates of GERD, irritable bowel syndrome, gastric or intestinal functional disease, and gastritis/colitis. Male topical-steroid users with AR had higher rates of GERD and peptic ulcers. Conclusion AR was associated with DDs in both sexes. However, the influence of AR on clinical visit frequency varied among specific DD groups. Topical steroid usage for AR was associated with some DDs, but the association requires future evaluation.

AIM To investigate the effects of hydrogen-rich water (HRW) treatment on prevention of ethanol (EtOH)-induced early fatty liver in mice. METHODS In vitro reduction of hydrogen peroxide by HRW was determined with a chemiluminescence system. Female mice were randomly divided into five groups: control, EtOH, EtOH + silymarin, EtOH + HRW and EtOH + silymarin + HRW. Each group was fed a Lieber-DeCarli liquid diet containing EtOH or isocaloric maltose dextrin (control diet). Silymarin was used as a positive control to compare HRW efficacy against chronic EtOH-induced hepatotoxicity. HRW was freshly prepared and given at a dosage of 1.2 mL/mouse trice daily. Blood and liver tissue were collected after chronic-binge liquid-diet feeding for 12 wk. RESULTS The in vitro study showed that HRW directly scavenged hydrogen peroxide. The in vivo study showed that HRW increased expression of acyl ghrelin, which was correlated with food intake. HRW treatment significantly reduced EtOH-induced increases in serum alanine aminotransferase, aspartate aminotransferase, triglycerol and total cholesterol levels, hepatic lipid accumulation and inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. HRW attenuated malondialdehyde level, restored glutathione depletion and increased superoxide dismutase, glutathione peroxidase and catalase activities in the liver. Moreover, HRW reduced TNF-α and IL-6 levels but increased IL-10 and IL-22 levels. CONCLUSION HRW protects against chronic EtOH-induced liver injury, possibly by inducing acyl ghrelin to suppress the pro-inflammatory cytokines TNF-α and IL-6 and induce IL-10 and IL-22, thus activating antioxidant enzymes against oxidative stress.

The present study aimed to investigate faecal calprotectin as a diagnostic marker to differentiate between patients with inflammatory bowel disease (IBD) and those with irritable bowel syndrome (IBS). A total of 20 healthy control subjects, 26 patients with IBS and 58 patients with IBD, including 22 with ulcerative colitis (UC) and 36 with Crohn's disease (CD), were recruited for the present study. Calprotectin was analysed in stool samples, and C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were assessed in blood samples. CRP and calprotectin levels, and the ESR were observed to be significantly higher in patients with CD and UC compared with those of the healthy control subjects (P

BackgroundRotavirus and norovirus are the most common known causes of viral gastroenteritis in children. This study examined the association between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and disease severity in the acute phase of rotavirus and norovirus gastroenteritis in children, and it also explored the role of fecal cytokine levels in children with viral and bacterial gastroenteritis.MethodsThis prospective study enrolled patients aged 4 months to 14 years admitted with acute gastroenteritis in a tertiary care center. Peripheral blood samples were collected for IL-6 and IL-8 assays within the first 3 days of diarrhea. Stool samples were obtained from the patients in the first 24 hours after admission.ResultsSerum IL-6 and IL-8 were measured in children with viral (n = 66) and bacterial (n = 23) infections, and in healthy controls (n = 10). In the acute phase of gastroenteritis, a moderately positive correlation was found between serum IL-6 levels and disease severity (rs = 0.41, p

The one-time programmable (OTP) cell with intra-Fin-cell-isolation (IFCI) on the FinFET high-k metal gate (HKMG) CMOS process is proposed and demonstrated. The field-enhanced dielectric breakdown at Fin corners enables this OTP cell to be operated at low program voltage with fast program speed. The new intra-Fin cell-to-cell isolation eliminates the required wide spacing in the conventional isolation schemes, which successfully shields the neighboring cells from program and read disturbs. Without introducing extra masks or process steps, the CMOS compatible IFCI OTP cell achieves an ultrasmall cell size of 0.076 $\mu \text{m}^{2}$ . More than six orders of ON-/OFF-read window is achieved under 4 V programming within 20 $\mu \text{s}$ .

To evaluate the correlation between fecal calprotectin (fC), C-reactive protein (CRP), and endoscopic disease score in Asian inflammatory bowel disease (IBD) patients.Stool samples were collected and assessed for calprotectin levels by Quantum Blue Calprotectin High Range Rapid test. Crohn's disease endoscopic index of severity (CDEIS) and ulcerative colitis endoscopic index of severity (UCEIS) were used for endoscopic lesion scoring.A total of 88 IBD patients [36 patients with Crohn's disease (CD) and 52 with ulcerative colitis (UC)] were enrolled. For CD patients, fC correlated with CDEIS (r = 0.465, P = 0.005) and CRP (r = 0.528, P = 0.001). fC levels in UC patients correlated with UCEIS (r = 0.696, P0.0001) and CRP (r = 0.529, P = 0.0005). Calprotectin could predict endoscopic remission (CDEIS6) with 50% sensitivity and 100% specificity (AUC: 0.74) in CD patients when using 918 μg/g as the cut-off. When using 191 μg/g as the cut-off in UC patients, calprotectin could be used for predicting endoscopic remission (UCEIS3) with 88% sensitivity and 75% specificity (AUC: 0.87).fC correlated with both CDEIS and UCEIS. fC could be used as a predictor of endoscopic remission for Asian IBD patients.

To examine differences in clinical characteristics among children with norovirus, rotavirus, and bacterial gastroenteritis and investigate the outcomes in children with sporadic norovirus gastroenteritis. The study included patients aged 4 mo to 14 y who had acute gastroenteritis and were admitted to a tertiary care center between April 2008 and July 2009. The clinical features and laboratory findings of acute gastroenteritis were recorded. Fecal specimens were collected and tested for viruses, bacteria, and parasites. A total of 198 children (median age, 2.1 y) with acute gastroenteritis were studied. The pathogens identified included norovirus (n = 38), rotavirus (n = 47), adenovirus (n = 5), astrovirus (n = 1), bacteria (n = 43), and mixed infections (n = 7). No causative organisms were identified in 57 patients. The norovirus-infected group had a significantly higher proportion of those still vomiting 1 d after the onset of vomiting (p

This paper studies a two-party supply chain in which a retailer orders a short-life-cycle product from a supplier. The supplier establishes a production plan using a market forecast and determines his wholesale price. And then the retailer decides the order quantities and sells the product to the customers and declares a quoted lead time L at the retail price p. When the selling period begins, demand may disrupt. To cope with such demand disruption, the supplier may alter his wholesale price, which in turn influences the retailer's order quantity, the quoted lead time and the retail price. Our objective is to explore supply chain coordination via quantity discount in the presence of demand change, and to derive conditions under which the supply chain is coordinated to achieve maximum profit. A numerical example is given that illustrates the supply chain members' decisions in the absence and in the presence of demand change.