IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1.

T helper (Th)2 cytokines such as interleukin (IL)-4 and IL-13 control immune function by acting on leukocytes. They also regulate multiple responses in non-hematopoietic cells. During pregnancy, IL-4 and IL-13 facilitate alveologenesis of mammary glands. This particular morphogenesis generates alveoli from existing ducts and requires substantial cell proliferation. Using 3D cultures of primary mouse mammary epithelial cells, we demonstrate that IL-4 and IL-13 promote cell proliferation, leading to enlargement of mammary acini with partially filled lumens. The mitogenic effects of IL-4 and IL-13 are mediated by STAT6 as inhibition of STAT6 suppresses cell proliferation and improves lumen formation. In addition, IL-4 and IL-13 stimulate tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Prolonged treatment with these cytokines leads to increased IRS-1 abundance, which, in turn, amplifies IL-4- and IL-13-stimulated IRS-1 tyrosine phosphorylation. Through signaling crosstalk between IL-4/IL-13 and insulin, a hormone routinely included in mammary cultures, IRS-1 tyrosine phosphorylation is further enhanced. Lowering IRS-1 expression reduces cell proliferation, suggesting that IRS-1 is involved in IL-4- and IL-13-stimulated cell proliferation. Thus, a Th2-dominant cytokine milieu during pregnancy confers mammary gland development by promoting cell proliferation.

Transcriptional repression of Aurora-A gene by wild-type p53 through directly binding to its promoter with histone deacetylase 1 and mSin3a.

In this study, we firstly showed that p53 transcriptionally represses Aurora-A gene expression through directly binding to its promoter. DNA affinity precipitation assay and chromatin immunoprecipitation assay indicated that p53 physically bound to the Aurora-A promoter. Moreover, the in vitro and in vivo assays showed that p53 directly bound to the Aurora-A promoter together with histone deacetylase 1 (HDAC1) and mSin3a as corepressors. Furthermore, we identified that the nucleotides -360 to -354 (CCTGCCC), upstream of the Aurora-A transcriptional start site, was responsible for the p53-mediated repression. Mutation within this site disrupted its interaction with p53, mSin3a and HDAC1, as well as attenuated the repressive effect of p53 on Aurora-A promoter activity. Treatment with trichostatin A (TSA), a HDAC1 inhibitor, disrupted the interaction of p53-HDAC1-mSin3a complex with the nucleotides -365∼-345 region, and enhanced the Aurora-A promoter activity and gene expression. Additionally, knockdown of p53 or mSin3a also drastically blocked the formation of p53-HDAC1-mSin3a repressive complex onto this promoter region and elevated the Aurora-A promoter activity and gene expression. Moreover, the p53-HDAC1-mSin3a repressive complex also involved in the inhibition of Aurora-A gene expression upon cisplatin treatment. Finally, the clinical investigation showed that Aurora-A and p53 exhibited an inverse correlation in both the expression level and prognostic status, and the low p53/high Aurora-A showed the poorest prognosis of NSCLC patients. Our findings showed novel regulatory mechanisms of p53 in regulating Aurora-A gene expression in NSCLC cells.

15-year experience of laparoscopic single anastomosis (mini-)gastric bypass: comparison with other bariatric procedures.

BACKGROUND: Laparoscopic single anastomosis (mini-)gastric bypass (LSAGB) has been validated as a safe and effective treatment for morbid obesity. However, data of the long-term outcome remain lacking. METHODS: Between October 2001 and December 2015, 1731 morbidly obese patients who received LSAGB as primary bariatric procedure at the Min-Sheng General Hospital were recruited. Surgical outcome, weight loss, resolution of comorbidities, and late complications were followed, then compared with groups of laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG). All data derived from a prospective bariatric database and a retrospective analysis were conducted. RESULTS: The average patient age was 33.8 ± 10.4 years with a mean body mass index (BMI) of 40.4 ± 7.7 kg/m2. Of them, 70.0% were female while 30.0% were male. Mean operating time, intraoperative blood, and hospital stay of LSAGB were 124.6 ± 38.8 min, 39.5 ± 38.7 ml, and 5.0 ± 4.1 days, respectively. The 30-day post-operative major complication occurred in 30 (1.7%) of LSAGB patients, 16 (2.0%) of LRYGB, and 15 (1.4%) of LSG patients. The follow-up rates at 1, 5, and 10 years were 89.3, 52.1, and 43.6%, respectively. At postoperative 1, 5, and 10 years, the mean percentage of weight loss (%WL) of LSAGB patients were 32.7, 32.2, and 29.1%, and mean BMI became 27, 26.9, and 27 kg/m2, respectively. The LSAGB had a higher weight loss than LRYGB and LSG at 2-6 years after surgery. LSG had a lower remission rate in dyslipidemia comparing to LSAGB and LRYGB. The overall revision rate of LSAGB is 4.0% (70/1731) which was lower than the 5.1% in LRYGB and 5.2% in the LSG. CONCLUSION: LSAGB is an effective procedure for treating morbid obesity and metabolic disorders, which results in sustained weight loss and a high resolution of comorbidities.

Near-infrared cholecysto-cholangiography with indocyanine green may secure cholecystectomy in difficult clinical situations: proof of the concept in a porcine model.

BACKGROUND: Biliary injuries remain a major concern in laparoscopic cholecystectomy. New intraoperative guidance modalities, including near-infrared fluorescence cholangiography, are under evaluation. Initial results showed limitations in visualizing the biliary tree in specific clinical situations. The aim of this study was to examine the feasibility and potentiality of fluorescence cholecysto-cholangiography performed with a direct injection of indocyanine green (ICG) in the gallbladder and to compare it to systemic injection in such situations. MATERIALS AND METHODS: Seven pigs were included in this non-survival study. In two pigs, the gallbladder was punctured by a percutaneous needle, and 1 mL of ICG in different concentrations (0.001, 0.01, 0.1, and 1 mg/mL) was sequentially injected. Visibility and pattern of the fluorescent signal around Calot's triangle were examined and compared with those of two control pigs receiving 2.5 mg of intravenous ICG, 30 min prior to the operation. Different scenarios of cholecystitis were modeled using an injection of a mixture of blood and agarose gel around Calot's triangle area in the remaining three pigs, and the applicability of direct intragallbladder injection methods was evaluated. RESULTS: The fluorescent signal was identified immediately after intragallbladder injection, and the cystic duct became visible by 0.1 and 1 mg/mL of ICG. The whole cystic duct and the infundibulum of the gallbladder were clearly enhanced by intragallbladder ICG injection, but not by systemic injection. In the cholecystitis models, the cystic duct could be identified only after partial dissection, and fluorescence visualization of the gallbladder infundibulum provided crucial information to find the correct starting point of dissection. CONCLUSIONS: Fluorescence cholecysto-cholangiography through direct intragallbladder ICG injection could rapidly provide an adequate visualization of gallbladder neck and cystic duct and might be a valid option to increase the safety of cholecystectomy in case of cholecystitis.

Panax ginseng Fraction F3 Extracted by Supercritical Carbon Dioxide Protects against Oxidative Stress in ARPE-19 Cells.

In our previous work, the ethanolic extract of Panax ginseng C. A. Meyer was successively partitioned using supercritical carbon dioxide at pressures in series to yield residue (R), F1, F2, and F3 fractions. Among them, F3 contained the highest deglycosylated ginsenosides and exerted the strongest antioxidant and anti-inflammatory activities. The aim of this study was to investigate the protective effects of P. ginseng fractions against cellular oxidative stress induced by hydrogen peroxide (H2O2). Viability of adult retinal pigment epithelium-19 (ARPE-19) cells was examined after treatments of different concentrations of fractions followed by exposure to H2O2. Oxidative levels (malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reactive oxygen species (ROS)) and levels of activity of antioxidant enzymes were assessed. Results showed that F3 could dose-dependently protected ARPE-19 cells against oxidative injury induced by H2O2. F3 at a level of 1 mg/mL could restore the cell death induced by H2O2 of up to 60% and could alleviate the increase in cellular oxidation (MDA, 8-OHdG, and ROS) induced by H2O2. Moreover, F3 could restore the activities of antioxidant enzymes suppressed by H2O2. In conclusion, F3 obtained using supercritical carbon dioxide fractionation could significantly increase the antioxidant capacity of P. ginseng extract. The antioxidant capacity was highly correlated with the concentration of F3.

Higher risk of type 2 diabetes in young women with polycystic ovary syndrome: A 10-year retrospective cohort study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common disorder in women of reproductive age. Over the last few decades, research studies have revealed that PCOS is strongly associated with metabolic disorders, including metabolic syndrome, obesity, insulin resistance and prediabetes. Clinical observation has shown that women with PCOS are expected to have an increased risk of developing type 2 diabetes (T2DM) in the future. AIM: To assess the hazard ratio (HR) of T2DM between women with/without PCOS. METHODS: This population-based, retrospective cohort study evaluated data retrieved from the National Health Insurance Research Database. The subjects were women with PCOS (n = 2545) identified on the basis of diagnosis, testing, or treatment codes, and women without PCOS as controls (n = 2545). The HR of T2DM between women with or without PCOS was the main outcome measure analyzed. RESULTS: Our study found that, during a 10-year follow-up period, the overall incidence of T2DM was 6.25 per 1000 person-years in the PCOS group compared with 1.49 in the control group. After adjustment for potential confounding variables, the overall incidence of T2DM was higher in the PCOS group vs the control group (HR = 5.13, 95%CI: 3.51-7.48, P < 0.0001). The risk of developing T2DM subsequent to PCOS decreased with increasing diagnosis age: the adjusted HR was 10.4 in the 18-24-year age group, 5.28 in the 25-29-year age group, and 4.06 in the 29-34-year age group. However, no such significant association was noted in women older than 35 years. CONCLUSION: These findings highlight the importance of prompting a more aggressive treatment to prevent diabetes in women diagnosed with PCOS at a young age, and, in contrast, the lessened importance of this type of intervention in women diagnosed with PCOS at a late reproductive age.

Mitochondrial AAA protease gene associated with immune infiltration is a prognostic biomarker in human ovarian cancer.

Early diagnosis and identification of prognostic markers for ovarian cancer can significantly improve survival and reduce mortality. The role of the YME1L1 signaling axis in genetic alterations and immune infiltration of the tumor microenvironment remains unclear. Bioinformatics web resources, including GEPIA2, cBioPortal, Oncomine, Kaplan-Meier Plotter, and TIMER, were used to analyze the expression profile, prognostic value, and immune infiltration of YME1L1. We further performed a tissue microarray analysis of paraffin-embedded tissues from 60 patients with ovarian cancer, recorded at the FIGO/TNM cancer staging. Here, we used multi-omics analysis of multiple histological datasets to map the role of epigenetic and genetic alterations of YME1L1 in tumor immune infiltration and the prognosis of cancer patients. We explored YME1L1 gene expression profiles by systematically analyzing the association between YME1L1 expression and the prognosis of patients with ovarian cancer confirmed in multiple databases. High expression levels of YME1L1 were associated with poor overall and disease-free survival. Together, our studies suggest that YME1L1 may modulate tumor survival and immune features and contribute to tumor immune invasion, poor prognosis, and immunotherapy failure. Our findings may have clinical implications for the design of treatment strategies, prognosis assessment, and follow-up management of patients receiving immunotherapy for various cancers.

Experience of the First 100 OAGB in China: OAGB In Situ Technique.

BACKGROUND: One anastomosis gastric bypass (OAGB) is gradually accepted worldwide but still new in China. MATERIALS AND METHODS: Retrospective review of the patients who received OAGB in a new bariatric/metabolic surgical center in China and compared the data with a center of excellence in Taiwan. All in-patient and outpatient follow-up data were analyzed. The main outcome measures were (1) operation risk (2) weight loss (3) diabetes remission. RESULTS: Between August 2019 and October 2021, 100 consecutive patients who received OAGB in situ in China and 225 patients who received OAGB with the same technique were recruited from Taiwan. Taiwan patients were older (39.2 ± 10.6 vs. 33.3 ± 8.8 years old, p < 0.001), and to have more diabetes (32.4% vs. 20.0%, p = 0.022) comparing to the patients of China. Operation time was significantly longer for Taiwan patients (172.4 ± 36.9 vs. 128.5 ± 29.8, p < 0.001). Taiwan patients lost more blood during the operation (35.5 ± 25.2 vs. 22.4 ± 15.6, p < 0.001) but patients in China need more time to postoperative flatus passage (1.3 ± 0.5 vs. 2.0 ± 0.5, p < 0.001). There was no major surgical complication in this study, minor complication rates were similar low for both groups (1.0% vs. 1.8%, p = 0.891). At 1 year after surgery, %TWL and %EWL of both centers were similar (33.9 ± 7.43% vs. 32.6 ± 11.2%, p = 0.91; 81.9 vs. 19.8 vs. 85.4 ± 13.2, p = 0.798). T2DM remission (HbA1c < 6.5%) was 100% for patients of China and 95.9% for patients of Taiwan (p = 0.836). CONCLUSIONS: OAGB in situ is a safe and effective bariatric/metabolic surgery. With proper training and proctorship, these results are reproduceable in a new bariatric/metabolic surgical center in China.

Probiotics for gallstone prevention in patients with bariatric surgery: A prospective randomized trial.

BACKGROUND: Gall stone disease was known to increase after bariatric surgery. Ursodeoxycholic acid (UDCA) might reduce the gallstone formation rate after bariatric surgery. However, other option for gallstone prevention was unclear. We reported the result of a randomized trial comparing the gallstone prevention efficacy of probiotics and digestive enzyme versus UDCA. METHODS: This prospective, randomized trial was held in an institute of Taiwan. Patients were eligible for inclusion if their body-mass index (BMI) was 32.5 kg/m2 or higher with the presence of comorbidity, or 27.5 kg/mw or higher with not-well controlled type 2 diabetes, and were aged 18-65 years. Participant were randomized assigned (1:1:1) to probiotic, digestive enzyme or UDCA. The primary endpoint was assessed in the incidence of gallstone disease at 6 months after surgery. This study is registered with ClinicalTrials.gov. number NCT03247101, and is now completed. RESULTS: From January 2016 to December 2018, of 186 patients screened for eligibility, 152 were randomly assigned to probiotic (52) or digestive enzyme (52) or UDCA (52). In the per-protocol population, mean age was 35.9 years (SD 10.6), mean BMI was 40.3 kg/m2 (SD 6.9), 57(58.2%) were female. After 6 months, the incidence of gall bladder diseased was 15.2%, in the probiotics group, 17.6% in UDCA group and 29.1% in digestive enzyme groups, confirming non-inferiority of probiotic (p = 0.38). Female gender was identified as a risk factor for gall bladder disease after bariatric surgery (odds ratio = 4.61, 95% confidence interval = 1.05, 20.3, p = 0.04). The poor drug compliance rate was 19.5%, 22.7% and 26.2% in probiotics, UDCA and digestive enzyme group respectively. UDCA group had a higher drug adverse effect than probiotic group (15.9% vs. 2.4%, p = 0.03). CONCLUSION: Probiotic is not inferior to UDCA regarding gall bladder disease prevention after bariatric surgery at 6 months.

Change of cardiovascular risk associated serologic biomarkers after gastric bypass: A comparison of diabetic and non-diabetic Asian patients.

BACKGROUND: While clinical findings demonstrate a superior benefit of cardiovascular (CV) risk reduction in obese patients with type 2 diabetes mellitus (T2D) receiving bariatric surgery over non-T2D patients, the mechanism is unclear. This study aimed to investigate the changes in the CV risk score and five CV-associated biomarkers after gastric bypass surgery. METHOD: We enrolled 80 obese subjects who underwent gastric bypass (40 T2D and 40 non-T2D). CV risks were assessed using the United Kingdom Prospective Diabetes Study (UKPDS) engine before and after surgery. Levels of five biomarkers -fasting serum fibroblast growth factor (FGF)-19, FGF-21, corin, oxidized low-density lipoprotein (ox-LDL), and soluble receptor for advanced glycation end-products (sRAGE)-were measured before surgery and one year after surgery. RESULTS: The T2D group was significantly older and had a higher CV risk score than the non-T2D group, but body mass index (BMI) was similar between the groups. Preoperative biomarker levels were similar in both the T2D and the non-T2D groups. One year after surgery, the percentage of total weight loss (%TWL) was similar between the two groups (32.2 ± 19.5% versus 34.1% ± 8.8%, p = 0.611). Complete T2D remission (hemoglobin A1c (HbA1c) < 6.0%) was achieved in 29 patients (72.5%). The 10-year CV risk scores by the UKPDS risk engine reduced significantly in both the T2D and the non-T2D groups, but more in the T2D group. Three of five biomarkers changed significantly after surgery: the FGF-19 increased from 195.6 ± 249.1 pg/mL to 283.2 ± 211.8 pg/mL, corin increased from 3.3 ± 2.3 ng/mL to 4.6 ± 3.7 ng/mL, and ox-LDL decreased from 148.5 ± 71.7-107.9 U/L; the P values were 0.002, 0.002 and < 0.001, respectively. The T2D group showed a significantly different change in FGF-19 increase and FGF-21 decrease compared to the non-T2D group. The changes in corin and ox-LDL levels were not different between the T2D and non-T2D groups. CONCLUSION: Gastric bypass surgery resulted in a higher UKPDS CV risk score reduction in obese T2D Asians than in those without. FGF-19 and FGF-21 may be associated with the underlying mechanism of this difference.

Aurora-A promotes gefitinib resistance via a NF-κB signaling pathway in p53 knockdown lung cancer cells.

Mutations of the p53 tumor suppressor gene are the most common mutations found in human tumors. There is increasing evidence that suggests that p53 status is a determinant of chemosensitivity of tumor cells. We have previously demonstrated that p53 is a crucial regulator in mediating gefitinib-induced cell death, which upregulates apoptosis-related molecules. However, the mechanism of p53 involvement in cellular resistance to gefitinib remains unclear. In this study, we found that human non-small cell lung cancer cells, A549, with wild-type p53 exhibited a low level of Aurora-A expression and were sensitive to treatment with gefitinib. p53-knockdown A549 cells exhibited a high level of Aurora-A expression and were resistant to gefitinib-mediated apoptosis induction. In addition, the silencing of Aurora-A expression using an Aurora-A specific siRNA in p53-knockdown cells sensitized the A549 cancer cells to gefitinib-mediated apoptosis, suggesting a role for Aurora-A in gefitinib resistance. The activation of Aurora-A was accompanied by destabilization of IκBα and an increase in NF-κB transcriptional activity and was correlated with gefitinib resistance. Conversely, knockdown of Aurora-A with a siRNA stabilized IκB protein suppressed NF-κB activation and reduced gefitinib resistance. Additionally, ectopic expression of an active form of Aurora-A increased the degradation of IκB, the activation of NF-κB and the enhancement of gefitinib resistance in comparison with parental cells. These results suggest that Aurora-A is potentially involved in promoting gefitinib resistance via the activation of NF-κB pathway. Our findings also suggest that p53 not only stimulates apoptosis-related event but also inhibits the drug-resistance ability of Aurora-A, and consequently promotes the gefitinib-induced cellular apoptotic process.

Peritoneal recurrence in serosa-negative gastric adenocarcinoma after curative surgery.

BACKGROUND/AIMS: The rate of recurrence increases in proportion to the degree of tumor depth, even after curative resection for gastric adenocarcinoma. Serosal exposure is considered as an important risk factor of peritoneal recurrence. However, some patients with serosa-negative cancer were found to have peritoneal recurrence. There are few reports concerning risk factors of peritoneal recurrence in serosa-negative gastric adenocarcinoma. The aim of this study is to evaluate the incidence and risk factors of peritoneal recurrence in serosa-negative gastric adenocarcinoma after curative resection. METHODOLOGY: Total 1128 serosa-negative gastric cancer patients (574 pT1, 251 pT2, 303 pT3) diagnosed as gastric adenocarcinoma that underwent R0 resection from 1988 to 2005 were enrolled. RESULTS: Peritoneal recurrence was observed in 50 (4.4%) patients, including 3 pT1, 3 pT2 and 44 pT3 patients. The incidence of peritoneal recurrence increased significantly with tumor invading subserosa (pT3). Multivariate analysis showed that the independent risk factor of peritoneal recurrence was tumor depth. CONCLUSIONS: The incidence of peritoneal recurrence in serosa-negative cancer is low, and tumor depth is a significant risk factor. We should be aware of peritoneal recurrence during follow-up, especially for patients with subserosal tumor invasion.

Long-Term Efficacy of Bariatric Surgery for the Treatment of Super-Obesity: Comparison of SG, RYGB, and OAGB.

BACKGROUND: The most appropriate procedure for the treatment of super obesity (BMI > 50 kg/m2) is unknown. We aimed to evaluate the safety, long-term (> 5 years) weight loss, and adverse events between three commonly performed procedures, sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and one anastomosis gastric bypass (OAGB) in super-obese patients. METHODS: Between January 2002 and December 2015, 498 successive patients with super morbid obesity (BMI > 50), who underwent SG or RYGB or OAGB, were recruited. Surgical outcome, weight loss, resolution of co-morbidities, and late complications were followed and compared between the 3 groups. All data derived from a prospective bariatric database and a retrospective analysis was conducted. RESULTS: The average patient age was 32.1 ± 10.4 years, with a mean body mass index (BMI) of 56.0 ± 6.7 kg/m2. Of them, 190 (38.9%) underwent SG, 62 (12.4%) RYGB, and 246 (49.4%) OAGB. There was no difference in basic characters between the 3 groups except SG had fewer diabetic patients. RYGB group had higher intraoperative blood loss, longer operating time, and hospital stay than the other 2 groups. RYGB had a higher 30-days post-operative major complication rate (4.8%) than SG (0.5%) and OAGB (0.8%). The follow-up rate at 1 and 5 years was 89.4% and 52.0%. At post-operative 5 years, OAGB had a higher total weight loss (40.8%) than SG (35.1%), but not RYGB (37.2%). SG had a lower remission rate in dyslipidemia comparing to OAGB and RYGB, but T2DM remission rate was no different between the groups. The overall revision rate is 5.4% (27/498) of the whole group, and SG had a lower revision rate (2.6%) than RYGB (8.1%) and OAGB (6.9%). CONCLUSION: SG is an effective and durable primary bariatric procedure for the treatment of super obesity and metabolic disorders. OAGB had a similar operation risk to SG but resulted in a better weight loss than SG.

MicroRNA­10b modulates cisplatin tolerance by targeting p53 directly in lung cancer cells.

MicroRNA (miRNA or miR)­10b is an oncogenic miRNA associated with metastasis that is present in various types of tumor, including lung cancer. However, whether miR­10b is involved in different malignant characteristics, such as drug resistance or stemness, remains unclear. Therefore, the present study investigated whether miR­10b is an upstream regulator of p53. Ectopic expression of miR­10b­agomir decreased the expression of p53 and its downstream effectors, such as Bax and p53 upregulated modulator of apoptosis. Two non­canonical sites, including 1,580­1,587 and 2,029­2,035, located in p53 3'­untranslated region (UTR) were affected by the presence of miR­10b. In functional assays, upregulation of the p53 signaling pathway following cisplatin treatment was associated with decreased levels of miR­10b and upregulation of the luciferase activity of wild­type, but not 1,584, 2,032­dual­mutant, p53 3'­UTR. The ectopic expression of miR­10b­agomir attenuated the stability of p53 3'­UTR and the expression of p53 and its downstream effectors induced by cisplatin. By contrast, the knockdown of miR­10b induced the stability of p53 3'­UTR and increased levels of p53 and the sensitivity of A549 cells to cisplatin treatment. Similar results were also observed for Beas 2B cells. In the clinical investigation, p53 exhibited two distinct associations (cocurrent and countercurrent) with miR­10b in patients with lung cancer. Patients with lung cancer with low p53 and high miR­10b levels exhibited the poorest prognosis, while those with high p53 and low miR­10b exhibited the most favorable prognosis. These findings indicate a novel pathway in which cisplatin induces the levels of p53 by increasing mRNA stability via miR­10b, indicating a novel oncogenic role of miR­10b in promoting the malignant characteristics of non­small cell lung carcinoma.

Twenty years' experience of laparoscopic 1-anastomosis gastric bypass: surgical risk and long-term results.

BACKGROUND: Laparoscopic 1- (single-) anastomosis gastric bypass (OAGB) was developed as a simplified technique of Roux-en-Y gastric bypass (RYGB), but super long-term data are lacking. OBJECTIVES: To evaluate the risks and long-term results of OAGB over a period of 20 years. SETTING: Tertiary teaching hospital. METHODS: A total of 2223 patients underwent OAGB from 2001 to 2020; the mean age was 35.3 ± 11.4 years (range, 14-71 yr), 70.2% were female, and the mean body mass index was 40.2 ± 11.9 kg/m2. All data were kept in a prospective bariatric database. Patients were divided into 4 groups, based on the 5-year period in which their surgery was performed, and a retrospective analysis was conducted. RESULTS: The means for operating time, intraoperative blood loss, and length of hospital stay after OAGB were 131.9 ± 40.1 minutes, 38.5 ± 30.7 mL, and 4.5 ± 4.0 days, respectively. There were 27 patients (1.2%) with 30-day postoperative major complications overall, but the group rate decreased to .4% in the last 5-year period. At postoperative years 5, 10, and 15, the percentages of total weight loss were 31.9%, 29.6%, and 29.5%, respectively, and the percentages of excess weight loss were 77.2%, 68.4%, and 65.5%, respectively. Among 739 patients (33.2%) with type 2 diabetes (T2D), the rates of complete remission (glycated hemoglobin < 60%) at 5, 10, and 15 years were 67.3%, 73.8%, and 66.7%, respectively. The weight loss and antimetabolic effects were similar in each 5-year period, but a significant malnutrition effect was observed. A total of 113 (5.1%) patients needed revision surgery at follow-up, due to malnutrition (n = 51), weight regain (n = 24), acid or bile reflux (n = 22), marginal ulcer (n = 8), ileus (n = 3), and other causes (n = 5). At 15 years, the overall revision rate was 11.9% (27/226), and 80% of the patients were very satisfied with their procedures. CONCLUSION: Our results showed that OAGB is a safe and durable primary bariatric procedure, with sustained weight loss and a high resolution of T2D up to 20 years post surgery in Taiwan, although malnutrition is a major side effect.

Attenuating role of withaferin A in the proliferation and migration of lung cancer cells via a p53-miR-27a/miR-10b pathway.

MicroRNAs (miRNAs/miRs) are known to play a key role in tumorigenesis and usually serve as therapeutic targets in cancer treatment. In the present study, the inhibitory effects and the targeting miRNAs of withaferin A (WA) were investigated in human lung cancer cells. Different lung cancer cell lines were administrated with different concentrations of WA for different time interval followed by western blot or reverse transcription-quantitative PCR analyses to determine the underlying signaling pathway. The results demonstrated that WA decreased the viability of lung cancer cells in a caspase-dependent manner. Further investigations indicated that treatment with WA induced the expression of proapoptotic molecules, p53 and Bax, and decreased Bcl-2 expression in A549 cells. Notably, the results demonstrated that WA also decreased the motility of lung cancer cells in a dose-dependent manner, at a relatively lower concentration. Western blot analysis revealed increased E-cadherin and decreased vimentin expression levels in lung cancer cells treated with WA. In addition, two oncomiRs, including miR-10b and miR-27a, which regulate the expression of E-cadherin and Bax, respectively, were downregulated in the presence of WA. The ectopic expression of miR-10b mimics was able to recover the WA-decreased motility of lung cancer cells, which was accompanied by a reduction in E-cadherin expression. Conversely, the ectopic expression of miR-27a mimics decreased the expression of Bax and recovered the viability of lung cancer cells attenuated by WA. In addition, the ectopic expression of p53-wild type decreased the expression levels of both miR-10b and miR-27a, whereas p53 knockdown induced their expression. Transient knockdown of p53 decreased the inhibitory effects of WA in the motility and viability of lung cancer cells, suggesting an association between WA-p53-miR-10b/27a and motility/viability. Further investigations demonstrated that p53 knockdown in lung cancer stable cell lines exhibited higher levels of both miR-10b and miR-27a, and higher motility and viability following treatment with WA. However, suppression of miR-10b and miR-27a effectively decreased motility and viability, respectively, following treatment with WA. Taken together, the results of the present study suggest that WA inhibits the functionality of lung cancer cells by decreasing the expression levels of both miR-10b and miR-27a in a p53-dependent manner.

One Anastomosis Gastric Bypass for the Treatment of Type 2 Diabetes: Long-Term Results and Recurrence.

BACKGROUND: Bariatric/metabolic surgery has been incorporated into the therapeutic treatment of type 2 diabetes mellitus (T2DM). Among many bariatric/metabolic procedures, one anastomosis gastric bypass (OAGB) is one of the most effective procedures but long-term data about T2DM recurrence after OAGB are lacking. METHODS: Outcomes of 134 patients who had undergone OAGB for the treatment of T2DM with long-term (5 years) follow-up were assessed in a retrospective cohort study. The remission of T2DM after OAGB surgery was evaluated in different groups using a scoring system composed of the age, BMI, C-peptide level, duration of T2DM (ABCD score), and percent of total weight loss (%TWL). RESULTS: The %TWL and percent of excess weight loss (%EWL) of the OAGB patients at 5 years after surgery were 29.2 (10.6) and 72.1(27.5), respectively. The mean BMI decreased from 39.5(7.9) to 27.6(5.3) kg/m2 and mean glycated hemoglobin A1C (HbA1c) decreased from 8.9 to 5.9% in OAGB patients at 5 years after OAGB. The complete T2DM remission rate of OAGB was 76.1% at 1 year and 64.2% at 5 years after surgery. Forty-one (57.8%) out of 71 patients who completed a 10-year follow-up remained in complete T2DM remission. The T2DM recurrence rate of OAGB patients was 15.7% at 5 years after surgery. CONCLUSIONS: OAGB is highly effective in inducing T2DM remission but a significant number of patients will still have T2DM recurrence. To select patient with an ABCD score > 5 and maintaining a weight loss greater than 30% is important for durable T2DM remission after OAGB.

Variation in Small Bowel Length and Its Influence on the Outcomes of Sleeve Gastrectomy.

PURPOSE: Small bowel length is drawing attention in the development of gastrointestinal bariatric/metabolic surgery, but the importance of the length of the small bowel in bariatric/metabolic is not clear. The present study was conducted to investigate variations in small bowel length and their clinical significance in patients undergoing laparoscopic sleeve gastrectomy (LSG). MATERIALS AND METHODS: Small bowel length was measured in 620 patients diagnosed with obesity who underwent LSG between March 2014 and August 2018. Prospectively obtained demographic and clinical data were investigated, focusing on the association between small bowel length and weight loss. RESULTS: Small bowel length varied widely among patients (mean 739.8 + 115.7 cm, range 380-1050 cm). Linear regression analysis revealed a significant association between small bowel length and body height, body weight, waist circumference, and serum levels of low-density lipoprotein cholesterol, hemoglobin, C-peptide, glycated hemoglobin (A1C), and gamma-glutamyl transferase (r-GT). Multivariate analysis confirmed that body height and serum A1C% levels independently predicted small bowel length in bariatric patients, strongly with body height (p < 0.001) but weakly with A1C%(p = 0.021). One-year follow-up rate was 75.3% (467/620), and small bowel length did not influence weight loss or the reduction of obesity related cardiovascular risk factors after LSG. CONCLUSION: In this study, small bowel length varied widely among bariatric patients and was strongly associated with body height and weakly with serum A1C levels. Small bowel length has no significant role in weight loss or the resolution of cardiovascular risk factors after LSG.

Methyl antcinate A from Antrodia camphorata induces apoptosis in human liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway.

We investigated the effects of antcin A, antcin C, and methyl antcinate A (MAA) isolated from Antrodia camphorata on the proliferation of human liver cancer cell lines Huh7, HepG2, and Hep3B and the normal cell rat hepatocytes. The three compounds selectively inhibit the proliferation of tumor cells rather than normal cells, with IC(50) values ranging from 30.2 to 286.4 microM. The compound MAA was a more potent cytotoxic agent than antcins A and C with IC(50) values of 52.2, 78.0, and 30.2 microM against HepG2, Hep3B, and Huh7 cells, respectively. To elucidate the molecular mechanism, treatment of Huh7 cells with 100 microM MAA induced an apoptotic cell death, which was characterized by the appearance of sub-G1 population, DNA fragmentation, TUNEL positive cells, and caspase activation. MAA triggered the mitochondrial apoptotic pathway, as indicated by an increase in the protein expression of Bax, Bak, and PUMA, as well as a decrease in Bcl-(XL) and Bcl-2 and disruption of mitochondrial membrane potential and promotion of mitochondrial cytochrome c release, as well as activation of caspases-2, -3, and -9. We also found that pretreatment with inhibitors of caspases-2, -3, and -9 noticeably blocked MAA-triggered apoptosis. Furthermore, intracellular reactive oxygen species (ROS) generation and NADPH oxidase activation were observed in MAA-stimulated Huh7 cells. Mechanistic studies showed that MAA induces mitochondrial translocation of cofilin. When Huh7 cells were treated with cyclosporine A and bongkrekic acid, an inhibitor of the mitochondria permeability transition pore, the levels of cell death induced by MAA were significantly attenuated. Additionally, pretreatment of Huh7 cells with antioxidants ascorbic acid and N-acetyl cysteine markedly attenuated the MAA-induced apoptosis by upregulation of Bax, Bak, and PUMA, mitochondrial translocation of cofilin, activation of caspase-3, and cell death. Taken together, our results provide the first evidence of the activation of the ROS-dependent cofilin- and Bax-triggered mitochondrial pathway as a critical mechanism of MAA-induced cell death in liver cancer cells.

Laparoscopic Sleeve Gastrectomy for Type 2 Diabetes Mellitus: Long-Term Result and Recurrence of Diabetes.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is becoming a primary bariatric/metabolic surgical procedure for treating obesity and related type 2 diabetes mellitus (T2D). This study presents the long-term outcome of LSG about the remission and recurrence of T2D. METHODS: A total of 59 obese patients (38 women and 21 male) with T2D (mean body mass index [BMI] 37.6 ± 5.1 kg/m2) who underwent LSG from 2006 to 2014 with complete 5 years followed up were selected for present study. The remission of T2D was evaluated in stratified groups using the ABCD scoring system which is composed of the age, BMI, C-peptide, and duration of T2D. RESULTS: The weight loss at 5 years after surgery was 23.5% and the mean BMI decreased to 27.7 ± 4.5 kg/m2. The mean HbA1c decreased from 8.1 to 6.1% at 5 years. The 1-year and 5-year complete remission rate (HbA1c < 6.0%) was 62.7% and 42.4%. Thirteen patients (35.1%) out of 37 patients who had their T2D remission at 1 year had their T2D recurrent at 5 years. Patients with ABCD score higher than 5 had a higher long-term T2D remission rate and less recurrence of their T2D than those with ABCD score less than 5. The remission and recurrence of T2D after were associated with a weight loss more than 20%. CONCLUSION: LSG is an effective procedure for T2D treatment but a significant portion of patients had their T2D recurrence at long-term. LSG is better recommended to patients with their ABCD score ≥ 5 and dedication to maintain a good weight loss is important.