Comparative Analysis of Enbloc or Piecemeal Removal After Enbloc Resection of Gastrointestinal Stromal Tumors.

OBJECTIVE: To investigate the safety and prognosis of enbloc or piecemeal removal after enbloc resection of a gastric GIST by comparing the clinical data of endoscopic en block resection and piecemeal removal (EP) and en block resection and complete removal (EC) of gastric GISTs. METHODS: A total of 111 (43 endoscopic piecemeal, and 68 complete removal) patients with gastric GIST's ≥ 2 cm in diameter who underwent endoscopic therapy from January 2016 to June 2020 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. In all cases, it was ensured that the tumor was intact during the resection, however, it was divided into EP group and EC group based on whether the tumor was completely removed or was cut into pieces which were then removed. The patients' recurrence-free survival rate and recurrence-free survival (RFS) were recorded. RESULTS: There was no statistically significant difference in RFS rates between the two groups (P = 0.197). The EP group had relatively high patient age, tumor diameter, risk classification, and operation time. However, there was no statistically significant difference in the number of nuclear fission images, postoperative hospitalization time, postoperative fasting time, complication rate and complication grading between the two groups (P > 0.05). CONCLUSION: Endoscopic piecemeal removal after en block resection of gastric GIST is safe and effective and achieves similar clinical outcomes as complete removal after en block resection.

TGF-ß-driven LIF expression influences neutrophil extracellular traps (NETs) and contributes to peritoneal metastasis in gastric cancer.

Gastric cancer (GC), notorious for its poor prognosis, often advances to peritoneal dissemination, a crucial determinant of detrimental outcomes. This study intricately explores the role of the TGFß-Smad-LIF axis within the tumor microenvironment in propagating peritoneal metastasis, with a specific emphasis on its molecular mechanism in instigating Neutrophil Extracellular Traps (NETs) formation and encouraging GC cellular functions. Through a blend of bioinformatics analyses, utilizing TCGA and GEO databases, and meticulous in vivo and in vitro experiments, LIF was identified as pivotally associated with GC metastasis, notably, enhancing the NETs formation through neutrophil stimulation. Mechanistically, TGF-ß was substantiated to elevate LIF expression via the activation of the Smad2/3 complex, culminating in NETs formation and consequently, propelling peritoneal metastasis of GC. This revelation uncovers a novel potential therapeutic target, promising a new avenue in managing GC and mitigating its metastatic propensities.

Effect of Abdominal Compression on Total Single-Balloon Enteroscopy Rate: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether abdominal compression significantly increased the total enteroscopy rate in single-balloon enteroscopy (SBE). METHODS: Consecutive patients who underwent SBE at 2 hospitals were prospectively included between June 1, 2020, and September 30, 2021. They were randomly divided into an abdominal compression group and a non-abdominal compression group with use of sealed envelopes generated by a computer. Total enteroscopy rates were compared between the groups. RESULTS: The study included 200 patients. The total enteroscopy rates were 73% and 16% in the abdominal compression and non-abdominal compression groups, respectively (relative risk, 13.55; 95% CI, 6.79 to 27.00; P<.001). The total enteroscopy rate was higher in the 70 patients who were identified to have undergone no previous abdominal surgery or small intestinal stenosis than in the 32 patients who had undergone such procedures in the abdominal compression group (84% vs 47%; relative risk, 6.08; 95% CI, 2.36 to 15.67; P<.001). Relevant positive findings were not significantly different between the groups (58% vs 45%; P=.07). Binary logistic regression analysis found abdominal compression to be associated with a better total enteroscopy rate (odds ratio, 16.68; 95% CI, 7.92 to 35.15; P<.001), and the presence of previous abdominal surgery or small intestinal stenosis was associated with difficulty in completing the total enteroscopy procedure (odds ratio, 0.26; 95% CI, 0.12 to 0.58; P<.01). CONCLUSION: Abdominal compression significantly increased the total enteroscopy rate in SBE. Complete total enteroscopy may be challenging in patients with a history of abdominal surgery or small intestinal stenosis.

The adsorption mechanisms of oriental plane tree biochar toward bisphenol S: A combined thermodynamic evidence, spectroscopic analysis and theoretical calculations.

Garden pruning waste is becoming a problem that intensifies the garbage siege. It is of great significance to purify polluted water using biochar prepared from garden pruning waste. Herein, the interaction mechanism between BPS and oriental plane tree biochar (TBC) with different surface functional groups was investigated by adsorption experiments, spectroscopic analysis and theoretical calculations. Adsorption kinetics and isotherm of BPS on TBC can be satisfactorily fitted into pseudo-second-order kinetic and Langmuir models, respectively. A rapid adsorption kinetic toward BPS was achieved by TBC in 15 min. As compared with TBC prepared at low temperature (300 °C) (LTBC), the maximum adsorption capacity of TBC prepared at high temperature (600 °C) (HTBC) can be significantly improved from 46.7 mg g-1 to 72.9 mg g-1. Besides, the microstructure and surface functional groups of HTBC were characterized using SEM, BET-N2, and XPS analysis. According to density functional theory (DFT) theoretical calculations, the higher adsorption energy of HTBC for BPS was mainly attributed to π-π interaction rather than hydrogen bonding, which was further supported by the analysis of FTIR and Raman spectra as well as the adsorption thermodynamic parameters. These findings suggested that by improving π-π interaction through high pyrolysis temperature, BPS could be removed and adsorbed by biochar with high efficacy, cost-efficiency, easy availability, and carbon-negative in nature, contributing to global carbon neutrality.

Gastric cancer cell-derived extracellular vesicles elevate E2F7 expression and activate the MAPK/ERK signaling to promote peritoneal metastasis through the delivery of SNHG12.

Cancer cell-derived extracellular vesicles (EVs) have extensive application in the formation of their environment, including metastasis. This study explored the ability of gastric cancer (GC) cell-derived EVs-mediated microRNA-129-5p/E2F transcription factor 7/mitogen-activated protein kinase/extracellular regulated protein kinase (miR-129-5p/E2F7/MAPK/ERK) axis to affect the peritoneal metastasis of GC by delivering lncRNA small nucleolar RNA host gene 12 (SNHG12). EV-derived lncRNA and SNHG12/miR-129-5p/E2F7 network were determined by bioinformatics analysis. The regulatory relationship among SNHG12, miR-129-5p, and E2F7 was verified using a combination of dual-luciferase reporter gene, RNA immunoprecipitation, and RNA pull-down assays. The SNHG12, miR-129-5p, and E2F7 expression was measured by RT-qPCR. After GC cell-derived EVs were isolated and co-cultured with human peritoneal mesothelial cells (HPMCs), the uptake of EVs by HPMCs was observed under laser scanning confocal microscopy. Cell viability and apoptosis were examined using cell counting kit-8 and flow cytometry, respectively. Western blot analysis was performed to measure the mesothelial-mesenchymal transition (MMT)-related protein expression. The pathological and morphological characteristics of metastatic tumors in nude mice were observed by hematoxylin-eosin staining. A high SNHG12 expression was correlated with the poor prognosis of patients with GC. GC-derived EVs led to increased HPMC apoptosis and MMT by transferring SNHG12, whereas the knockdown of SNHG12 annulled the aforementioned results. SNHG12 sponged miR-129-5p to boost E2F7 expression and activate the MAPK/ERK signaling, thus inducing HPMC apoptosis and MMT. In vivo experiments further verified that EVs derived from GC cells promoted peritoneal metastasis in nude mice. GC cell-derived EVs elevated the E2F7 expression and activated the MAPK/ERK signaling to promote peritoneal metastasis through the delivery of SNHG12.

Xanthine oxidase activity in thiopurine curative Chinese inflammatory bowel disease patients.

Xanthine oxidase (XO) competes with thiopurine S-methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6-mercaptopurine (6-MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine-induced adverse effects (AEs) existed. Clinical data and blood samples were collected from 140 IBD patients before receiving AZA/6-MP therapy, and the erythrocyte XO activity was measured. The XO activities of all patients were 20.29 ± 4.43 U/g Hb. No sex difference in XO activity was observed (p = .728), and the XO activity showed no difference between the UC and CD patients (p = .082). AEs were observed in 41 (29.3%) patients including leukopenia (26, 18.57%), gastrointestinal intolerance (11, 7.86%), flu-like symptom (5, 3.57%), alopecia (5, 3.57%), and hepatotoxicity (1, 0.71%). XO activity was significantly lower in the patients with AEs than in those without AEs (18.40 ± 3.73 vs. 21.07 ± 4.48 U/g Hb, p = .001), especially in the patients with leukopenia (18.29 ± 3.68 vs. 21.07 ± 4.48 U/g Hb, p = .004). However, no significant difference in XO activity was found between patients with and without other AEs. Decreased XO activity was observed in the patients who developed flu-like symptoms (17.58 ± 3.50 U/g Hb) and alopecia (18.67 ± 2.91 U/g Hb) compared to those who did not, although the differences did not reach statistical significance. These findings suggested that patients with low XO expression might have a high risk of thiopurine-induced toxicity.

Methylation of microRNA-338-5p by EED promotes METTL3-mediated translation of oncogene CDCP1 in gastric cancer.

Unmasking the complex regulatory pathways that mediate the malignant phenotypes of cancer cells can provide novel targets for therapies that could limit the recurrence and metastasis of gastric cancer (GC). Herein, we intended to clarify the role of embryonic ectoderm development protein (EED), microRNA-228-5p (miR-338-5p), methyltransferase like 3 (METTL3) and CUB domain containing protein 1 (CDCP1) in GC. Differentially expressed miRNAs and their target genes were extracted by in silico analysis. The studies revealed high expression of EED in GC tissues and cell lines and it high expression in GC patients was shown to be associated with poor prognosis. The chromatin immunoprecipitation assay identified that EED methylated miR-338-5p to inhibit its expression. EED knockdown could restrain the proliferative and invasive abilities of GC cells by inducing miR-338-5p. Furthermore, miR-338-5p targeted m6A methylase METTL3, while METTL3 amplified the translation of CDCP1 via m6A activity which led to accelerated proliferation and invasion of GC cells. Moreover, in vivo experiments validated that EED promoted the progression of GC through mediating the miR-338-5p/METTL3/CDCP1 axis. Collectively, EED downregulated miR-338-5p through histone methylation, which in turn impaired miR-338-5p-dependent METTL3 inhibition and enhanced CDCP1 translation, therefore contributing to the development of GC.

Function of intestinal barrier protected by regulating the miR-199a-3p in ulcerative colitis: Modulation of IL-23/IL-17A axis.

Ulcerative colitis is a chronic inflammatory bowel disorder, which is having higher mortality rate. The present report evaluates the protective effect of miR-199a-3p oligomer for the treatment of Ulcerative colitis (UC). Ulcerative colitis was induced by administration of dextran sulfate sodium [DSS (3%)] with drinking water for the duration of one week in mice and miR-199a-3p oligomer was treated for the same duration. Effect of miR-199a-3p oligomer was determined by estimating the body weight, blood stool and length of colon in UC mice. Inflammatory cytokines, oxidative stress parameters and Treg/Th17 ratio was determined in the serum, intestinal and spleen tissue of UC mice. mRNA expression of TGFß, Foxp3, RORγt and STAT3 was estimated in the intestinal tissue of UC mice. Moreover, permeability of intestine was determined by estimating the expression of FITC-dextran in the serum and expression of junction protein in the tissue of UC mice. The data of the study suggest that treatment with miR-199a-3p oligomer ameliorates the altered condition in ulcerative colitis mice. There was reduction in the level of cytokines and parameters of oxidative stress in the intestine of miR-199a-3p oligomer than UC group. Moreover, intestinal permeability was enhanced in miR-199a-3p oligomer treated UC mice. The level of Th17 in the serum and mRNA expression of TGFß, Foxp3, RORγt and STAT3 was attenuated in miR-199a-3p oligomer treated UC mice. In conclusion, the data of the study suggest that treatment with miR-199a-3p oligomer ameliorates intestinal barrier in ulcerative colitis by down regulating the IL-17A/IL-23 axis.

The impact of glutathione S-transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases.

Azathioprine (AZA) is a thiopurine prodrug which is widely used in patients with inflammatory bowel disease (IBD). However, the use is limited in one-third of patients because of adverse drug reactions (ADRs) or a lack of clinical response. It has been considered that the polymorphic enzyme thiopurine S-methyltransferase (TPMT) plays an important role in the in vivo process of AZA and the occurrence of its myelotoxicity. Glutathione S-transferase (GST) mutation is another pharmacogenetic polymorphism which is probably involved in AZA metabolism and tolerance. The aim of this study was to investigate the association among GST polymorphism, enzyme activity and AZA-related ADRs in Chinese Han patients with IBD. We found that the patients who became neutropenic had a significantly higher GSTs activity when compared with of the patients who did not develop ADRs (analysis of variance, P < 0.001). There was also a significant underrepresentation of GSTP1*-105V allele among patients developing ADRs (odds ratio [OR] = 0.125, 95% confidence interval [CI] = 0.022-0.709, P = 0.0012). The patients with higher GST activity constituted a pharmacogenetic high risk group for leucopenia during AZA treatment. GST-P1 Ile105/Ile105 genotype appeared to be a promising marker indicating predisposition to AZA-related ADRs.

The CTLA4 +49A/G polymorphism is associated with an increased risk of Hashimoto's thyroiditis in Asian but not Caucasian populations: an updated meta-analysis.

The polymorphism +49A/G in the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene has been implicated in susceptibility to Hashimoto's thyroiditis (HT), but the findings are not clear-cut. This study aimed to investigate the association between CTLA-4 polymorphisms and HT risk using an updated meta-analysis. A meta-analysis was carried out of 14 previous studies that investigated the CTLA-4 +49A/G polymorphism and HT risk. +49A/G was associated with a significantly increased HT risk in both allele analysis and all genetic models (allele analysis: G vs. A: P < 0.001, OR = 1.379, 95 % CI = 1.244-1.529). Subgroup analysis by ethnicity showed a significantly increased HT risk with the G allele and all other genetic models in the Asian subgroup (P < 0.001). In the Caucasian subgroup, no significant association was detected between the CTLA-4 +49 G allele and HT, or in the genetic model analysis (P = 0.05). This gene-based analysis indicates that the cumulative effect of the +49A/G polymorphism in CTLA-4 is associated with HT in Asians, but appears to have no effect on HT in Caucasians.

Comparison of Xilei-san, a Chinese herbal medicine, and dexamethasone in mild/moderate ulcerative proctitis: a double-blind randomized clinical trial.

BACKGROUND: Xilei-san is a traditional Chinese herbal medicine that has proven to be of possible use in the treatment of ulcerative proctitis (UP) in a pilot study. OBJECTIVES: This study was intended to compare Xilei-san with dexamethasone enemas in subjects with mild-to-moderate active UP. METHODS: A double-blind randomized study was performed in 35 subjects. During the initial 8 weeks, the subjects received an enema of Xilei-san or dexamethasone at bedtime, then discontinued the treatment and were followed for 12 weeks. All of the subjects received 3 g/day oral mesalazine during the entire study. The disease activity was assessed at inclusion and at weeks 4, 8, and 20. RESULTS: Both treatments showed significant improvement in clinical, endoscopic, and histological grades in comparison with the baseline. CONCLUSIONS: Xilei-san enemas are comparable to dexamethasone enemas in this study. This medicine is safe, well accepted, and may be an alternative drug in the treatment of mild-to-moderate active UP.

Polymorphisms in the vitamin D receptor gene and risk of autoimmune thyroid diseases: a meta-analysis.

Environmental and genetic factors are thought to be involved in the pathogenesis of autoimmune thyroid diseases (AITD), which include Graves' disease, Hashimoto's thyroiditis. Polymorphisms of vitamin D receptor (VDR) were implicated in AITDs risk. To date, many studies have evaluated the association between a functional polymorphism in the VDR gene and AITDs risk; however, the result is still ambiguous and inconclusive. To address the association of VDR gene FokI (rs10735810), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232) polymorphisms with AITD risk by meta-analysis. By searching the relevant literature, a total of eight studies were identified and meta-analyzed. HWE for each study are checked. Crude odds ratios (OR) with 95 % confidence intervals (CIs) were used to assess the strength of association in the allele polymorphism, codominant model, dominant model, and recessive model. The result indicates that the BsmI or TaqI polymorphisms is significantly associated with AITD risk (OR = 0.801 95 % CI 0.705, 0.910, Pz = 0.001 for B vs. b; OR = 0.854, 95 % CI 0.757, 0.963, Pz = 0.010 for t vs. T), while the ApaI or FokI polymorphism do not. In the subgroup analysis in Europeans, the decreased risk of AITD remained for the B or t variant. This gene-based analysis indicates that, based on current evidence from published studies, the cumulative effect of BsmI or TaqI polymorphisms in VDR is significantly associated with AITD.

The potential influence of 5-aminosalicylic acid on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients.

OBJECTIVE: To investigate the potential influence of 5-aminosalicylic acid (5-ASA) on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients. METHODS: (a) The retrospective study included inflammatory bowel disease patients treated with azathioprine (AZA)/6-mercaptopurine (6-MP). Thiopurine methyltransferase (TPMT) activity and 6-thioguanine nucleotide (6-TGN) levels were detected at stable medication points. (b) The prospective study was performed in active disease patients: 4 weeks of AZA 50 mg/day followed by concomitant 5-ASA 3 g/day for another 4 weeks. 6-TGN was analyzed at weeks 4 and 8. RESULTS: (a) Of the 139 retrospective study patients, 45 were on AZA/6-MP+5-ASA and 94 on AZA/6-MP alone. The myelotoxicity rates were 47 and 16%, respectively. Multivariates regression analysis indicated that the administration of concomitant 5-ASA was the only risk factor associated with myelotoxicity (odds ratio=3.45, 95% confidence interval 1.31-9.04, P=0.01). (b) Thiopurine methyltransferase activity was not significantly different between patients on AZA/6-MP+5-ASA and patients on AZA/6-MP alone (P=0.78). (c) 6-TGN levels were significantly higher in samples on AZA/6-MP+5-ASA than those on AZA/6-MP (P=0.003) alone. (d) Sixteen patients completed the prospective study. After 4 weeks on AZA 50 mg/day, 6-TGN levels of 13 patients were less than 230 pmol/8×10 RBC. After another 4 weeks' cotreatment with mesalazine 3 g/day, 12 patients had 6-TGN levels at least 230 pmol/8×10 RBC, five patients had 6-TGN levels at least 420 pmol/8×10 RBC, and two of these five patients developed myelotoxicity. CONCLUSION: The risk of thiopurine-induced myelotoxicity markedly increases in patients treated with combined 5-ASA and 2 mg/kg/day AZA therapy, which may be correlated to the increase in 6-TGN. 50 mg daily AZA when concomitant 5-ASA might help maintain an effective 6-TGN level without increasing the risk of myelotoxicity.

Hypoxanthine guanine phosphoribosyltransferase activity is related to 6-thioguanine nucleotide concentrations and thiopurine-induced leukopenia in the treatment of inflammatory bowel disease.

BACKGROUND: Thiopurine drugs are widely used in the treatment of inflammatory bowel disease (IBD). The polymorphic enzyme thiopurine S-methyltransferase (TPMT) is of importance for thiopurine metabolism and adverse events occurrence. The role of other thiopurine-metabolizing enzymes is less well known. This study investigated the effects of TPMT and hypoxanthine guanine phosphoribosyltransferase (HPRT) activities on 6-thioguanine nucleotides (6-TGNs) concentrations and thiopurine-induced leukopenia in patients with IBD. METHODS: Clinical data and blood samples were collected from 120 IBD patients who were receiving azathioprine (AZA)/6-mercaptopurine (6-MP) therapy. Erythrocyte TPMT, HPRT activities and 6-TGNs concentrations were determined. HPRT activity and its correlation with TPMT activity, 6-TGNs level, and leukopenia were evaluated. RESULTS: The HPRT activity of all patients ranged from 1.63-3.33 (2.31 ± 0.36) µmol/min per g Hb. HPRT activity was significantly higher in patients with leukopenia (27, 22.5%) than without (P < 0.001). A positive correlation between HPRT activity and 6-TGNs concentration was found in patients with leukopenia (r = 0.526, P = 0.005). Patients with HPRT activity > 2.70 µmol/min per g Hb could have an increased risk of developing leukopenia (odds ratio = 7.47, P < 0.001). No correlation was observed between TPMT activity and HPRT activity, 6-TGNs concentration, or leukopenia. CONCLUSIONS: High levels of HPRT activity could be a predictor of leukopenia and unsafe 6-TGN concentrations in patients undergoing AZA/6-MP therapy. This could partly explain the therapeutic response or toxicity that could not be adequately explained by the polymorphisms of TPMT.

[The risk factor for low bone mineral density in patients with inflammatory bowel disease].

OBJECTIVE: To evaluate the prevalence of low bone mineral density in patients with inflammatory bowel disease (IBD)and to identify its risk factors. METHODS: A cross-sectional survey was carried out in IBD patients. Anthropometric measures, biochemical markers of nutrition and bone mineral density measurement were completed for these patients as well as healthy control subjects. RESULTS: Seventy-seven Crohn's disease (CD) and 43 ulcerative colitis (UC) patients were enrolled, and 37 healthy volunteers were recruited as healthy controls (HC). The T value of CD patients, UC patients and HC was -1.72 +/- 1.20, -1.26 +/- 1.12 and -0.62 +/- 0.87 respectively and the T value of CD patients was significantly lower than that of HC (P = 0.000). The prevalence of osteoporosis in CD, UC and HC was 23.3%, 14.0% and 0 respectively. The prevalence of osteoporosis in CD was higher than that in HC (P = 0.003). Logistic regression analysis indicated that low BMI (BMI < or = 18.4 kg/m(2)) was an independent risk factor for osteoporosis both in CD (OR = 11.25, 95%CI 3.198 - 39.580, P = 0.000) and in UC (OR = 14.50, 95%CI 1.058 - 88.200, P = 0.045) patients. Age, disease duration, clinical activity active index (CDAI), oral steroid therapy, immunosuppressant treatment and serum vitamin D concentration were not found to be correlated with osteoporosis in IBD patients. CONCLUSIONS: Low bone mineral density is common in both CD and UC patients and low BMI is an independent risk factor for osteoporosis in IBD patients.