Phase 1b study of first-line fuzuloparib combined with modified FOLFIRINOX followed by fuzuloparib maintenance monotherapy in pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. METHODS: This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8-12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). RESULTS: As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0-74.0) and disease control rate of 94.4% (95% CI, 72.7-99.9). CONCLUSIONS: First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04228601.

Final analysis of camrelizumab plus chemotherapy for untreated advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st trial.

BACKGROUND: The interim analysis of the randomized phase 3 ESCORT-1st study demonstrated significantly longer overall survival (OS) and progression-free survival (PFS) for camrelizumab-chemotherapy than placebo-chemotherapy in untreated advanced/metastatic esophageal squamous cell carcinoma (ESCC). Here, we present the final analysis of this study and investigate potential indicators associated with OS. METHODS: Patients were randomized 1:1 to receive camrelizumab (200 mg) or placebo, both in combination with up to six cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were administered intravenously every 3 weeks. The co-primary endpoints were OS and PFS assessed by the independent review committee. FINDINGS: As of April 30, 2022, the median OS was significantly longer in the camrelizumab-chemotherapy group compared to the placebo-chemotherapy group (15.6 [95% confidence interval (CI): 14.0-18.4] vs. 12.6 months [95% CI 11.2-13.8]; hazard ratio [HR]: 0.70 [95% CI 0.58-0.84]; one-sided p < 0.0001), with 3-year OS rates of 25.6% and 12.8% in the two groups, respectively. The 2-year PFS rates were 20.4% in the camrelizumab-chemotherapy group and 3.4% in the placebo-chemotherapy group. Adverse events were consistent with those reported in the interim analysis. Higher PD-L1 expression correlated with extended OS, and multivariate analysis identified sex and prior history of radiotherapy as independent indicators of OS. CONCLUSIONS: The sustained and significant improvement in efficacy with camrelizumab-chemotherapy compared to placebo-chemotherapy, along with the absence of accumulating or delayed toxicities, supports the long-term use of camrelizumab-chemotherapy as a standard therapy in untreated advanced/metastatic ESCC. FUNDING: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Association between circHIPK3/miR-378a-3p/HDAC4 axis and osteoporotic fractures: A comprehensive investigation.

BACKGROUND: Osteoporotic fractures (OFs) are a significant public health issue, which can lead to pain and impaired mobility. The underlying mechanisms of OFs remain unclear, but recent studies have suggested that the circRNA-miRNA-mRNA pathway may play a crucial role. PURPOSE: This study aimed to investigate the potential involvement of the circHIPK3/miR-378a-3p/HDAC4 pathway in the pathogenesis of OFs. METHODS: We collected tissue and serum samples from 10 patients with OFs and 10 healthy controls. The expression levels of circHIPK3, miR-378a-3p, and HDAC4 were measured by qPCR and WB. Additionally, we quantified the serum levels of bone metabolism-related indicators (ALP, OC, TRAP, OCIF, ODF) using ELISA. RESULTS: Our results revealed significant upregulation of circHIPK3 and HDAC4 in both tissue and serum samples from OF patients compared with controls. Simultaneously, we detected a lower expression level of miR-378a-3p in OF tissues and serum than that in the control group. Furthermore, the serum levels of bone metabolism-related indicators ALP, TRAP, OCIF, and ODF were significantly higher in OF patients than in the control group. Interestingly, the serum level of OCIF was lower in OF patients than in the control group. CONCLUSION: Our study provides important evidence for the involvement of the circHIPK3/miR-378a-3p/HDAC4 pathway in the pathogenesis of OFs. The upregulation of circHIPK3 and HDAC4 and downregulation of miR-378a-3p observed in OF patients suggests their potential regulatory effects on bone metabolism. Meanwhile, abnormal expression of serum bone metabolism-related indicators may contribute to the development of OFs by disrupting the balance of bone remodeling.

CLDN18.2 and 4-1BB bispecific antibody givastomig exerts antitumor activity through CLDN18.2-expressing tumor-directed T-cell activation.

BACKGROUND: Claudin18.2 (CLDN18.2) is a tight junction protein that has been identified as a clinically proven target in gastric cancer. Stimulation of 4-1BB with agonistic antibodies is also a promising strategy for immunotherapy and 4-1BB+ T cells were reported to be present within the tumor microenvironment of patients with gastric cancer. However, hepatotoxicity-mediated by 4-1BB activation was observed in clinical trials of agonistic anti-4-1BB monoclonal antibodies. METHODS: To specifically activate the 4-1BB+ T cells in tumor and avoid the on-target liver toxicity, we developed a novel CLDN18.2×4-1BB bispecific antibody (termed 'givastomig' or 'ABL111'; also known as TJ-CD4B or TJ033721) that was designed to activate 4-1BB signaling in a CLDN18.2 engagement-dependent manner. RESULTS: 4-1BB+ T cells were observed to be coexisted with CLDN18.2+ tumor cells in proximity by multiplex immunohistochemical staining of tumor tissues from patients with gastric cancer (n=60). Givastomig/ABL111 could bind to cell lines expressing various levels of CLDN18.2 with a high affinity and induce 4-1BB activation in vitro only in the context of CLDN18.2 binding. The magnitude of T-cell activation by givastomig/ABL111 treatment was closely correlated with the CLDN18.2 expression level of tumor cells from gastric cancer patient-derived xenograft model. Mechanistically, givastomig/ABL111 treatment could upregulate the expression of a panel of pro-inflammatory and interferon-γ-responsive genes in human peripheral blood mononuclear cells when co-cultured with CLDN18.2+ tumor cells. Furthermore, in humanized 4-1BB transgenic mice inoculated with human CLDN18.2-expressing tumor cells, givastomig/ABL111 induced a localized immune activation in tumor as evident by the increased ratio of CD8+/regulatory T cell, leading to the superior antitumor activity and long-lasting memory response against tumor rechallenge. Givastomig/ABL111 was well tolerated, with no systemic immune response and hepatotoxicity in monkeys. CONCLUSIONS: Givastomig/ABL111 is a novel CLDN18.2×4-1BB bispecific antibody which has the potential to treat patients with gastric cancer with a wide range of CLDN18.2 expression level through the restricted activation of 4-1BB+ T cells in tumor microenvironment to avoid the risk of liver toxicity and systemic immune response.

Repeat peroral endoscopic myotomy with simultaneous submucosal and muscle dissection as a salvage option for recurrent achalasia.

BACKGROUND: For recurrent achalasia after initial peroral endoscopic myotomy (POEM) failure, repeat POEM (Re-POEM) has been reported as a treatment option. However, severe esophageal interlayer adhesions caused by previous procedures impede the successful establishment of a submucosal tunnel and lead to aborted Re-POEM procedures. Our team previously described POEM with simultaneous submucosal and muscle dissection (POEM-SSMD) as a feasible solution for achalasia with severe interlayer adhesions. AIM: To investigate the effectiveness and safety of Re-POEM with simultaneous submucosal and muscle dissection (Re-POEM-SSMD). METHODS: A total of 1049 patients with achalasia who underwent successful endoscopic myotomy at the Digestive Endoscopic Center of Chinese PLA General Hospital from December 2014 to May 2022 were reviewed. Patients with recurrent achalasia who experienced initial POEM clinical failure were retrospectively included in this study. The primary endpoint was retreatment clinical success, defined as an Eckardt score ≤ 3 during the postretreatment follow-up and no need for additional treatment. Procedure-related adverse events, changes in manometric lower esophageal sphincter (LES) pressure and reflux complications, as well as procedure-related parameters, were recorded. RESULTS: Sixteen patients underwent Re-POEM (9 patients) or Re-POEM-SSMD (7 patients) successfully at a median of 45.5 mo (range, 4-95 mo) after initial POEM. During a median follow-up period of 31 mo (range, 7-96 mo), clinical success (Eckardt score ≤ 3) was achieved in 8 (88.9%) and 6 (85.7%) patients after Re-POEM and Re-POEM-SSMD, respectively (P = 0.849). The median Eckardt score dropped from 4 (range, 3-8) at preretreatment to 1 (range, 0-5) at postretreatment in the Re-POEM group (P = 0.025) and from 5 (range, 2-8) to 2 (range, 0-4) in the Re-POEM-SSMD group (P < 0.001). The mean manometric LES pressure decreased from 23.78 ± 9.04 mmHg to 11.45 ± 5.37 mmHg after Re-POEM (P < 0.001) and from 26.80 ± 7.48 mmHg to 11.05 ± 4.38 mmHg after Re-POEM-SSMD (P < 0.001). No serious adverse events were recorded in both groups. CONCLUSION: In conclusion, Re-POEM-SSMD appears to be a safe and effective salvage therapy for recurrent achalasia with severe interlayer adhesions.

Linked color imaging vs Lugol chromoendoscopy for esophageal squamous cell cancer and precancerous lesion screening: A noninferiority study.

BACKGROUND: Lugol chromoendoscopy (LCE) has served as a standard screening technique in high-risk patients with esophageal cancer. Nevertheless, LCE is not suitable for general population screening given its side effects. Linked color imaging (LCI) is a novel image-enhanced endoscopic technique that can distinguish subtle diff-erences in mucosal color. AIM: To compare the diagnostic performance of LCI with LCE in detecting esophageal squamous cell cancer and precancerous lesions and to evaluate whether LCE can be replaced by LCI in detecting esophageal neoplastic lesions. METHODS: In this prospective study, we enrolled 543 patients who underwent white light imaging (WLI), LCI and LCE successively. We compared the sensitivity and specificity of LCI and LCE in the detection of esophageal neoplastic lesions. Clinicopathological features and color analysis of lesions were assessed. RESULTS: In total, 43 patients (45 neoplastic lesions) were analyzed. Among them, 36 patients (38 neoplastic lesions) were diagnosed with LCI, and 39 patients (41 neoplastic lesions) were diagnosed with LCE. The sensitivity of LCI was similar to that of LCE (83.7% vs 90.7%, P = 0.520), whereas the specificity of LCI was greater than that of LCE (92.4% vs 87.0%, P = 0.007). The LCI procedure time in the esophageal examination was significantly shorter than that of LCE [42 (34, 50) s vs 160 (130, 189) s, P < 0.001]. The color difference between the lesion and surrounding mucosa in LCI was significantly greater than that observed with WLI. However, the color difference in LCI was similar in different pathological types of esophageal squamous cell cancer. CONCLUSION: LCI offers greater specificity than LCE in the detection of esophageal squamous cell cancer and precancerous lesions, and LCI represents a promising screening strategy for general populations.

Prospective single-center feasible study of innovative autorelease bile duct supporter to delay adverse events after endoscopic papillectomy.

BACKGROUND: Conventional endoscopic papillectomy (EP) is safe and effective for the treatment of small papilla adenoma to even large laterally spreading tumors of duodenum lesions. As reported by some existing studies, temporarily placing a prophylactic stent in the pancreatic and bile duct can lower the risk of this perioperative complication. AIM: To evaluate the usefulness, convenience, safety, and short-term results of a novel autorelease bile duct supporter after EP procedure, especially the effectiveness in preventing EP. METHODS: A single-center comparison study was conducted to verify the feasibility of the novel method. After EP, a metallic endoclip and human fibrin sealant kit were applied for protection. The autorelease bile duct supporter fell into the duct segment and the intestinal segment. Specifically, the intestinal segment was extended by nearly 5 cm as a bent coil. The bile was isolated from the pancreatic juice using an autorelease bile duct supporter, which protected the wound surface. The autorelease bile duct supporter fell off naturally and arrived in colon nearly 10 d after the operation. RESULTS: En bloc endoscopic resection was performed in 6/8 patients (75%), and piecemeal resection was performed in 2/8 of patients (25%). None of the above patients were positive for neoplastic lymph nodes or distant metastasis. No cases of mortality, hemorrhage, delayed perforation, pancreatitis, cholangitis or duct stenosis with the conventional medical treatment were reported. The autorelease bile duct supporter in 7 of 8 patients fell off naturally and arrived in colon 10 d after the operation. One autorelease bile duct supporter was successfully removed using forceps or snare under endoscopy. No recurrence was identified during the 8-mo (ranging from 6-9 mo) follow-up period. CONCLUSION: In brief, it was found that the autorelease bile duct supporter could decrease the frequency of procedure-associated complications without second endoscopic retraction. Secure closure of the resection wound with clips and fibrin glue were indicated to be promising and important for the use of autorelease bile duct supporters. Well-designed larger-scale comparative studies are required to confirm the findings of this study.

Comparison between endoscopic submucosal tunnel dissection and endoscopic submucosal dissection for superficial neoplasia at esophagogastric junction: a case-matched controlled study of a single center from China.

BACKGROUND: So far, little evidence is available for the comprehensive comparison of endoscopic submucosal tunnel dissection (ESTD) with endoscopic submucosal dissection (ESD) for the treatment of superficial neoplasia at esophagogastric junction (EGJ). METHODS: EGJ superficial neoplasia patients with ESTD treatment between January, 2021 and August, 2020 were retrospectively reviewed and individually matched at 1:1 ratio with those with ESD treatment according to lesion size, specimen area and lesion location, forming ESTD and ESD group, respectively. A sample size of 17 patients was collected for each group. Treatment outcomes including resection time, specimen area, and resection speed as well as occurrence of complications were evaluated. RESULTS: Compared with ESD group, ESTD group got shorter resection time (111.00 ± 11.70 min for ESD group vs. 71.59 ± 6.18 min for ESTD group, p = 0.008) and faster section speed (0.23 ± 0.03 cm2/min for ESD group vs. 0.37 ± 0.06 cm2/min for ESTD group, p = 0.012). No complication was found to occur in ESTD group, while 1 patient with MP damage and 1 with delayed bleeding was found in ESD group. CONCLUSION: For the treatment of EGJ superficial neoplasia, ESTD is a safer and more effective and reliable endoscopic technique compared with ESD.

Effects of dapagliflozin in the progression of atherosclerosis in patients with type 2 diabetes: a meta-analysis of randomized controlled trials.

AIMS: At present, an increasing number of studies are trying to determine whether dapagliflozin has a significant effect on the occurrence and development of atherosclerosis in patients with type 2 diabetes mellitus (T2DM), but there is no consensus. In addition, the former meta-analyses, relying on only a few previous studies and a minimal number of research indicators, have not been able to draw sufficient conclusions simultaneously. Consequently, we conducted a meta-analysis to evaluate the effectiveness of dapagliflozin in the occurrence and development of atherosclerosis in patients with T2DM. METHODS: We searched electronic databases (PubMed, Embase, Cochrane, and Scopus) and reference lists in relevant papers for articles published in 2011-2021. We selected studies that evaluated the effects of dapagliflozin on the risk factors related to the occurrence or development of atherosclerosis in patients with T2DM. A fixed or random-effect model calculated the weighted average difference of dapagliflozin on efficacy, and the factors affecting heterogeneity were determined by Meta-regression analysis. RESULTS: Twelve randomized controlled trials (18,758 patients) were incorporated in our meta-analysis. In contrast with placebo, dapagliflozin was associated with a significantly increase in high density lipoprotein-cholesterol (HDL-C) [MD = 1.39; 95% CI (0.77, 2.01); P < 0.0001], Δflow-mediated vasodilatation (ΔFMD) [MD = 1.22; 95% CI (0.38, 2.06); P = 0.005] and estimated Glomerular Filtration Rate(eGFR) [MD = 1.94; 95% CI (1.38, 2.51); P < 0.00001]. Furthermore, dapagliflozin had a tremendous advantage in controlling triglycerides (TG) in subgroups whose baseline eGFR < 83 ml/min/1.73m2 [MD = - 10.38; 95% CI (- 13.15, - 7.60); P < 0.00001], systolic blood pressure (SBP) [MD = - 2.82; 95% CI (- 3.22, - 2.42); P < 0.00001], HbA1c, BMI, body weight and waist circumference. However, dapagliflozin has an adverse effect on increasing total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C). Besides, there were no significant changes in other indicators, including adiponectin and C-peptide immunoreactivity. CONCLUSIONS: Our pooled analysis suggested that dapagliflozin has a terrifically better influence over HDL-C, ΔFMD, and eGFR, and it concurrently had a tremendous advantage in controlling TG, SBP, DBP, HbA1c, BMI, body weight, and waist circumference, but it also harms increasing TC and LDL-C. Furthermore, this study found that the effect of dapagliflozin that decreases plasma levels of TG is only apparent in subgroups of baseline eGFR < 83 ml/min/1.73m2, while the subgroup of baseline eGFR ≥ 83 ml/min/1.73m2 does not. Finally, the above results summarize that dapagliflozin could be a therapeutic option for the progression of atherosclerosis in patients with T2DM. Systematic review registration PROSPERO CRD42021278939.

Probing Synergistic Targets by Natural Compounds for Hepatocellular Carcinoma.

BACKGROUND: Designing combination drugs for malignant cancers has been restricted due to the scarcity of synergy-medicated targets, while some natural compounds have demonstrated potential to enhance anticancer effects. METHODS: We here explored the feasibility of probing synergy-mediated targets by Berberine (BER) and Evodiamine (EVO) in hepatocellular carcinoma (HCC). Using the genomics-derived HCC signaling networks of compound treatment, NF-κB and c-JUN were inferred as key responding elements with transcriptional activity coinhibited during the synergistic cytotoxicity induction in BEL-7402 cells. Then, selective coinhibitors of NF-κB and c-JUN were tested demonstrating similar synergistic antiproliferation activity. RESULTS: Consistent with in vivo experiments of zebrafish, coinhibitors were found to significantly reduce tumor growth by 79% and metastasis by 96% compared to blank control, accompanied by anti-angiogenic activity. In an analysis of 365 HCC individuals, the low expression group showed significantly lower malignancies and better prognosis, with the median survival time increased from 67 to 213%, compared to the rest of the groups. CONCLUSION: Together, NF-κB and c-JUN were identified as promising synergistic inducers in developing anti-HCC therapies. Also, our method may provide a feasible strategy to explore new targeting space from natural compounds, opening opportunities for the rational design of combinational formulations in combatting malignant cancers.

Blinatumomab-induced T cell activation at single cell transcriptome resolution.

BACKGROUND: Bi-specific T-cell engager (BiTE) antibody is a class of bispecific antibodies designed for cancer immunotherapy. Blinatumomab is the first approved BiTE to treat acute B cell lymphoblastic leukemia (B-ALL). It brings killer T and target B cells into close proximity, activating patient's autologous T cells to kill malignant B cells via mechanisms such as cytolytic immune synapse formation and inflammatory cytokine production. However, the activated T-cell subtypes and the target cell-dependent T cell responses induced by blinatumomab, as well as the mechanisms of resistance to blinatumomab therapy are largely unknown. RESULTS: In this study, we performed single-cell sequencing analysis to identify transcriptional changes in T cells following blinatumomab-induced T cell activation using single cells from both, a human cell line model and a patient-derived model of blinatumomab-mediated cytotoxicity. In total, the transcriptome of 17,920 single T cells from the cell line model and 2271 single T cells from patient samples were analyzed. We found that CD8+ effector memory T cells, CD4+ central memory T cells, naïve T cells, and regulatory T cells were activated after blinatumomab treatment. Here, blinatumomab-induced transcriptional changes reflected the functional immune activity of the blinatumomab-activated T cells, including the upregulation of pathways such as the immune system, glycolysis, IFNA signaling, gap junctions, and IFNG signaling. Co-stimulatory (TNFRSF4 and TNFRSF18) and co-inhibitory (LAG3) receptors were similarly upregulated in blinatumomab-activated T cells, indicating ligand-dependent T cell functions. Particularly, B-ALL cell expression of TNFSF4, which encodes the ligand of T cell co-stimulatory receptor TNFRSF4, was found positively correlated with the response to blinatumomab treatment. Furthermore, recombinant human TNFSF4 protein enhanced the cytotoxic activity of blinatumomab against B-ALL cells. CONCLUSION: These results reveal a target cell-dependent mechanism of T-cell activation by blinatumomab and suggest that TNFSF4 may be responsible for the resistant mechanism and a potential target for combination therapy with blinatumomab, to treat B-ALL or other B-cell malignancies.

Diagnosis of coronary artery spasm by ergonovine provocation test of radial artery.

We investigated the sensitivity, specificity and safety of ergonovine provocation test of radial artery in the diagnosis of coronary artery spasm (CAS). The patients who came to our hospital for chest pain from January to June 2020 as well as had coronary stenosis < 50% and no radial artery stenosis, were enrolled in this study. These patients were divided into CAS group and control group after intracoronary ergonovine provocation test. All patients underwent ergonovine provocation test of radial artery, the inner diameter (D0 and D1) and the peak systolic velocities (PSV0 and PSV1) of the radial artery were measured by ultrasound before and after ergonovine provocation. The predictive value of ergonovine provocation test of radial artery for the diagnosis of CAS was analyzed using receiver operator characteristic (ROC) curve. There were 19 patients in the CAS group and 28 patients in the control group. Low density lipoprotein cholesterol and smoking rate were significantly higher in the CAS group than in the control group (all P < 0.05), but there were no significant differences in other items (P > 0.05) between the two groups. In the ergonovine provocation test of radial artery, degree of radial artery stenosis was significantly higher in the CAS group [41.50% (35.60%, 50.00%)] than in the control group [11.25% (5.15%, 23.00%)] (P = 0.000), but there were no siginificant differences in D0, PSV0 and PSV1 between the two groups (P > 0.05). The area under ROC curve of ergonovine (120 µg) provocation test of radial artery for the diagnosis of CAS was 0.912 with 95%CI: 0.792-0.975, P = 0.001, cut-off of 31%, specificity of 92.86% and sensitivity of 84.21%. The ergonovine (120 µg) provocation test of radial artery did not cause any adverse reactions. We concluded that the ergonovine provocation test of radial artery has high sensitivity, specificity and safety in the diagnosis of CAS.

Multiparameter magnetic resonance imaging of liver fibrosis in a bile duct ligation mouse model.

BACKGROUND: Bile duct ligation (BDL) in animals is a classical method for mimicking cholestatic fibrosis. Although different surgical techniques have been described in rats and rabbits, mouse models can be more cost-effective and reproducible for investigating cholestatic fibrosis. Magnetic resonance imaging (MRI) has made great advances for noninvasive assessment of liver fibrosis. More comprehensive liver fibrotic features of BDL on MRI are important. However, the utility of multiparameter MRI to detect liver fibrosis in a BDL mouse model has not been assessed. AIM: To evaluate the correlation between the pathological changes and multiparameter MRI characteristics of liver fibrosis in a BDL mouse model. METHODS: Twenty-eight healthy adult male balb/c mice were randomly divided into four groups: sham, week 2 BDL, week 4 BDL, and week 6 BDL. Multiparameter MRI sequences, included magnetic resonance cholangiopancreatography, T1-weighted, T2-weighted, T2 mapping, and pre- and post-enhanced T1 mapping, were performed after sham and BDL surgery. Peripheral blood and liver tissue were collected after MRI. For statistical analysis, Student's t-test and Pearson's correlation coefficient were used. RESULTS: Four mice died after BDL surgery; seven, six, five and six mice were included separately from the four groups. Signal intensities of liver parenchyma showed no difference on TI- and T2-weighted images. Bile duct volume, ΔT1 value, T2 value, and the rate of liver fibrosis increased steadily in week 2 BDL, week 4 BDL and week 6 BDL groups compared with those in the sham group (P < 0.01). Alanine aminotransferase and aspartate transaminase levels initially surged after surgery, followed by a gradual decline over time. Strong correlations were found between bile duct volume (r = 0.84), T2 value (r = 0.78), ΔT1 value (r = 0.62), and hepatic fibrosis rate (all P < 0.01) in the BDL groups. CONCLUSION: The BDL mouse model induces changes that can be observed on MRI. The MRI parameters correlate with the hepatic fibrosis rate and allow for detection of cholestatic fibrosis.

Endoscopic versus surgical resection in the management of gastric schwannomas.

BACKGROUND AND AIMS: Gastric schwannoma (GS) is not well clinically recognized and surgical resection (SR) remains the mainstay of treatment. Recently, endoscopic resection (ER) appears to be a safe and effective alternative. However, its comparative outcomes with SR is lacking. Our aim was to first compare clinical outcomes and costs between ER and SR in the management of GSs. METHODS: A total of 46 consecutive patients with GSs who underwent ER (n = 16) or SR (n = 30) in our large tertiary center between July 2007 and Oct 2018 were included. Clinicopathologic features, clinical outcomes, medical costs and follow-up were retrospectively reviewed and compared between two groups. RESULTS: Baseline characteristics are comparable except for a smaller tumor size in ER group (22.9 vs 41.0 mm, p = 0.002). Complete resection was achieved in 87.5% of patients with ER and 100% of patients with SR (p = 0.116). The ER group had a significant shorter operative time (91.6 vs 128.2 min), less blood loss (16.9 vs 62.7 mL) and lower operation cost (21,054.4 vs 30,843.4 RMB) than SR group (all p < 0.05). There was no significant difference in adverse events (12.5% vs 10%, p = 0.812) and length of postoperative hospital stay (8.3 vs 8.2 days, p = 0.945). During a long-term follow-up of mean 37.4 months (range 6-140 months), no residue, recurrence or metastasis was observed in both groups. CONCLUSIONS: Compared with SR, ER has the similar safety and efficacy in the management of GSs, but contributes to a shorter operation time and lower medical costs. ER may be considered as the first-line treatment, especially for patients with GSs smaller than 30 mm.

Hsa-miRNA-23a-3p promotes atherogenesis in a novel mouse model of atherosclerosis.

Of the known regulators of atherosclerosis, miRNAs have been demonstrated to play critical roles in lipoprotein homeostasis and plaque formation. Here, we generated a novel animal model of atherosclerosis by knocking in LDLRW483X in C57BL/6 mice, as the W483X mutation in LDLR is considered the most common newly identified pathogenic mutation in Chinese familial hypercholesterolemia (FH) individuals. Using the new in vivo mouse model combined with a well-established atherosclerotic in vitro human cell model, we identified a novel atherosclerosis-related miRNA, miR-23a-3p, by microarray analysis of mouse aortic tissue specimens and human aortic endothelial cells (HAECs). miR-23a-3p was consistently downregulated in both models, which was confirmed by qPCR. Bioinformatics analysis and further validation experiments revealed that the TNFα-induced protein 3 (TNFAIP3) gene was the key target of miR-23a-3p. The miR-23a-3p-related functional pathways were then analyzed in HAECs. Collectively, the present results suggest that miR-23a-3p regulates inflammatory and apoptotic pathways in atherogenesis by targeting TNFAIP3 through the NF-κB and p38/MAPK signaling pathways.

Endoscopic submucosal excavation and endoscopic full-thickness resection for gastric schwannoma: five-year experience from a large tertiary center in China.

BACKGROUND AND AIMS: Endoscopic resection (ER) is an effective and safe method for gastric submucosal tumors, mostly composed of gastrointestinal stromal tumors and leiomyomas. The role of ER in gastric schwannoma (GS) has rarely been described. Our aim was to evaluate the efficacy and safety of ER for GS. METHODS: This is a retrospective study in consecutive patients who underwent ER for GS from March 2013 to October 2018 at our center. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. RESULTS: A total of 16 consecutive patients (9 females, 56.3%) were included, with a mean age of 50.4 years (range 25-75 years). The mean tumor size was 22.9 ± 15.1 mm (range 10-55 mm). Thirteen tumors (81.3%) were located in the middle third of the stomach and 12 tumors (75%) grew with intraluminal pattern. Endoscopic submucosal excavation (ESE) was performed in 7 patients while endoscopic full-thickness resection (EFTR) was done in 9 patients. R0 resection was achieved in 14 patients (87.5%). The mean operative time was 91.6 ± 52.8 min (range 36-203 min) and the mean postoperative length of hospital stays was 8.3 ± 2.7 days (range 6-13 days). No adverse events were encountered except for fevers in 2 patients. No patients required surgical resection or intervention. During long-term follow-up of mean 21.8 months (range 6-62 months), no residue, recurrence, or metastasis was observed. CONCLUSIONS: ER is effective and safe for patients with GS with favorable long-term outcomes.

Effect of polyglycolic acid sheet plus esophageal stent placement in preventing esophageal stricture after endoscopic submucosal dissection in patients with early-stage esophageal cancer: A randomized, controlled trial.

AIM: To assess the effect of polyglycolic acid (PGA) plus stent placement compared with stent placement alone in the prevention of post-endoscopic submucosal dissection (ESD) esophageal stricture in early-stage esophageal cancer (EC) patients. METHODS: Seventy EC patients undergoing ESD were enrolled in this randomized, controlled study. Patients were allocated randomly at a 1:1 ratio into two groups as follows: (1) PGA plus stent group (PGA sheet-coated stent placement was performed); and (2) Stent group (only stent placement was performed). This study was registered on http://www.chictr.org.cn (No. chictr-inr-16008709). RESULTS: The occurrence rate of esophageal stricture in the PGA plus stent group was 20.5% (n = 7), which was lower than that in the stent group (46.9%, n = 15) (P = 0.024). The mean value of esophageal stricture time was 59.6 ± 16.1 d and 70.7 ± 28.6 d in the PGA plus stent group and stent group (P = 0.174), respectively. Times of balloon dilatation in the PGA plus stent group were less than those in the stent group [4 (2-5) vs 6 (1-14), P = 0.007]. The length (P = 0.080) and diameter (P = 0.061) of esophageal strictures were numerically decreased in the PGA plus stent group, whereas no difference in location (P = 0.232) between the two groups was found. Multivariate logistic analysis suggested that PGA plus stent placement (P = 0.026) was an independent predictive factor for a lower risk of esophageal stricture, while location in the middle third (P = 0.034) and circumferential range = 1/1 (P = 0.028) could independently predict a higher risk of esophageal stricture in EC patients after ESD. CONCLUSION: PGA plus stent placement is more effective in preventing post-ESD esophageal stricture compared with stent placement alone in EC patients with early-stage disease.

Insight into Aluminum Sulfate-Catalyzed Xylan Conversion into Furfural in a γ-Valerolactone/Water Biphasic Solvent under Microwave Conditions.

A simple and efficient biphasic system with an earth-abundant metal salt catalyst was used to produce furfural from xylan with a high yield of up to 87.8 % under microwave conditions. Strikingly, the metal salt Al2 (SO4 )3 exhibited excellent catalytic activity for xylan conversion, owing to a combination of Lewis and Brønsted acidity and its ability to promote good phase separation. The critical role of the SO42- anion was first analyzed, which resulted in the aforementioned characteristics when combined with the Al3+ cation. The mixed solvent system with γ-valerolactone (GVL) as the organic phase provided the highest furfural yield, resulting from its good dielectric properties and dissolving capacity, which facilitated the absorption of microwave energy and promoted mass transfer. Mechanistic studies suggested that the xylan-to-furfural conversion proceeded mainly through a hydrolysis-isomerization-dehydration pathway and the hexa-coordinated Lewis acidic [Al(OH)2 (aq)]+ species were the active sites for xylose-xylulose isomerization. Detailed kinetic studies of the subreaction for the xylan conversion revealed that GVL regulates the reaction rates and pathways by promoting the rates of the key steps involved for furfural production and suppressing the side reactions for humin production. Finally, the Al2 (SO4 )3 catalyst was used for the production of furfural from several lignocellulosic feedstocks, revealing its great potential for other biomass conversions.

Switch-on fluorescent strategy based on crystal violet-functionalized CdTe quantum dots for detecting L-cysteine and glutathione in water and urine.

The concentration of L-cysteine (Cys) and glutathione (GSH) is closely related to the critical risk of various diseases. In our study, a new rapid method for the determination of Cys and GSH in water and urine samples has been developed using a fluorescent probe technique, which was based on crystal violet (CV)-functionalized CdTe quantum dots (QDs). The original QDs emitted fluorescence light, which was turned off upon adding CV. This conjugation of CV and QDs could be attributed to electrostatic interaction between COO- of mercaptopropionic acid (MPA) on the surface of QDs and N+ of CV in aqueous solution. In addition, Förster resonance energy transfer (FRET) also occurred between CdTe QDs and CV. After adding Cys or GSH to the solution, Cys or GSH exhibited a stronger binding preference toward Cd2+ than Cd2+-MPA, which disturbed the interaction between MPA and QDs. Thus, most MPA was able to be separated from the surface of QDs because of the participation of Cys or GSH. Then, the fluorescence intensity of the CdTe QDs was enhanced. Good linear relationships were obtained in the range of 0.02-40 µg mL-1 and 0.02-50 µg mL-1, and the detection limits were calculated as 10.5 ng mL-1 and 8.2 ng mL-1, for Cys and GSH, respectively. In addition, the concentrations of biological thiols in water and urine samples were determined by the standard addition method using Cys as the standard; the quantitative recoveries were in the range of 97.3-105.8%, and relative standard deviations (RSDs) ranged from 2.5 to 3.7%. The method had several unique properties, such as simplicity, lower cost, high sensitivity, and environmental acceptability. Graphical abstract Crystal violet-functionalized CdTe quantum dots for detecting L-cysteine and glutathione with switch-on fluorescent strategy.

Systemic inoculation of Escherichia coli causes emergency myelopoiesis in zebrafish larval caudal hematopoietic tissue.

Emergency granulopoiesis occurs in response to severe microbial infection. However, whether and how other blood components, particularly monocytes/macrophages and their progenitors, including hematopoietic stem/progenitor cells (HSPCs), participate in the process and the underlying molecular mechanisms remain unknown. In this study, we challenged zebrafish larvae via direct injection of Escherichia coli into the bloodstream, which resulted in systemic inoculation with this microbe. The reaction of hematopoietic cells, including HSPCs, in the caudal hematopoietic tissue was carefully analysed. Both macrophages and neutrophils clearly expanded following the challenge. Thus, emergency myelopoiesis, including monopoiesis and granulopoiesis, occurred following systemic bacterial infection. The HSPC reaction was dependent on the bacterial burden, manifesting as a slight increase under low burden, but an obvious reduction following the administration of an excessive volume of bacteria. Pu.1 was important for the effective elimination of the microbes to prevent excessive HSPC apoptosis in response to stress. Moreover, Pu.1 played different roles in steady and emergency monopoiesis. Although Pu.1 was essential for normal macrophage development, it played suppressive roles in emergency monopoiesis. Overall, our study established a systemic bacterial infection model that led to emergency myelopoiesis, thereby improving our understanding of the function of Pu.1 in this scenario.