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Fusobacterium nucleatum (Fn) is reportedly involved in poor prognosis of oesophageal squamous cell carcinoma (ESCC), but the responsible mechanisms remain unclear. The present study aimed to explore the function of Fn in ESCC progression, and to identify the key genes or signals involved. Fluorescence in situ hybridization and quantitative PCR assays were applied to measure the abundance of Fn in ESCC tissues, finding that ESCC tissues displayed a higher abundance of Fn compared to adjacent tissues. Furthermore, Fn abundance in advanced ESCC tissues was found to be higher than that in early stage ESCC. The proliferation assays and wound healing assays indicated that Fn infection promoted ESCC cell proliferation and migration. Based on high-throughput sequencing, cytochrome P450 1A1 (CYP1A1) was the most significantly upregulated (eightfold increase) gene, and AKT signalling was activated in KYSE-450 cells treated with Fn. Knocking down CYP1A1 or inactivating AKT signalling with LY294002 downregulated p-AKT

Objective: Acute acalculous cholecystitis (AAC) is characterized by acute onset, rapid progression, high mortality, and various complications. Cyclophilin D (CypD) regulates the mitochondrial permeability transition pore (MPTP) and is involved in the occurrence of ischemia-reperfusion injury and inflammation, however, the role of CypD in AAC remains unclear. Methods: Guinea pigs of 300–350 g were randomly divided into three groups, namely the sham group, the common bile duct ligation-24h group (CBDL-24h group), and CBDL-48h group. Western blot and qRT-PCR were applied to analyze the differential expression of CypD in each group, and transmission electron microscopy was employed to detect changes in mitochondrial structure. Inhibiting the activity of CypD by Cyclosporine A (CsA), we evaluated the difference of mitochondrial utilizing mitochondrial swelling, reactive oxygen species (ROS) detection and mitochondrial membrane potential. Results: Compared with sham group, the prolongation of obstruction aggravated gallbladder inflammation and upregulated CypD expression in the CBDL-24h and CBDL-48h groups. The degree of mitochondrial swelling was increased, and the opening of MPTP was prolonged in the CBDL-24h and 48h groups. Decreasing the expression of CypD could repress the opening of MPTP, prevent manipulation of the mitochondrial membrane potential, and ultimately diminish the levels of intracellular ROS and apoptosis. Conclusion: CypD plays a proinflammatory role in the development of AAC by regulating the opening of MPTP. Inhibiting the activity of CypD could reduce the levels of ROS and apoptosis, rescue the function of mitochondria and finally alleviated AAC. Therefore, CypD might serve as a potential therapeutic target for ACC.

Hydrogen sulfide (HA rat model of IBS was established using chronic water avoidance stress (WAS). Colonic pathological alterations were detected histologically. Intestinal motility was determined by intestinal transit time (ITT) and fecal water content (FWC). Visceral sensitivity was assessed using the visceromotor response (VMR) to colorectal distension (CRD). Real-time PCR, Western blotting, and immunostaining were performed to identify the expression of CBS in the colon. The contractions of distal colon were studied in an organ bath system and HAfter 10 days of WAS, the ITT was decreased and FWC was increased, and the VMR magnitude in response to CRD was enhanced. The colonic CBS expression and HDecreased CBS/H

To evaluate the clinical efficacy and safety of apatinib combined with intensity-modulated radiation therapy (IMRT) in patients with unresectable hepatocellular carcinoma (uHCC).Open-label, single-arm, exploratory clinical trial of apatinib combined with IMRT for uHCC patients. Patients aged 18-75 years with adequate hematological, liver, and renal functions and Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were enrolled in this study from March 2017 to September 2020. Patients were received IMRT (biological effective dose: 46-60 Gy) and continuous apatinib (250-500 mg/day) oral administration until HCC progression or unacceptable toxic effects. The endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), objective response rate (ORR), and safety. The trial registration number is ChiCTR-OPC-17011890.A total of 33 patients have taken part in the study. The median age was 58 years old (range 32-77), 27 (81.9%) patients were ECOG PS 0-1, and 28 (84.9%) patients were male. In addition, 25 (75.7%) patients suffered from hepatitis B, 32 cases (97.0%) were in Barcelona Clinic Liver Cancer (BCLC) Stages B-C, and eight (24.2%) had portal vein involvement. Moreover, 12 (36.4%) and 21 (63.6%) patients received apatinib as first-line and second or later-line therapy, respectively. The average follow-up was 11.4 months, the median PFS was 7.8 months (95% confidence interval: 3.9-11.7). The OS rates at 6 and 12 months were 96.7% and 66.2%. The ORR and DCR were 15.1% and 81.8%, respectively. Hepatic toxicity was the most common treatment-related adverse events in Grades 3-4 (12.1%). No radiation-induced liver disease and Grade 5 toxicity were recorded.Apatinib combined with IMRT is a safe and effective method to improve PFS and DCR and has good anti-tumor activity in patients with uHCC.

BackgroundThrombospondin-2 (THBS2) is a versatile glycoprotein that regulates numerous biological functions, including the apoptosis-proliferation balance in endothelial cells, and it has been linked to tumor angiogenesis. However, the role of THBS2 in human cancer remains unknown. This study aimed to determine THBS2 expression in pan-cancer, understand whether THBS2 is associated with its prognosis, and to identify possible roles of THBS2 in tumor immunity and the extracellular matrix (ECM).MethodsData about THBS2 expression in cancers and normal tissues were downloaded from the Genotype-Tissue Expression (GTEx) and UCSC Xena and analyzed using the ONCOMINE database, Perl programming language, and the Gene Expression Profiling and Interactive Analyses vision 2 (GEPIA2) web server. Survival prognosis was analyzed using the survival, survminer, and forestplot packages in R v. 4.0.3 and the limma package in R . Immune and matrix components were also analyzed using R v. 4.0.3. Most importantly, we partially validated the role and mechanism of THBS2 in pancreatic and gastric cancers in vitro using PANC1 and BGC-823 cell lines.ResultsThrombospondin-2 was significantly overexpressed in 17 of the 33 investigated cancers, and linked to a poor prognosis in pan-cancer survival analysis, especially in adrenocortical (ACC), kidney renal papillary cell (KIRP), and stomach (STAD) carcinomas, kidney chromophobe (KICH), and pancreatic adenocarcinoma (PAAD). Immune infiltration and THBS2 expression were also related. The expression of THBS2 has been linked to immune scores, stromal scores, and immune checkpoint markers in various cancers. The PPI network revealed that THBS2 is associated with multiple extracellular matrix proteins and immune proteins. Knockdown of THBS2 decreased the expression of CD47 and MMP-2 as well as the proliferation, migration, and invasion of PANC1 and BGC-823 cells in vitro. ConclusionsOur findings suggested that THBS2 could be a prognostic biomarker that acts as a bridge between the ECM and immune infiltration in various types of cancers, and that it promoted the progression of numerous types of cancers, especially PAAD and STAD.

A novel type of interstitial tissue cells in the biliary tree termed telocytes (TCs), formerly known as interstitial Cajal‐like cells (ICLCs), exhibits very particular features which unequivocally distinguish these cells from interstitial cells of Cajal (ICCs) and other interstitial cell types. Current research substantiates the existence of TCs and ICCs in the biliary system (gallbladder, extrahepatic bile duct, cystic duct, common bile duct and sphincter of Oddi). Here, we review the distribution, morphology and ultrastructure of TCs and ICCs in the biliary tree, with emphasis on their presumptive roles in physiological and pathophysiological processes.

A medical school in China engaged in reform in 2009 by adapting the medical curriculum of the University of Chicago, USA. Freshmen volunteered for the reform and 50 were randomly selected while the rest remained in the traditional curriculum. In 2014 a study was conducted to determine whether the views of traditional and reform curriculum students on their respective educational experience differed and to identify reform areas that needed improvement. A survey was administered to graduating students to gauge their views on basic science and clinical science education, clerkships, general medical education, and readiness for residency training. Frequency distributions, Mann-Whitney U tests, and Chi-squared tests were used for analysis. Reform curriculum students were more positive about their basic science and clinical science instruction. Clerkships were only somewhat satisfactory to students in both curricula. Reform curriculum students were more likely than those following the traditional curriculum to consider instruction in clinical decision-making and patient care as ‘adequate’. Instruction in population health was considered inadequate by the majority of students. Reform curriculum students were more confident about their preparedness for residency. The traditional curriculum was in need of reform. Reform has been effectively implemented and has increased student confidence and satisfaction with their education although there is room for improvement.

Background The mechanisms underlying chronic and persistent pain associated with chronic pancreatitis (CP) are not completely understood. The cholinergic system is one of the major neural pathways of the pancreas. Meanwhile, this system plays an important role in chronic pain. We hypothesized that the high affinity choline transporter CHT1, which is a main determinant of cholinergic signaling capacity, is involved in regulating pain associated with CP. Methods CP was induced by intraductal injection of 2% trinitrobenzene sulfonic acid (TNBS) in Sprague-Dawley rats. Pathological examination was used to evaluate the inflammation of pancreas and hyperalgesia was assessed by measuring the number of withdrawal events evoked by application of the von Frey filaments. CHT1 expression in pancreas-specific dorsal root ganglia (DRGs) was assessed through immunohistochemistry and western blotting. We also intraperitoneally injected the rats with hemicholinium-3 (HC-3, a specific inhibitor of CHT1). Then we observed its effects on the visceral hyperalgesia induced by CP, and on the acetylcholine (ACh) levels in the DRGs through using an acetylcholine/acetylcholinesterase assay kit. Results Signs of CP were observed 21 days after TNBS injection. Rats subjected to TNBS infusions had increased sensitivity to mechanical stimulation of the abdomen. CHT1-immunoreactive cells were increased in the DRGs from rats with CP compared to naive or sham rats. Western blots indicated that CHT1 expression was significantly up-regulated in TNBS-treated rats when compared to naive or sham-operated rats at all time points following surgery. In the TNBS group, CHT1 expression was higher on day 28 than on day 7 or day 14, but there was no statistical difference in CHT1 expression on day 28 vs. day 21. Treatment with HC-3 (60 μg/kg, 80 μg/kg, or 100 μg/kg) markedly enhanced the mechanical hyperalgesia and reduced ACh levels in a dose-dependent manner in rats with CP. Conclusion We report for the first time that CHT1 may be involved in pain modulation in CP, as it plays an important role in pain inhibition. Increased CHT1 activity or the up-regulation of its expression may be used to treat pain in patients with CP.

Background Irritable bowel syndrome (IBS) is a common disease with intestinal dysmotility, whose mechanism remains elusive. The endocannabinoid system is emerging as an important modulator of gastrointestinal (GI) motility in multiple diseases, but its involvement in IBS is unknown. We aimed to determine whether cannabinoid 2 (CB2) receptor modulates intestinal motility associated with stress-induced IBS. Methods A rat IBS model was established by chronic water avoidance stress (WAS). Colonic pathological alterations were detected histologically and intestinal motility was assessed by intestinal transit time (ITT) and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response (VMR) to colorectal distension (CRD). Real-time PCR, western blot, and immunostaining were performed to identify colonic CB2 receptor expression. Colonic muscle strip contractility was studied by isometric transducers and nitric oxide (NO) was detected by the Griess test. The effects of AM1241, a selective agonist of CB2 receptors, on colonic motility were examined. Key results After 10 days of WAS exposure, ITT was decreased and FWC elevated while VMR magnitude in response to CRD was significantly enhanced. Colon CB2 protein and mRNA levels increased and density of CB2-positive macrophages in the mucosa and enteric neurons in the myenteric plexus was higher than in controls. Pharmacological enhancement of CB2 activity by AM1241 relieved colonic hypermotility in WAS rats in a concentration-dependent manner via inhibition of p38 phosphorylation and elevation of NO production. Conclusion CB2 receptor may exert an important inhibitory effect in stress-induced colonic hypermotility by modulating NO synthesis through p38 mitogen-activated protein kinase signaling. AM1241 could be used as a potential drug to treat disorders with colonic hypermotility.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Paeoniflorin, a natural product and active ingredient of Paeonia lactiflora, has been demonstrated to have many pharmacological effects including antiinflammatory and antihyperglycemic activity. We investigated the effects of paeoniflorin on NAFLD in mice and its underlying mechanisms. We examined this hypothesis using a well-established animal model of NAFLD. The effects of paeoniflorin on inflammation and glucolipid metabolism disorder were evaluated. The corresponding signaling pathways were measured using real-time polymerase chain reaction (PCR). We demonstrated that the mice developed obesity, dyslipidemia, and fatty liver, which formed the NAFLD model. Paeoniflorin attenuated NAFLD and exhibited potential cardiovascular protective effects in vivo by lowering body weight, hyperlipidemia, and insulin resistance; blocking inflammation; and inhibiting lipid ectopic deposition. Further investigation revealed that the antagonistic effect on hyperlipidemia and lipid ectopic deposition was related to lowering the lipid synthesis pathway (de novo pathway, 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoAR)), promoting fatty acid oxidation [peroxisome proliferator-activated receptor-alpha (PPARα), carnitine palmitoyltransferase-1, etc.] and increasing cholesterol output (PPARγ-liver X receptor-α-ATP-binding cassette transporter-1); the inhibitory effects on inflammation and hyperglycemia were mediated by blocking inflammatory genes activation and reducing gluconeogenic genes expression (phosphoenolpyruvate carboxykinase and G6Pase). These results suggest that paeoniflorin prevents the development of NAFLD and reduces the risks of atherosclerosis through multiple intracellular signaling pathways. It may therefore be a potential therapeutic compound for NAFLD.

To cultivate students' ability to use the pharmacology principles in medical practice, case-oriented self-learning and review has partly replaced lecture-based teaching in our pharmacology course. The aim of this study is to investigate the effects of an innovative teaching model in pharmacology teaching on the performance of medical undergraduates.A total of 185 third-year medical students participated in the study in 2011 and 2012. The students were randomized into the study group (case-oriented self-learning and review) and control group (traditional lecture-based teaching). Examination performances between the students in the 2 groups were compared, and questionnaires were designed for both the students participating in the study group and the teachers to assess the new teaching method.Mid-term examination performances in 2011 and 2012 were significantly better for the students in the study group than those in the control group (P0.01). On the final examination in 2011, significantly more students received an assessment of "excellent" in the study group than in the control group (P0.05). Moreover, students in the study group performed better than those in the control group on the final examination in 2012. The data from the questionnaires indicated that both teachers and students in the study group generally held positive attitudes toward the innovative teaching model.Case-oriented self-learning and review can improve students' internalization of basic pharmacological principles and provide a greater opportunity for self-study and collaborative study. The examination composition can affect the efficacy of the assessment of problem solving abilities.