Fail to reach the bilioenteric anastomosis is the main cause of treatment failure during single-balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (SBE-assisted ERCP) in patients after bilioenteric Roux-en-Y anastomosis. We aim to evaluate factors influencing the endoscopic insertion failure. We retrospectively reviewed the clinical data of 231 cases undergoing SBE-assisted ERCP from January 2016 to December 2021. Treatment details and outcomes were studied to analyze the factors involved in endoscopic insertion failure. The enteroscopy success rate and procedural success rate were 88.3

BACKGROUND:Gallbladder cancer (GBC) is a leading cause of cancer-related death worldwide, and its prognosis remains poor, with 5-year survival of approximately 5%. In this study, we analyzed the involvement of a novel proteoglycan, Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), in the tumor progression and prognosis of human GBC. METHODS:SPOCK1 expression levels were measured in fresh samples and stored specimens of GBC and adjacent nontumor tissues. The effect of SPOCK1 on cell growth, DNA replication, migration and invasion were explored by Cell Counting Kit-8, colony formation, EdU retention assay, wound healing, and transwell migration assays, flow cytometric analysis, western blotting, and in vivo tumorigenesis and metastasis in nude mice. RESULTS:SPOCK1 mRNA and protein levels were increased in human GBC tissues compared with those in nontumor tissues. Immunohistochemical analysis indicated that SPOCK1 levels were increased in tumors that became metastatic, compared with those that did not, which was significantly associated with histological differentiation and patients with shorter overall survival periods. Knockdown of SPOCK1 expression by lentivirus-mediated shRNA transduction resulted in significant inhibition of GBC cell growth, colony formation, DNA replication, and invasion in vitro. The knockdown cells also formed smaller xenografted tumors than control GBC cells in nude mice. Overexpression of SPOCK1 had the opposite effects. In addition, SPOCK1 promoted cancer cell migration and epithelial-mesenchymal transition by regulating the expression of relevant genes. We found that activation of the PI3K/Akt pathway was involved in the oncogenic functions of SPOCK1 in GBC. CONCLUSIONS:SPOCK1 activates PI3K/Akt signaling to block apoptosis and promote proliferation and metastasis by GBC cells in vitro and in vivo. Levels of SPOCK1 increase with the progression of human GBC. SPOCK1 acts as an oncogene and may be a prognostic factor or therapeutic target for patients with GBC.

Gallbladder cancer (GBC), the most common malignancy of the bile duct, is highly aggressive and has an extremely poor prognosis, which is a result of early metastasis. As it is regulated being at multiple levels, the metastatic cascade in GBC is complex. Recent evidence suggests that microRNAs (miRNAs) are involved in cancer metastasis and are promising therapeutic targets. In this study, miR-101 was significantly downregulated in tumor tissues, particularly in metastatic tissues. In GBC patients, low miR-101 expression was correlated with tumor size, tumor invasion, lymph node metastasis, TNM stage, and poor survival. Moreover, miR-101 was an independent prognostic marker for GBC. Additionally, miR-101 inhibited GBC cell proliferation, migration, invasion, and TGF-β-induced epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the gene encoding the zinc finger protein X-linked (ZFX) was identified as a direct target of miR-101. More importantly, miR-101 significantly reduced activation of the MAPK/Erk and Smad signaling pathways, resulting in inhibition of TGF-β-mediated induction of EMT. Altogether, our findings demonstrate a novel mechanism by which miR-101 attenuates the EMT and metastasis in GBC cells and suggest that miR-101 can serve as a potential biomarker and therapeutic target for GBC management.

BackgroundCholedochojejunal/hepaticojejunal anastomotic stenosis (CJS/HJS) is significant clinical problem associated with decreased survival postsurgery. Endoscopic retrograde cholangiopancreatography (ERCP) using single-balloon enteroscopy (SBE) is the first-line management strategy for such conditions. However, studies on the risk factors and outcomes of endoscopic management strategies for CJS/HJS in biliary duct injury (BDI) are extremely limited.MethodsWe conducted a retrospective review of patients with symptomatic BDI who underwent choledochojejunal/hepaticojejunal Roux-en-Y anastomosis between April 2009 and April 2019. The primary endpoint was CJS/HJS recurrence. The secondary endpoint was early (i.e., emergent or unplanned) repeat SBE-ERCP (ER-SBE-ERCP). We also evaluated the details of initial therapy, complications, and treatment for CJS or HJS recurrence.ResultsFrom April 2009 to April 2019, 112 patients were treated, and 45 (40.2%) BDI patients developed CJS/HJS. Operation type (P < 0.001), salvage surgery timing (P = 0.005), hepatic artery injury (P = 0.001), bile leakage after surgery (P < 0.001) and recurrent cholangitis (P < 0.001) were significantly associated with anastomotic stenosis. The overall CJS/HJS recurrence rate was 27.9% (12/43). Of all the patients, 79.1% (34/43) underwent balloon dilation at the anastomotic stenosis site; stent placement was performed in 33 of 43 patients (76.8%). The complication rate was 7% (3/43).Initial balloon dilation (P = 0.024) was associated with the proportion of patients requiring ER-SBE-ERCP. Predictors of CJS/HJS recurrence on bivariate analysis included initial balloon dilation (P < 0.001) and ER-SBE-ERCP (P < 0.001). On multivariate analysis, ER-SBE-ERCP was significantly associated with CJS/HJS recurrence, likely reflecting the presence of more severe lesions or higher baseline risks for recurrence, rather than being a direct cause of recurrence.ConclusionsInitial balloon dilation is associated with a decreased risk of CJS/HJS recurrence. ER-SBE-ERCP is more commonly performed in patients with severe anastomotic lesions or higher baseline risks for recurrence, which may contribute to the higher observed recurrence rates of CJS/HJS in this group.

The journal retracts the article, titled “Schisandrin B induces apoptosis and cell cycle arrest of gallbladder cancer cells” [...]

IntroductionCurrently, there is no established guideline for the application of ERCP in children with choledochal cyst. This study aimed to investigate the safety and effectiveness of ERCP in managing preoperative complications of choledochal cyst in children, as well as the timing for definitive surgery following ERCP.MethodsWe conducted a retrospective review of medical records for 68 pediatric patients who presented with complications of choledochal cyst, including pancreatitis and biliary obstruction combined with cholangitis. All patients underwent ERCP treatment followed by definitive surgery. The primary outcomes assessed included treatment efficacy, post-ERCP complication, and the impact of ERCP on definitive surgical procedures.ResultsAmong the 68 patients studied, 41 presented with pancreatitis, while the remaining patients had biliary obstruction and cholangitis. Sixty-five patients successfully completed their treatments, with 64 experiencing alleviation of symptoms. Significant improvements were observed in serum amylase levels and liver function tests following ERCP. Post-ERCP complications occurred in three cases, including one case of pancreatitis and two cases of infection. The median interval between ERCP and surgery was 11 days. There was no significant difference in primary outcomes, such as surgical duration, rate of minimally invasive surgery, conversion to open surgery, intraoperative bleeding volume, intraoperative blood transfusion, postoperative complications, or average length of hospital stay, between the early surgery group (≤2 weeks) and the late surgery group (>2 weeks).ConclusionsERCP was proved to be a safe and effective intervention for alleviating preoperative complications in pediatric patients with choledochal cyst. Early definitive surgery following ERCP did not significantly impact the perioperative outcomes of pediatric patients.

Purpose Currently, there is no established guideline for the application of ERCP in children with choledochal cyst. This study aimed to investigate the safety and effectiveness of ERCP in nmanaging preoperative complications of choledochal cyst in children, as well as the timing for definitive surgery following ERCP. Methods We conducted a retrospective review of medical records for 68 pediatric patients who presented with complications of choledochal cyst, including pancreatitis and biliary obstruction combined with cholangitis. All patients underwent ERCP treatment followed by definitive surgery. The primary outcomes assessed included treatment efficacy, post-ERCP complication, and the impact of ERCP on definitive surgical procedures. Results Among the 68 patients studied, 41 presented with pancreatitis, while the remaining patients had biliary obstruction and cholangitis. Sixty-five patients successfully completed their treatments, with 64 experiencing alleviation of symptoms. Significant improvements were observed in serum amylase levels and liver function tests following ERCP. Post-ERCP complications occurred in three cases, including one case of pancreatitis and two cases of infection. The median interval between ERCP and surgery was 11 days. There was no significant difference in primary outcomes, such as surgical duration, rate of minimally invasive surgery, conversion to open surgery, intraoperative bleeding volume, intraoperative blood transfusion, postoperative complications, or average length of hospital stay, between the early surgery group (≤ 2 weeks) and the late surgery group (> 2 weeks). Conclusion ERCP was proved to be a safe and effective intervention for alleviating preoperative complications in pediatric patients with choledochal cyst. Early definitive surgery following ERCP did not significantly impact the perioperative outcomes of pediatric patients.

BACKGROUND:Although overnight fasting is recommended prior to endoscopic retrograde cholangiopancreatography (ERCP), the benefits and safety of high-carbohydrate fluid diet (CFD) intake 2 h before ERCP remain unclear. This study aimed to analyze whether high-CFD intake 2 h before ERCP can be safe and accelerate patients' recovery. METHODS:This prospective, multicenter, randomized controlled trial involved 15 tertiary ERCP centers. A total of 1330 patients were randomized into CFD group ( n = 665) and fasting group ( n = 665). The CFD group received 400 mL of maltodextrin orally 2 h before ERCP, while the control group abstained from food/water overnight (>6 h) before ERCP. All ERCP procedures were performed using deep sedation with intravenous propofol. The investigators were blinded but not the patients. The primary outcomes included postoperative fatigue and abdominal pain score, and the secondary outcomes included complications and changes in metabolic indicators. The outcomes were analyzed according to a modified intention-to-treat principle. RESULTS:The post-ERCP fatigue scores were significantly lower at 4 h (4.1 ± 2.6 vs. 4.8 ± 2.8, t = 4.23, P <0.001) and 20 h (2.4 ± 2.1 vs. 3.4 ± 2.4, t = 7.94, P <0.001) in the CFD group, with least-squares mean differences of 0.48 (95% confidence interval [CI]: 0.26-0.71, P <0.001) and 0.76 (95% CI: 0.57-0.95, P <0.001), respectively. The 4-h pain scores (2.1 ± 1.7 vs. 2.2 ± 1.7, t = 2.60, P = 0.009, with a least-squares mean difference of 0.21 [95% CI: 0.05-0.37]) and positive urine ketone levels (7.7% [39/509] vs. 15.4% [82/533], χ2 = 15.13, P <0.001) were lower in the CFD group. The CFD group had significantly less cholangitis (2.1% [13/634] vs. 4.0% [26/658], χ2 = 3.99, P = 0.046) but not pancreatitis (5.5% [35/634] vs. 6.5% [43/658], χ2 = 0.59, P = 0.444). Subgroup analysis revealed that CFD reduced the incidence of complications in patients with native papilla (odds ratio [OR]: 0.61, 95% CI: 0.39-0.95, P = 0.028) in the multivariable models. CONCLUSION:Ingesting 400 mL of CFD 2 h before ERCP is safe, with a reduction in post-ERCP fatigue, abdominal pain, and cholangitis during recovery. TRAIL REGISTRATION:ClinicalTrials.gov , No. NCT03075280.

Abstract Background Gastric cancer (GC), a molecularly heterogeneous disease, is the third leading cause of cancer death worldwide. The majority of GC cases worldwide occur in East Asia, predominantly China. Mutational Signature Framework offers an elegant approach to identify mutational processes present in tumors. Methods To identify mutational signature patterns, we conducted whole exome sequencing (WES) analysis in Chinese patients with GC. Mutect2 and MutsigCV were used to identify significantly mutated genes in 175 Chinese GC cases using paired tumor-normal tissues. We investigated mutational signatures using Catalogue of Somatic Mutations in Cancer (COSMIC) Version 2 (V2) and Version 3 (V3). Results We identified 104 mutated genes with P < 0.01. Seven genes (OR6B1, B2M, ELF3, RHOA, RPL22, TP53, ARIDIA) had q < 0.0001, including six previously associated with GC. Mutational signatures (COSMIC-V3) observed include 14 single base substitutions (SBS), one doublet base substitution (DBS) Signature A, and one InDel (ID2). The most frequent SBS signatures (SBS05, SBS01, SBS15, SBS20, SBS40) were also observed in 254 White GC cases from The Cancer Genome Atlas (TCGA) Project. However, SBS01 and SBS20 showed significant differences between Whites vs. All Asians (19.3% vs. 11.3% for SBS 1 (P = 0.012) and 11.4% vs. 5.9% for SBS20 (P = 0.025), respectively). Using COSMIC V2, signatures 6, 15, and 1 were the most frequent in Chinese GC cases. Further, most Chinese GC cases carried multiple signatures. Conclusions This effort represents the most detailed mutational signatures analysis of GC cases from China to date. Results hold promise for new insights in understanding risk and prognosis factors in GC.

To evaluate the long-term efficacy of single-balloon enteroscopy endoscopic retrograde cholangiography (SBE-ERC) for the treatment of biliary obstruction and to analyze the factors affecting the recurrence of benign bilioenteric anastomotic stricture after SBE-ERC treatment. The clinical data of patients with biliary diseases treated with SBE-ERC after choledochojejunostomy in our hospital from January 2015 to December 2021 were analyzed retrospectively for the success rates of diagnosis and treatment and the incidence of complications. Patients who were diagnosed with benign bilioenteric anastomotic stricture were followed up. The independent factors affecting recurrence were obtained by univariate and multivariate analyses using the Kaplan‒Meier method and Cox proportional hazard regression model. A total of 289 SBE-ERCs were performed in 165 patients. The overall success rate was 83.0 χ^2 =5.366, P = 0.021), a diameter of balloon dilatation during the last endoscopic treatment less than 0.8 cm ( χ^2 =4.552, P = 0.033), and the presence of a thread in the anastomosis ( χ^2 =8.921, P = 0.003) as risk factors for recurrence. A non-indwelling biliary plastic stent ( χ^2 =14.868, P < 0.001) and undergoing only one ERCP treatment ( χ^2 =13.313, P = 0.001) were risk factors for the recurrence of benign stricture after SBE-ERC resection. Multivariate analysis revealed that the absence of a stent (HR = 0.15, 95

BACKGROUND:Endoscopic retrograde cholangiopancreatography (ERCP) has found extensive use in pediatric patients; however, challenges persist in the application of therapeutic ERCP in infants.CASE PRESENTATION:This case report details the presentation of a 5.9-kilogram infant with obstructive jaundice and suspected hemolytic anemia who underwent ERCP to alleviate biliary obstruction. The infant was admitted due to clay-colored stools, jaundice, and liver injury. Ultrasound and magnetic resonance cholangiopancreatography (MRCP) revealed dilation of the common bile duct (CBD) accompanied by the presence of stones. ERCP was conducted using a JF-260V duodenoscope under general anesthesia. Successful stone extraction and biliary drainage were achieved.CONCLUSIONS:In centers with considerable expertise in ERCP and pediatric anesthesia, the use of a conventional adult duodenoscope for therapeutic ERCP in infants can be considered safe and feasible, provided careful and stringent patient selection criteria are applied. In the future, clear guidelines and standardized protocols for the indications and procedures of pediatric ERCP should be established.

Background:Pancreaticojejunal anastomotic stenosis (PJS) after pancreaticoduodenectomy (PD) is difficult to treat. Single-balloon enteroscope-assisted endoscopic retrograde pancreatography (SBE-assisted ERP) is a safe way to treat PJS with the strength of minimally invasion and repeatability, but since its technical difficulty and few patient number, data on long-term outcomes remain limited. The optimal treatment is still unknown. We aim to study the safety, effectiveness, and long-term outcome of single balloon enteroscopy-assisted (SBE-assisted) therapeutic ERP in patients with PJS in this study.Methods:The clinical information of patients undergoing SBE-assisted therapeutic ERP from March 2016 to March 2021 were retrospectively analyzed. All patients were diagnosed as PJS and without any contraindication for therapeutic endoscopy. Treatment details, postoperative complications, factors influencing technical success rate were evaluated. Long-term outcomes results were obtained by clinical or telephone follow-up.Results:Sixteen patients with median age of 51 years were included in this study, surgical reconstruction methods including PD with Whipple reconstruction, PD with Child reconstruction, pylorus-preserving pancreaticoduodenectomy (PpPD) with Whipple reconstruction. Eight patients were successfully treated. No serious complications happened. Risk factors for the failure of pancreaticojejunal anastomotic site identification include the digestive tract reconstruction sequence, pancreaticojejunostomy method, pancreatic duct tube implantation, pancreatic duct width before surgery, and pancreatic fistula during perioperative period. The median follow-up time was 77.2 months, the mean indwelling time of the stent was 62.3 months [interquartile range (IQR), 6.8-153.7 months]. Two of eight patients developed recurrent PJS. The variation in body mass index (BMI) was +2.46 in the non-recurrence group compared to -1.09 in the recurrence group and -2.12 in the endoscopic retrograde cholangiopancreatography (ERCP) treatment failure group.Conclusions:ERP intervention should be carried out early once PJS occurs in order to increase success rate. BMI is a crucial indicator which can reflex PJS rehabilitation degree during follow-up. In order to reduce PJS recurrence rate, a wider pancreatic stent and a longer stent indwelling time are recommended.

Background: Pancreatic fistula (PF) is the main complication in patients undergoing pancreaticoduodenectomy. Computed tomography (CT) value can reflect pancreatic tissue characteristics which is related to PF. This study was designed to study the relationship between the preoperative CT value and pancreatic fistula. Methods: We retrospectively reviewed the clinical and medical data of patients undergoing pancreaticoduodenectomy from 2017 to 2021. The pancreatic CT value and the CT value ratios of the pancreas and abdominal aorta (PCT/ACT) were measured and compared between the PF group and non-PF group. The values in different PF severity groups were compared using variance analysis. A cut-off value was selected by receiver operating characteristic (ROC) curve. Single-factor and multiple-factor analysis were performed to evaluate Correlation between PF and CT. Results: One hundred and twenty-seven cases were included in this study. The PCT/ACT in the PF group was significantly lower than that in the non-PF group (P<0.001), and the PCT/ACT value was correlatively lower in the severe PF group than in the mild PF group (P=0.008). A cutoff value of 0.99 was selected by ROC curves analysis. Further multifactor analysis identified PCT/ACT <0.99 to be an independent preoperative predictor [odds ratio (OR): 11.3, P<0.01]. Conclusions: The preoperative pancreatic CT value can indirectly reflect the histological condition of the pancreas and thus may related to postoperative PF after pancreaticoduodenectomy and provide useful information for surgeons in deciding upon the pancreaticojejunostomy method.

毕Ⅱ式吻合是远端胃大部切除的主要吻合方式.有研究发现,毕Ⅱ式胃切除术后病人胆管结石的发病率高于一般人群[1].其改变胃肠道正常的生理解剖结构,增加内镜逆行胰胆管造影术(endoscopic retrograde cholangiopancreatography, ERCP)的操作难度,为最高难度级别[2].在毕Ⅱ式胃切除术后ERCP操作的内镜选择上,《中国经内镜逆行胰胆管造影术指南(2018版)》推荐将侧视镜作为首选,前视镜作为侧视镜失败的备选方案[3].笔者结合本中心10年来近300例病人的操作治疗经验,浅析侧视镜行毕Ⅱ式胃切除术后胆管结石ERCP的要领与策略,供内镜同道参考.

目的:研究内镜逆行胰胆管造影术(endoscopic retrograde cholangiopancreatography,ERCP)治疗胆总管巨大结石,分析先乳头球囊扩张再机械碎石与先碎石再乳头球囊扩张两组对取石效率及术后并发症发生的影响.方法:对2021年1月至2022年1月期间,于我院行ERCP取石治疗的40例胆总管巨大结石病人进行前瞻性研究.采用随机数字表法将病人随机分为先碎后扩组和先扩后碎组,每组各20例.比较两组的取石时间、取石效率(cm3/min)、结石残留率及术后胰腺炎发生率等参数的差异.结果:所有病人均通过一次ERCP完成取石.两组病人的结石最大径、结石单发或多发、结石总体积(cm3)、取石时间、操作时间差异均无统计学意义.先碎后扩组的取石效率高于先扩后碎组[(0.91±0.58)(cm3/min)比(0.51±0.17)(cm3/min),P=0.048],而器械出入乳头口次数少于先扩后碎组[(4.9±1.7)次比(7.9±2.2)次,P=0.021].两组术后结石残留率和ERCP术后胰腺炎发生率差异无统计学意义.先碎后扩组术后24 h淀粉酶水平[(196±158)U/L比(332±265)U/L,P=0.02]和高淀粉酶血症发生病例(2例比8例,P=0.028)显著低于先扩后碎组.两组均未出现重症胰腺炎、胃肠道出血、十二指肠穿孔等严重并发症.结论:ERCP治疗困难胆总管结石时采用先机械碎石后乳头球囊扩张的顺序可提高取石效率,减少取石器械出入乳头次数,并降低术后高淀粉酶血症的发生率.

目的 探讨内镜治疗结直肠癌根治术后吻合口漏疗效的影响因素.方法 回顾性分析2015年1月—2020年12月71例行内镜辅助治疗结直肠癌根治术后吻合口漏患者的临床资料,包括性别、年龄、术前血红蛋白水平、糖化血红蛋白、血清白蛋白水平、肿瘤位置、肿瘤分期、有无新辅助化疗史、吻合口漏发生时间、内镜治疗时间、漏口大小、内镜治疗方式、术后症状缓解情况、引流液量、住院时间等.将患者按治疗效果分为完全缓解组和部分缓解组,比较2组各项指标的差异.结果 71例患者中,42例内镜治疗后吻合口漏完全缓解,治疗有效率为59.15％;29例内镜治疗后漏口未完全闭合;吻合口漏治疗有效者的治疗后3 d平均引流液量少于吻合口漏未完全闭合者,差异有统计学意义(P＜0.01).完全缓解组与部分缓解组患者糖化血红蛋白水平、漏口大小、确诊吻合口漏至接受内镜治疗的时间比较,差异有统计学意义(P＜0.05或P＜0.01).多因素分析发现,确诊吻合口漏至接受内镜治疗时间、漏口大小、糖化血红蛋白水平是疗效的独立影响因素(P＜0.05或P＜0.01).结论 确诊吻合口漏至接受内镜治疗时间、漏口大小、糖化血红蛋白水平是内镜辅助治疗结直肠癌根治术后吻合口漏疗效的独立影响因素.当发生结直肠癌吻合口漏时,应积极控制血糖及糖化血红蛋白水平,行早期内镜治疗,并根据漏口大小选择合适的方式,从而使患者获得最大的临床受益.

Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis-associated gallbladder cancer lncRNA (lncRNA-PAGBC), which we find to be an independent prognostic marker in GBC Functional analysis indicates that lncRNA-PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA-PAGBC competitively binds to the tumour suppressive microRNAs miR-133b and miR-511. This competitive role of lncRNA-PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA-PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC.

Fibrinogen plays an important role in tumor progression. Here, we explored the role of fibrinogen in gallbladder cancer (GBC) metastasis. The plasma fibrinogen level in M1 GBC patients was higher than in M0 GBC patients, indicating that fibrinogen may participate in GBC metastasis. Treatment of GBC cell lines with fibrinogen promoted metastasis and induced the expression of intercellular adhesion molecule 1 (ICAM1). ICAM1 overexpression promoted metastasis and knockdown inhibited it. The cell adhesion and transendothelial migration of GBC cells were enhanced by fibrinogen treatment and ICAM1 overexpression. In addition, the medium of fibrinogen-treated and overexpression-ICAM1 NOZ cells exhibited enhanced macrophages recruitment. This may work in concert to promote angiogenesis. Immunohistochemistry results on clinical specimens showed that higher fibrinogen levels, higher ICAM1 expression, higher blood vessel density, and higher macrophage levels were present simultaneously. Collectively, this study indicates fibrinogen promotes metastasis and extravasation by inducing ICAM1 expression to enhance tumor cell migration, cell adhesion, transendothelial migration and promote angiogenesis and increase vascular endothelial permeability.