Application of Bone Marrow Mesenchymal Stem Cells Effectively Eliminates Endotoxemia to Protect Rat from Acute Liver Failure Induced by Thioacetamide.

BACKGROUND: Endotoxemia is related to worse clinical outcomes in acute liver failure (ALF), but its management remains unsatisfactory. In this study, we aimed to assess whether the application of bone marrow mesenchymal stem cells (BMSCs) could eliminate endotoxemia and protect rats against ALF induced by thioacetamide (TAA). METHODS: BMSCs were isolated from rats and identified by the specific morphology, differentiation potential, and surface markers. The optimal dose of TAA for this study was explored and TAA-induced ALF rats were randomized to three groups: the normal control group (Saline), ALF group (TAA + Saline), and BMSCs-treated group (TAA + BMSCs). The intestinal migration and differentiation of BMSCs was tracked in vivo, and intestinal permeability, endotoxin and inflammatory cytokines, histology, and mortality were analyzed. Moreover, we added the inhibitor of the PI3K/AKT/mTOR signaling pathway into the co-culture system of BMSCs with enterocytes and then performed CK and Villin expression experiments to assess the role of PI3K/AKT/mTOR signal pathway in the intestinal differentiation of BMSCs. RESULTS: BMSCs migrated to the intestinal injury sites and differentiated into enterocytes, intestinal permeability was decreased compared with the ALF group. The higher expression of endotoxin and inflammatory cytokines were reversed after BMSCs transplantation in rats with ALF. Mortality and intestinal lesion were significantly decreased. Blocking the PI3K/AKT/mTOR signal pathway inhibited BMSCs' intestinal differentiation in vitro. CONCLUSION: BMSCs can eliminate endotoxemia and reduce mortality in rats with ALF, and the PI3K/AKT/mTOR signal pathway is involved in intestinal differentiation. BMSCs transplantation could be a potential candidate for the treatment of endotoxemia in ALF.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Management and outcomes of surgical patients with intestinal Behçet's disease and Crohn's disease in southwest China.

BACKGROUND: Gastrointestinal involvement in Behçet's disease (GIBD) and Crohn's disease (CD) are inflammatory diseases sharing a considerable number of similarities. However, different from CD, the operative and postoperative management of GIBD remains largely empirical because of the lack of comprehensive treatment guidelines. AIM: To compare surgical patients with GIBD and those with CD in a medical center and identify notable clinical features and effective postoperative treatment for surgical patients with GIBD. METHODS: We searched patients diagnosed with CD and GIBD who underwent operations for gastrointestinal complications from 2009 to 2015 at West China Hospital of Sichuan University. A total of 10 surgical patients with GIBD and 106 surgical patients with CD were recruited. Information including demographic data, medication, and operative and postoperative parameters were collected and analyzed. As the incidence of surgical GIBD is low, their detailed medical records were reviewed and compared to previous studies. Moreover, the prognoses of CD and GIBD were evaluated respectively between groups treated with biological and non-biological agents. RESULTS: Indication for first surgery was often acute intestinal perforation for GIBD patients (7/10 vs 0/106, P < 0.001), whereas intestinal fistulae (0/10 vs 44/106, P = 0.013) and ileus (0/10 vs 40/106, P = 0.015) were the indications for surgical CD patients. Approximately 40% of patients with GIBD and 23.6% of patients with CD developed postoperative complications, 50% of patients with GIBD and 38.7% of patients with CD had recurrence postoperatively, and 40% (4/10) of patients with GIBD and 26.4% (28/106) of patients with CD underwent reoperations. The average period of postoperative recurrence was 7.87 mo in patients with Behçet's disease (BD) and 10.43 mo in patients with CD, whereas the mean duration from first surgery to reoperation was 5.75 mo in BD patients and 18.04 mo in CD patients. Surgical patients with GIBD more often used corticosteroids (6/10 vs 7/106, P < 0.001) and thalidomide (7/10 vs 9/106, P < 0.001) postoperatively, whereas surgical patients with CD often used infliximab (27/106), azathioprine, or 6-mercaptopurine (74/106) for maintenance therapy. CONCLUSION: Patients suffering GIBD require surgery mostly under emergency situations, which may be more susceptible to recurrence and reoperation and need more aggressive postoperative treatment than patients with CD.

Artificial intelligence technique in detection of early esophageal cancer.

Due to the rapid progression and poor prognosis of esophageal cancer (EC), the early detection and diagnosis of early EC are of great value for the prognosis improvement of patients. However, the endoscopic detection of early EC, especially Barrett's dysplasia or squamous epithelial dysplasia, is difficult. Therefore, the requirement for more efficient methods of detection and characterization of early EC has led to intensive research in the field of artificial intelligence (AI). Deep learning (DL) has brought about breakthroughs in processing images, videos, and other aspects, whereas convolutional neural networks (CNNs) have shone lights on detection of endoscopic images and videos. Many studies on CNNs in endoscopic analysis of early EC demonstrate excellent performance including sensitivity and specificity and progress gradually from in vitro image analysis for classification to real-time detection of early esophageal neoplasia. When AI technique comes to the pathological diagnosis, borderline lesions that are difficult to determine may become easier than before. In gene diagnosis, due to the lack of tissue specificity of gene diagnostic markers, they can only be used as supplementary measures at present. In predicting the risk of cancer, there is still a lack of prospective clinical research to confirm the accuracy of the risk stratification model.

Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression.

Angiogenesis enhances cancer metastasis and progression, however, the roles of transcription regulation in angiogenesis are not fully defined. ZNF322A is an oncogenic zinc-finger transcription factor. Here, we demonstrate a new mechanism of Kras mutation-driven ZNF322A transcriptional activation and elucidate the interplay between ZNF322A and its upstream transcriptional regulators and downstream transcriptional targets in promoting neo-angiogenesis. Methods: Luciferase activity, RT-qPCR and ChIP-qPCR assays were used to examine transcription regulation in cell models. In vitro and in vivo angiogenesis assays were conducted. Immunohistochemistry, Kaplan-Meier method and multivariate Cox regression assays were performed to examine the clinical correlation in tumor specimens from lung cancer patients. Results: We validated that Yin Yang 1 (YY1) upregulated ZNF322A expression through targeting its promoter in the context of Kras mutation. Reconstitution experiments by knocking down YY1 under KrasG13V activation decreased KrasG13V-promoted cancer cell migration, proliferation and ZNF322A promoter activity. Knockdown of YY1 or ZNF322A attenuated angiogenesis in vitro and in vivo. Notably, we validated that ZNF322A upregulated the expression of sonic hedgehog (Shh) gene which encodes a secreted factor that activates pro-angiogenic responses in endothelial cells. Clinically, ZNF322A protein expression positively correlated with Shh and CD31, an endothelial cell marker, in 133 lung cancer patient samples determined using immunohistochemistry analysis. Notably, patients with concordantly high expression of ZNF322A, Shh and CD31 correlated with poor prognosis. Conclusions: These findings highlight the mechanism by which dysregulation of Kras/YY1/ZNF322/Shh transcriptional axis enhances neo-angiogenesis and cancer progression in lung cancer. Therapeutic strategies that target Kras/YY1/ZNF322A/Shh signaling axis may provide new insight on targeted therapy for lung cancer patients.

Multiomics Reveals Ectopic ATP Synthase Blockade Induces Cancer Cell Death via a lncRNA-mediated Phospho-signaling Network.

The EGFR tyrosine kinase inhibitor gefitinib is commonly used for lung cancer patients. However, some patients eventually become resistant to gefitinib and develop progressive disease. Here, we indicate that ecto-ATP synthase, which ectopically translocated from mitochondrial inner membrane to plasma membrane, is considered as a potential therapeutic target for drug-resistant cells. Quantitative multi-omics profiling reveals that ecto-ATP synthase inhibitor mediates CK2-dependent phosphorylation of DNA topoisomerase IIα (topo IIα) at serine 1106 and subsequently increases the expression of long noncoding RNA, GAS5. Additionally, we also determine that downstream of GAS5, p53 pathway, is activated by ecto-ATP synthase inhibitor for regulation of programed cell death. Interestingly, GAS5-proteins interactomic profiling elucidates that GAS5 associates with topo IIα and subsequently enhancing the phosphorylation level of topo IIα. Taken together, our findings suggest that ecto-ATP synthase blockade is an effective therapeutic strategy via regulation of CK2/phospho-topo IIα/GAS5 network in gefitinib-resistant lung cancer cells.

Suppressing growth and invasion of human hepatocellular carcinoma cells by celecoxib through inhibition of cyclooxygenase-2.

Purpose: Biomarkers are lacking in hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) and its metabolites play crucial roles in the process of inflammation-tumor transformation. This study was aimed to detect COX-2 expression in HCC tissues and evaluate the effects of a COX-2 inhibitor, celecoxib, on biological behaviors of HCC cell lines in vitro. Methods: COX-2 expression was detected by immunohistochemistry on a human HCC tissue microarray. The correlations of COX-2 expression with tumor clinicopathological variables and overall survival were analyzed. The proliferation, apoptosis, cell cycle distribution, invasion capacity, and related signaling molecules of HCC cells after incubated with COX-2 inhibitor celecoxib were evaluated in vitro. Results: Expression levels of COX-2 in HCC tissues were significantly higher than those in paracancerous tissues. The TNM stage III-IV, tumor size >5 cm, lymphovascular invasion and distant metastasis was higher in high COX-2 expression group compared with that in low COX-2 expression group. Patients with low COX-2 expression achieved better 5-year overall survival than those with high COX-2 expression. Treatment with celecoxib was sufficient to inhibit cell proliferation, promote apoptosis, and induce G0/G1 cell cycle arrest in HCC cells with concentration- and time-dependent manners. Celecoxib up-regulated E-cadherin protein through inhibiting COX-2-prostaglandin E2 (PGE2)-PGE2 receptor 2 (EP2)-p-Akt/p-ERK signaling pathway to suppress HCC cells migration and invasion. Conclusion: High COX-2 expression was associated with advanced TNM stage, larger tumor size, increased lymphovascular invasion and short survival. Targeting inhibition of COX-2 by celecoxib exhibited anti-tumor activities by suppressing proliferation, promoting apoptosis, and inhibiting the aggressive properties of HCC cells.

SK-Hep1: not hepatocellular carcinoma cells but a cell model for liver sinusoidal endothelial cells.

SK-Hep1 cells serve as a cell model of hepatocellular carcinoma and hepatocyte biology. However, SK-Hep1 cells are markedly different from normal hepatocytes and other hepatocellular carcinoma cells in their gene expression and protein levels. Furthermore, endothelial-specific makers and morphological characteristics are found in SK-Hep1 cells, indicating an endothelial origin. To confirm their cell phenotype, we investigated and compared the surface ultrastructure, endothelial function, and molecular markers of SK-Hep1 cells in vitro and in vivo. The results revealed that SK-Hep1 cells expressed endothelial-specific makers and exhibited the endothelial function of endocytosis and tubular formation. Capillary-like structures with CD31 expression were also observed in SK-Hep1 allografts in nude mice. Moreover, SK-Hep1 cells possessed fenestrae without diaphragms, consistent with liver sinusoidal endothelial cells, as seen by electron microscopy. In conclusion, SK-Hep1 cells would be better considered a cell model for liver sinusoidal endothelial cells instead of hepatocellular carcinoma cells.

High HIF-1α expression predicts poor prognosis of patients with colon adenocarcinoma.

Hypoxia inducible factor 1 alpha subunit (HIF-1α) is induced in hypoxic conditions and plays a crucial role in the neoangiogenesis and metastasis of cancer. In this study, we aimed to evaluate the expression of HIF-1α in colon adenocarcinoma and to explore its clinicopathological characteristics and prognosis. A tissue microarray involving colon adenocarcinoma tissues and their corresponding paracancerous tissues from 92 patients was utilized to detect HIF-1α. The expression of HIF-1α in colon adenocarcinoma tissues was significantly higher than it was in the corresponding paracancerous tissues (P < 0.001). Furthermore, similar results were observed in HCT116 and RKO human colon adenocarcinoma xenografts in node mice (P < 0.05). Additionally, augmented HIF-1α expression was positively associated with TNM stage III-IV (P = 0.025), the presence of distant metastasis and vascular invasion (P = 0.048), and the presence of positive lymph nodes (P = 0.041). A Kaplan-Meier survival analysis showed that up-regulation of HIF-1α was associated with poor 5-year or 10-year survival (P < 0.05). A multivariable Cox regression analysis also found HIF-1α was an independent risk factor for poor prognosis in colon adenocarcinoma. Thus, targeting HIF-1α might be a viable strategy to treat patients with colon adenocarcinoma.

[Effect of Proton Pump Inhibitors on Severe Acute Pancreatitis--a Prospective Randomized Trial].

OBJECTIVE: To evaluate the effect of proton pump inhibitors (PPIs) therapy on severe acute pancreatitis (SAP) patients. METHODS: Forty five patients with SAP recruited in our center from October 2015 to October 2016,were randomly assigned into two groups: convention group (C group,n=21) and convention+esomeprazole group (C+E group,n=24). C+E group received esomeprazole 40 mg/d intravenously for 1 week,whereas C group only received baseline treatment. Serum C-reactive protein (CRP),interleukin-6 (IL-6) and interleukin-8 (IL-8),tumor necrosis factor-α (TNF-α) and procalcitonin (PCT) were detected by ELISA on the first day (baseline) and the seventh day. Acute physiology and chronic health evaluation Ⅱ scores (APACHE Ⅱ),systemic inflammatory response syndrome scores (SIRS) and modified Marshall scoring system (Marshall) were obtained at 1 d (baseline),3 d and 7 d. Upper gastrointestinal manifestation (peptic ulcer) and gastric pH were detected by endoscopic examination at 7 d. Fecal occult blood test was performed at 7 d. RESULTS: No significant difference was found in CRP,IL-6,IL-8,TNF-α and PCT between the two groups ( P>0.05),also no difference in APACHE Ⅱ,SIRS and Marshall scores ( P>0.05). The gastric pH was remarkably higher in C+E group when compared to C group (5.02±1.61 vs.2.83±1.08, P<0.001). There was no significant difference in the incidence of peptic ulcer and the rate of positive fecal occult blood between the two groups. CONCLUSION: PPIs therapy did not show benefit on alleviating systemic inflammatory response and clinical scores in SAP patients,and didn't improve the prevention of peptic ulcer and gastrointestinal hemorrhage.

Carbohydrate antigen 125 and carcinoembryonic antigen in the differentiation of tuberculous peritonitis and peritonitis carcinomatosa.

Tumor markers could increase in both tuberculous peritonitis and peritonitis carcinomatosa, confusing the differentiation of these diseases. This study aimed to better understand the extent of elevation and diagnostic efficacies of carbohydrate antigen 125 (CA 125), carcinoembryonic antigen (CEA) and combinative use of them in tuberculous peritonitis and peritonitis carcinomatosa. Of 2998 patients reviewed, 101, 120 and 71 patients were assigned to TBP group (tuberculous peritonitis), non-OCA group (non-ovarian carcinoma-related peritonitis carcinomatosa) and OCA group (ovarian carcinoma-related peritonitis carcinomatosa), respectively. The composite index was calculated by CA 125 multiplying CEA. Receiver operator characteristic curves for CA 125, CEA and composite index were acquired. As a result, CA 125 value in OCA group was higher than other two groups (serum CA 125: P < 0.001; ascites CA 125: P < 0.001). On the other hand, non-OCA group had the highest CEA value among three groups (serum CEA: P < 0.001; ascites CEA: P < 0.001). Area under curves of serum/ascites composite index and serum/ascites CEA were larger than those of serum/ascites CA 125. Furthermore, ascites and serum composite index displayed the best sensitivity (0.907) and specificity (0.989), respectively. In conclusion, CA 125 increases in tuberculous peritonitis and non-ovarian carcinoma-related peritonitis carcinomatosa, but it elevates more in ovarian carcinoma-related peritonitis carcinomatosa. CEA is found to increase more significantly in non-ovarian carcinoma-related peritonitis carcinomatosa. CEA and composite index are helpful in distinguishing peritonitis carcinomatosa from tuberculous peritonitis, but composite index is slightly superior to CEA in the differential diagnosis.

Effects of octreotide on hepatic glycogenesis in rats with high fat diet­induced obesity.

Reduced hepatic glycogenesis is one of the most important causes of metabolic abnormalities in non­alcoholic fatty liver disease. Octreotide, a somatostatin analogue, has been demonstrated to promote weight loss and improve metabolic disorders in mice with high fat diet (HFD)­induced obesity. However, whether octreotide affects hepatic glycogenesis is unknown. The aim of the present study was to verify the effects of octreotide on hepatic glycogenesis in rats with HFD­induced obesity. Male Sprague­Dawley rats were fed a standard diet or a HFD for 24 weeks. Obese rats from the HFD group were further divided into a HFD­control group and an octreotide­administered group. Rats in the latter group were injected with octreotide for 8 days. Glucose and insulin tolerance tests were performed, and the area under the curve (AUC) was calculated. Following sacrifice, their body weights and lengths, fasting plasma glucose (FPG), fasting insulin (FINS), serum triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured. In addition, Lee's index and the homeostatic model assessment index were calculated. Hepatic TG, FFA levels and glycogen content were first determined. Hepatic steatosis in the obese rats was assessed based on hematoxylin and eosin and Oil Red O staining. Human hepatoblastoma HepG2 cells were divided into a control group, a palmitate (PA)­treated group and a PA + octreotide­treated group. Establishment of the in vitro fatty liver model using HepG2 cells was confirmed by Oil Red O staining. The expression of phosphorylated Akt and glycogen synthase kinase 3ß (GSK3ß) was detected by western blotting, and glycogen synthase (GS) mRNA levels were detected by reverse transcription­quantitative polymerase chain reaction. Compared with the control group, the body weight, Lee's index, AUC of the intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test, levels of FPG, FINS, TG, TC, FFA, ALT and AST, and HOMA index values were significantly increased in the obese rats. The body weight, levels of FPG and FINS, and the HOMA index were significantly reduced following octreotide treatment, whereas the decrease in Lee's index, the blood levels of ALT, AST, TC, TG and FFA, and the AUC did not reach statistical significance. Hepatic TG and FFA levels were significantly increased and hepatic glycogen content was significantly decreased in rats with HFD­induced obesity when compared with those in the control group. Octreotide intervention restored these alterations. The expression levels of phosphorylated Akt and GSK3ß protein expression, as well as GS mRNA levels in the HFD group were lower when compared with those in the control group, whereas octreotide treatment reversed these reductions. The in vitro experiments demonstrated that the reduced levels of phosphorylated Akt and GSK3ß protein, and GS mRNA in the PA­treated group were significantly reversed by octreotide treatment. In conclusion, the results indicate that octreotide improved hepatic glycogenesis and decreased FPG concentration in rats with HFD­induced obesity. These mechanisms may be associated with increased GS activity via the promotion of GSK3ß phosphorylation. Therefore, octreotide may be regarded as a novel therapeutic strategy for HFD­induced obesity and obesity­associated metabolic disorders.

Adjuvant celecoxib and lanreotide following transarterial chemoembolisation for unresectable hepatocellular carcinoma: a randomized pilot study.

Recurrence of hepatocellular carcinoma (HCC) after transarterial chemoembolisation (TACE) is common due to neoangiogenesis. Cyclooxygenase-2 inhibitors and somatostatin analogues were reported to inhibit tumour angiogenesis. The pilot randomized controlled trial was aimed to prospectively evaluate the protocol of TACE combined with celecoxib and lanreotide (TACE+C+L) in patients with unresectable and advanced HCC. A total of 71 patients with HCC were enrolled and randomly assigned to either TACE (n=35) or TACE+C+L (n=36) group. Overall survival, disease control rate (DCR), and adverse events were assessed during a 3-year follow-up period. The median overall survival of the TACE+C+L group (15.0 months) was doubled compared to that of TACE group (7.5 months), p = 0.012. DCR of the TACE+C+L group was significantly higher than that of the TACE group either at 6 months (72.2% vs 42.9%, p = 0.012) or at 12 months (61.1% vs 28.6%, p = 0.006). The median overall survivals (13 months vs 4.5 months, p = 0.013) and DCR at 12 months (50% vs 13.6%, p = 0.008) of patients with advanced HCC in TACE+C+L groups were significantly higher than those in TACE group. No significant difference of adverse events was observed between the two groups. The occurrence of post-embolisation syndrome in TACE+C+L group was significantly lower than that in TACE group (16.7% vs 60.0%, p = 0.001). In conclusion, the regimen of TACE+C+L prolonged overall survival, enhanced tumour response, reduced post-embolisation syndrome and was well-tolerable in the patients with unresectable HCC. It may be more beneficial for advanced HCC.

Correlations between VEGF-A expression and prognosis in patients with gastric adenocarcinoma.

Angiogenesis induced by vascular endothelial growth factor A (VEGF-A) plays a critical role in tumor growth and metastasis. The study aimed to evaluate the expression of VEGF-A in gastric adenocarcinoma and investigate its correlations with tumor clinicopathological features and prognostic significance. VEGF-A expression was detected by immunohistochemistry on a tissue microarray containing 90 pairs of human gastric adenocarcinoma and paracancerous tissues. Levels of VEGF-A in gastric adenocarcinoma were significantly higher than those in paracancerous tissues (P=0.018). Furthermore, the result was coincident with that of human gastric adenocarcinoma xenografts in nude-mice (P<0.01). In addition, the VEGF-A expression was positive correlation with TNM stage (P=0.047), tumor size (P=0.028), positive lymph nodes (P=0.002) and lymphovascular invasion (P=0.001). Finally, Kaplan-Meier survival analysis showed that VEGF-A up-regulation indicated a poor prognosis for overall survival (P=0.039). In conclusions, VEGF-A may be used as a biomarker for evaluating both the biological behavior of tumor and the prognosis in patients with gastric adenocarcinoma.

Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats.

Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway.

Epidemiological features of gastroenteropancreatic neuroendocrine tumors in Chengdu city with a population of 14 million based on data from a single institution.

AIM: Recent studies on gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in the United States as well as the European studies demonstrate an increasing GEP-NETs incidence. Most information on the epidemiology of neuroendocrine tumors comes from western countries. However, the epidemiological profile of GEP-NETs in West China is still unclear. The aim of study was to reflect the regional features of GEP-NETs in Chengdu city of West China based on data from a single institution. METHODS: West China Hospital (WCH), the largest university hospital located in Chengdu (West China) with population of 14.04 million, has established a serial of databases in recent years. According to the data from Medical Records Section of WCH and Chengdu Health Bureau, the total patients per year in WCH covered about 25.6-28% patients of Chengdu city during the 5 years. Therefore, we have used GEP-NETs diagnosed in WCH from 2009 to 2013 to reflect the regional epidemiological profile of GEP-NETs. RESULTS: GEP-NETs proportion in WCH increased 1.6-folds during past 5 years from 1.28/10(5) to 2.03/10(5) , P < 0.05. The average duration of symptom before diagnosis was 16.8 months. About 46.6% (115/248) of GEP-NETs were metastatic. Seventy-seven percent (190/248) of patients were over 40 years. Proportions of GEP-NETs from primary sites were rectum 30.6% (76/248), pancreas 23.4% (58/248), gastric 13.3% (33/248) and esophagus 11.3% (28/248). Proportions of insulinoma, vipoma and nonfunctional pancreatic neuroendocrine tumors (P-NETs) were 43.1% (25/58), 1.7% (1/58) and 55.2% (32/58) separately in the P-NETs. CONCLUSIONS: There is a distinct epidemiologic profile between West China and western countries based on a single institution data. The delayed diagnosis reflects inadequate disease awareness of GEP-NETs and paucity of research funding.

Inhibition of cyclooxygenase-2 alleviates liver cirrhosis via improvement of the dysfunctional gut-liver axis in rats.

Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis.

[The Expressions of Somatostatin and Cycloxygenase-2 in Chronic Hepatitis, Hepatic Cirrhosis, Precancerous Lesion and Hepatocellular Carcinoma].

OBJECTIVE: To investigate the expression difference of somatostatin (SST) , SST receptors (SSTR) and COX-2 in chronic hepatitis, hepatic cirrhosis, precancerous lesion and hepatocellular Carcinoma, and explore the relationship between portal hypertension and SST/SSTR expressions. METHODS: A series of human liver tissues were obtained from surgery, including normal liver 4 cases, chronic hepatitis 14 cases, hepatic cirrhosis 40 cases, precancerous lesion 40 cases and HCC tissues 40 cases. Peripheral bloods were collected from 20 patients before and after the operation of transjugular intrahepatic portosystemic shunt (TIPS). SSTR 1-5 subtypes in hepatic tissues were detected by immunohistochemical study and RT-PCR. Levels of SST and COX-2 were quantified by radioimmunoassay and Western blot. RESULTS: 90% of precancerosis expressed high levels of SSTR 2, 5 subtypes, and SSTR mainly distributed surrounding portal vein. At lest 60%o of HCC expressed SSTR 2, 5 subtypes, and there were positive correlations between levels of SSTR 1-5 and SST. Levels of SST in peripheral blood of cirrhotic patients significantly increased after TIPS(P<0. 05). Levels of COX-2 were highest in cirrhosis (about 90%), and decreased in precancerosis (about 80%) and HCC tissues. CONCLUSIONS: Precancerosis or early stage of HCC may be the optimum time for synergetic medication of SST analogue and COX-2 inhibitor.

Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer.

AZD6244 (ARRY-142886), a highly selective MAPK-ERK kinase inhibitor, has shown excellent clinical efficacy in many tumors. However, the anti-tumor and anti-angiogenesis efficacy of AZD6244 on gastric cancer has not been well characterized. In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. For absence of NRAS, KRAS and BRAF mutation, SGC7901 and BGC823 gastric cancer cells were relative resistance to AZD6244 in vitro. And such resistance was not attributed to the insufficient inhibition of ERK phosphorylation. However, tumor growth was significantly suppressed in SGC7901 xenografts by blockage of angiogenesis. This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244. Moreover, the anti-angiogenesis effect of AZD6244 may predominantly attribute to its modulation on VEGF through p-ERK - c-Fos - HIF-1α integrated signal pathways. In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. Targeting inhibition of p-ERK by AZD6244 suppress gastric cancer xenografts by blockage of angiogenesis without systemic toxicity. The anti-angiogenesis effect afford by AZD6244 may attribute to its modulation on p-ERK - c-Fos - HIF-1α - VEGF integrated signal pathways.