Immune-related adverse events associated with immune checkpoint inhibitors for advanced gastric and gastroesophageal junction cancer: A meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown promising efficacy in treatment and clinical management of advanced gastric and gastroesophageal junction cancer. However, the inhibitors also cause immune-related adverse events (irAEs). The current systematic review and meta-analysis study aimed to investigate the incidence and nature of irAEs caused by ICIs. AIM: To investigate the incidence and nature of irAEs in advanced gastric and gastroesophageal junction cancer. METHODS: This systematic review was registered with PROSPERO (Reg. number: CRD42020152291). Data included in this study were collected from patients diagnosed with advanced gastric cancer or gastroesophageal junction cancer and treated with ICIs. A systematic literature search was conducted using the PubMed, EMBASE, and Cochrane Library databases. Meta-analysis was carried out using the single sample rate method. Synthesis and analysis of the data was conducted using Stata/SE and Review Manager Software. RESULTS: The patients enrolled in the present study included 14 patients from 14 case reports, 326 patients from 6 case series, and 1249 patients from 8 clinical trials. It was found that the overall incidence of irAEs was 16% [95% confidence interval (CI): 11-20] for all grades and 3% (95%CI: 2-4) for the severe grade. It was evident that the incidence of irAEs varied with the type of inhibitor and organs. A comparative study of the anti-programmed cell death receptor-1 (PD-1) and anti-programmed death receptor-ligand 1 (PD-L1) treatments showed that the anti-PD-1 group had a higher overall incidence of irAEs (20%) as compared with that of the anti-PD-L1 group (13%). Results of this study showed that the endocrine system experienced the highest incidence of organ-specific irAEs (7.4%), including hypothyroidism, hyperthyroidism, thyroiditis, diabetes, and adrenal insufficiency, followed by gastroenterology (2.2%), pulmonology (1.8%), neurology (1.4%), dermatology (1.4%), hematology (0.8%), and hepatology (0.7%). In clinical trials, it was found that the incidence of death related to irAEs was 1% (95%CI: 0-2.0), whereby colitis and interstitial lung diseases were the leading causes of death. CONCLUSION: It was evident that the incidence and nature of irAEs are both organ- and inhibitor-specific. The anti-PD-1 group had the highest incidence of all irAEs grades including the severe grades of irAEs. Early identification and management of irAEs allows clinical oncologists to effectively consider the pros and cons and hence enables them to strike a balance.

Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta gene as a tumour suppressor in stomach adenocarcinoma.

Background: Stomach adenocarcinoma (STAD) is the most common type of gastric cancer. In this study, the functions and potential mechanisms of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta (HADHB) in STAD were explored. Methods: Different bioinformatics analyses were performed to confirm HADHB expression in STAD. HADHB expression in STAD tissues and cells was also evaluated using western blot, qRT-PCR, and immunohistochemistry. Further, the viability, proliferation, colony formation, cell cycle determination, migration, and wound healing capacity were assessed, and the effects of HADHB on tumour growth, cell apoptosis, and proliferation in nude mice were determined. The upstream effector of HADHB was examined using bioinformatics analysis and dual luciferase reporter assay. GSEA was also employed for pathway enrichment analysis and the expression of Hippo-YAP pathway-related proteins was detected. Results: The expression of HADHB was found to be low in STAD tissues and cells. The upregulation of HADHB distinctly repressed the viability, proliferation, colony formation, cell cycle progression, migration, invasion, and wound healing of HGC27 cells, while knockdown of HADHB led to opposite effects. HADHB upregulation impeded tumour growth and cell proliferation, and enhanced apoptosis in nude mice. KLF4, whose expression was low in STAD, was identified as an upstream regulator of HADHB. KLF4 upregulation abolished the HADHB knockdown-induced tumour promoting effects in AGS cells. Further, HADHB regulates the Hippo-YAP pathway, which was validated using a pathway rescue assay. Low expression of KLF4 led to HADHB downregulation in STAD. Conclusion: HADHB might function as a tumour suppressor gene in STAD by regulation the Hippo-YAP pathway.

Retraction Notice to: Long Noncoding RNA UCA1 Regulates PRL-3 Expression by Sponging MicroRNA-495 to Promote the Progression of Gastric Cancer.

[This retracts the article DOI: 10.1016/j.omtn.2019.10.020.].

Exosomes derived from human umbilical cord mesenchymal stem cells alleviate acetaminophen-induced acute liver failure through activating ERK and IGF-1R/PI3K/AKT signaling pathway.

This study aimed to investigate the therapeutic potential of human umbilical cord mesenchymal stem cells derived exosomes (hUCMSC-Exo) in acute liver failure (ALF) in mice as well as its underlying mechanism. We found that a single tail vein administration of hucMSC-Exo effectively enhanced the survival rate, inhibited apoptosis in hepatocytes, and improved liver function in APAP-induced mouse model of ALF. Furthermore, the deletion of glutathione (GSH) and superoxide dismutase (SOD), generation of malondialdehyde (MDA), and the over production of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP were also inhibited by hucMSC-Exo, indicating that hucMSC-Exo inhibited APAP-induced apoptosis of hepatocytes by reducing oxidative stress. Moreover, hucMSC-Exo significantly down-regulated the levels of inflammatory cytokines IL-6, IL-1ß, and TNF-α in APAP-treated livers. Western blot showed that hucMSC-Exo significantly promoted the activation of ERK1/2 and IGF-1R/PI3K/AKT signaling pathways in APAP-injured LO2 cells, resulting in the inhibition of apoptosis of LO2 cells. Importantly, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 could reverse the function of hucMSC-Exo on APAP-injured LO2 cells in some extent. Our results suggest that hucMSC-Exo offer antioxidant hepatoprotection against APAP in vitro and in vivo by inhibitiing oxidative stress-induced apoptosis via upregulation of ERK1/2 and PI3K/AKT signaling pathways.

Long Noncoding RNA UCA1 Regulates PRL-3 Expression by Sponging MicroRNA-495 to Promote the Progression of Gastric Cancer.

Gastric cancer (GC) is among the most frequently occurring malignancies worldwide. In recent years, long noncoding RNAs (lncRNAs) have been widely studied because of their ability to regulate the cellular processes involved with tumorigenesis. The present study aims to investigate the underlying molecular mechanism by which lncRNA urothelial carcinoma-associated 1 (UCA1) influences the progression of GC. Differentially expressed lncRNA UCA1 was initially identified by microarray-based analysis, after which a high expression of UCA1 was determined in GC tissues and cells. It is important to note that UCA1 could upregulate the expression of phosphatase of regenerating liver-3 (PRL-3) by sponging miR-495. The expression of UCA1 and miR-495 was altered in human GC cells to evaluate cell activity in vitro, as well as peritoneal metastasis and tumor formation ability in vivo. Results suggested that increased expression of UCA1 promoted cell proliferation, migration, and invasion, accompanied by suppressed cell apoptosis, as well as enhanced peritoneal metastasis and tumorigenesis of GC cells. Meanwhile, the upregulated expression of miR-495 could reverse the promotive effects exerted by UCA1. Taken conjointly, UCA1, as a competing endogenous RNA (ceRNA) of miR-495, could accelerate the development of GC by upregulating PRL-3, highlighting a potentially promising basis for the targeted intervention treatment of GC.

LINC00319 acts as a microRNA-335-5p sponge to accelerate tumor growth and metastasis in gastric cancer by upregulating ADCY3.

Gastric cancer (GC) is one of the most common cancers in the world and remains a heavy burden of health worldwide. Adenylate cyclase 3 (ADCY3) is a widely expressed membrane-associated protein in human tissues and has been identified to be a new molecular target of GC. Long noncoding RNAs have a substantial influence on tumorigenesis and progression of tumors by binding to microRNAs. Therefore, this study is to clarify the mechanism by which LINC00319 sponges micro RNA-335-5p (miR-335-5p) to influence the development of GC. Initially, microarray analysis identified GC-related differentially expressed LINC00319 and ADCY3 for this study. The interaction was confirmed that LINC00319 interacted with miR-335-5p to regulate ADCY3. Next, SGC-7901 cells presenting with the lowest LINC00319 expression and the highest miR-335-5p expression were transfected with LINC00319, miR-335-5p inhibitor, or ADCY3 vector to examine their roles in growth and metastasis of GC cells, which was further ascertained by in vivo experiments. LINC00319 was upregulated and miR-335-5p was downregulated in GC cells. LINC00319 overexpression, miR-335-5p inhibitor, or ADCY3 overexpression was shown to significantly elevate the expression of cyclin-dependent kinase 4 and metastasis associated 1, decrease that of growth arrest-specific 1, and promote tumor growth and metastasis by increasing proliferation and migration and reducing cell apoptosis. Importantly, it was found that overexpressed miR-335-5p exerted its tumor suppressive role in GC through downregulating ADCY3. Collectively, LINC00319 expedited growth and metastasis of GC by upregulating miR-335-5p-mediated ADCY3.NEW & NOTEWORTHY This study is carried out based on in vivo and in vitro studies in mice and gastric cancer (GC) cells with the aim of clarifying the role of LINC00319 on GC growth and metastasis, which associated with micro RNA-335-5p-mediated adenylate cyclase 3. Altogether, we identified LINC00319 to be a potential therapy to treat GC.

MicroRNA-140-5p inhibits cell proliferation, migration and promotes cell apoptosis in gastric cancer through the negative regulation of THY1-mediated Notch signaling.

Studies have highlighted the importance of microRNAs (miRs) in the development of various cancers, including gastric cancer (GC), a commonly occurring malignancy, accompanied by high recurrence and metastasis rate. The aim of the current study was to investigate the role of miR-140-5p in GC. Microarray expression profiles were initially employed to screen the differentially expressed gene related to GC, and the miR regulating the gene was predicted accordingly. The data obtained indicated that thymus cell antigen 1 (THY1) was differentially expressed in GC and confirmed to be a target gene of miR-140-5p. Poorly expressed miR-140-5p and highly expressed THY1 were observed in the GC tissues. SGC-7901 cells were treated with miR-140-5p mimic/inhibitor, siRNA against THY1 and siRNA against Notch1 in order to determine their regulatory roles in GC cell activities. The relationship of miR-140-5p, THY1 and the Notch signaling pathway was subsequently identified. Moreover, cell proliferation, migration, invasion and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), wound-healing, transwell assay and flow cytometry, respectively. The overexpression of miR-140-5p and silencing of THY1 resulted in a diminished expression of the Notch signaling pathway-related proteins, as well as inhibited proliferation, migration and invasion of GC cells, enhanced expression of pro-apoptotic proteins in addition to elevated apoptosis rate. Taken together, the present study suggests that miR-140-5p directly targets and negatively regulates THY1 expression and inhibits activation of the Notch signaling pathway, whereby the up-regulation of miR-140-5p inhibits development of GC, highlighting the promise of miR-140-5p as a potential target for GC treatment.

SPOCK1 as a potential cancer prognostic marker promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/AKT pathway.

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.

Inhibition of Aurora-B suppresses HepG2 cell invasion and migration via the PI3K/Akt/NF-κB signaling pathway in vitro.

In the present study, the effect of Aurora-B inhibition on HepG2 cell invasion and migration in vitro was investigated. A recombinant plasmid targeting the Aurora-B gene (MiR-Aurora-B) was used to inhibit Aurora-B expression in HepG2 cells. Cell migration and invasion were investigated using Transwell migration and invasion assays. The results demonstrated that cell invasion and migration were suppressed by inhibiting Aurora-B. In addition, the effect of Aurora-B inhibition on the activity of the phosphoinositide 3-kinase (PI3K)/Akt/nuclear factor (NF)-κB signaling pathway was investigated by analyzing the protein expression levels of phosphorylated (p)-Akt, Akt, NF-κB p65, matrix metalloproteinase (MMP)-2 and MMP-9 using western blot analysis. The results demonstrated that the protein expression levels of p-Akt, NF-κB p65, MMP-2 and MMP-9 were reduced significantly by inhibiting Aurora-B. Therefore, inhibition of Aurora-B was shown to suppress hepatocellular carcinoma cell migration and invasion by decreasing the activity of the PI3K/Akt/NF-κB signaling pathway in vitro.

Is there a role of surgery in patients with recurrent or metastatic gastrointestinal stromal tumours responding to imatinib: a prospective randomised trial in China.

OBJECTIVES: For advanced gastrointestinal stromal tumour (GIST) patients who are responding to imatinib mesylate, the role of surgery has not been formally demonstrated. This multicenter randomised controlled trial was designed to assess whether surgery to treat residual disease for patients with recurrent/metastatic GISTs responding to imatinib mesylate (IM) improved progression free survival (PFS) compared with IM treatment alone. METHODS: Between 3 and 12months after starting IM for recurrent/metastatic GISTs, eligible patients were randomised to two arms: Arm A (surgery for residual disease) and Arm B (IM treatment alone). In Arm A (19pts), surgery was performed to remove residual macroscopic lesions as completely as possible, and IM treatment continued after surgery. In Arm B (22pts), IM was given alone at a dose of 400mg per day until disease progression. The primary end-point was PFS measured from the date IM started. This study was registered in the ChiCTR registry with the ID number ChiCTR-TRC-00000244. RESULTS: This randomised trial was closed early due to poor accrual. Only 41 patients were enrolled as opposed to 210 patients planned. 2-year PFS was 88.4% in the surgery arm and 57.7% in the IM-alone arm (P=0.089). Median overall survival (mOS) was not reached in the surgery arm and 49months in patients with IM-alone arm (P=0.024). CONCLUSIONS: While no significant differences were observed in the two arms, this study suggests that surgical removal of the metastatic lesion may improve the outcome of advanced GIST patients and should stimulate additional research on this topic.

[Necessity of No.13 lymph node dissection in advanced gastric carcinoma].

OBJECTIVE: To investigate the feasibility and necessity of No.13 lymph node dissection for advanced gastric carcinoma. METHODS: Clinical data of 144 cases who were diagnosed as TNMII-III stage gastric carcinoma were collected from January 2007 to December 2009 in the Department of General Surgery at the First Affiliated Hospital of Nanchang University. Seventy-two cases who received D2 radical gastrectomy plus No.13 lymph node dissection were selected as the study group, and they were matched 1:1 to 72 cases who received D2 Radical gastrectomy (the control group) for TNMII-III stage gastric carcinoma. The differences in the intraoperative and postoperative parameters and survival time were compared, and the factors associated with No.13 lymph node metastasis were analyzed. RESULTS: There were no significant differences between the two groups in operative time [(2.8 ± 0.4) h vs. (2.7 ± 0.4) h], blood loss [(191.9 ± 81.5) ml vs. (186.0 ± 81.7) ml], the incidence of postoperative complications (18.1% vs. 15.3%), length of hospital stay [(12.3 ± 4.2) d vs. (11.9 ± 3.2) d] and 3-year survival rate (63% vs. 57%) (all P>0.05). In the study group, there were 15 patients (20.8%) with positive No.13 lymph nodes, and the 3-year survival rate was 13%, significantly lower compared to those with negative No.13 lymph node (73%, n=57) (P<0.05). Multivariate analysis showed that N stage (P<0.01) and histological type (P<0.05) were independently associated with No.13 lymph node metastasis. CONCLUSION: No.13 lymph node dissection for TNMII-III stage gastric cancer is feasible and necessary.

[Association of the jejunal mucosal structure and the tolerance of early postoperative enteral nutrition in gastric carcinoma patients at different ages].

OBJECTIVE: To explore the association of the changes of the jejunal mucosal structure and the tolerance of early postoperative enteral nutrition in gastric cancer patients at different ages. METHODS: Thirty patients of gastric carcinoma undergone total gastrectomy were enrolled in this study, including 16 cases over 65 years old and 14 cases under 40 years old. The specimens of jejunal mucosa were taken during operation and were observed by light and electronic microscopes. The height and width of the jejunal villus and the thickness of the jejunal mucosa were measured. All the patients received enteral nutrition from the second postoperative day to discharge. The complications related to enteral nutrition, such as abdominal pain, abdominal distention, and diarrhea, were observed. RESULTS: The height of the jejunal villus was longer in young age group than that of old age group. The width of the jejunal villus was shorter in young age group than that of old age group. The thickness of the jejunal mucosa was thinner in old age group than that of young age group. The changes of ultrastructure of the jejunal mucosal epithelial cell in old age group showed that microvilli are rare and disorder, mitochondrial cristaes were broken and dissolved. The young age group was normal in the ultrastructure. The complications related to enteral nutrition were more frequent in old age group than those in young age group, especially in abdominal distention and diarrhea (P<0.01). CONCLUSION: The atrophy of jejunal mucosa in old age patients with gastric carcinoma lead to decrease the tolerance and increase the complications of the postoperative enteral nutrition.

[Clinical analysis of prognostic factors for patients with gastrointestinal stromal tumors].

OBJECTIVE: To investigate the prognostic factors for patients with gastrointestinal stromal tumors (GIST). METHODS: From 2000 to 2003, clinical data of 41 cases with GIST were reviewed retrospectively. The clinicopathologic diagnosis was determined by immunochemistry. The relationships of the prognosis with mitotic counts, tumor size and location,range of tumor resection were analyzed. RESULTS: The patients with GIST had pathological section of high expression in CD117, CD34 and vimentin (92.7%, 82.9%, 78%, respectively). Patients with tumor location in intestine, tumor size > 5 cm,mitotic counts > 5/50HPF, incomplete resection had poorer outcome, compared with those with tumor location in stomach and colon,tumor size < or = 5 cm,mitotic counts < or = 5/50HPF and complete resection (all P< 0.05). CONCLUSION: Complete gross resection can improve prognosis for patients with GIST. Tumors with mitotic counts > or = 5/50HPF, tumor size more than 5 cm and tumor location in intestine are poor prognostic factors.

Simultaneous pancreas-kidney transplantation with portal-enteric drainage: a case report.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) with portal-enteric drainage is physiological effective in treatment of patients with diabetes mellitus complicated by end-stage renal disease. A case is reported with a review of our clinical experience. METHODS: A patient with type 2 diabetes complicated by renal failure was subjected to SPK transplantation with portal-enteric drainage. Pancreaticoduodenal allograft procured from corpse was transplanted to recipient's right abdomen with donor's portal vein anastomosed to recipient's superior mesenteric vein. Donor's plastic pancreas artery was anastomosed to recipient's right common iliac artery and donor's duodenum anastomosed to recipient's jejunum. The kidney allograft was transplanted ectopically to the contralateral iliac fossa. Postoperative immunosuppression includes tacrolimus (TAC)/mycophenolate mofetil (MMF)-based regimen and methylprednisolone or prednisone. RESULTS: On the 5th postoperative day, the level of blood creatinine decreased from 590 micromol/L to normal. Daily urine volume was about 2500 ml. On the 18th postoperative day, insulin was given up, and the levels of fasting blood-glucose and after meal blood-glucose were kept normal. No acute rejection symptoms or other complications were observed except infection of Pseudomonas aeruginosa. CONCLUSION: Combined pancreas and kidney transplantation with portal-enteric drainage is a physiological effective treatment for diabetic patients with end-stage renal disease.