Mesenchymal Stem Cells Versus Placebo for Perianal Fistulizing Crohn's Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Mesenchymal stem cells (MSCs)-based therapy for perianal fistulizing Crohn's disease (pfCD) has been extensively studies in the past decade. Its efficacy and safety had been preliminarily confirmed in some phase 2 or phase 3 clinical trials. This meta-analysis is performed to evaluate the efficacy and safety of MSCs-based therapy for pfCD. METHODS: Electronic databases (Pubmed, Cochrane Library, Embase) were searched for studies that reported the efficacy and safety of MSCs. And RevMan were used to assess the efficacy and safety. RESULTS: After screening, 5 randomized controlled trials (RCTs) were included in this meta-analysis. RevMan 5.4 for meta-analysis showed that: [Efficacy] Patients had definite remission after MSCs treatment, with an odds ratio (OR) of 2.06 (P < .0001, 95%CI 1.46, 2.89) vs controls. [Safety] The incidence of the most frequently reported TEAEs (treatment-emergent adverse events, TEAEs), perianal abscess and proctalgia, did not significantly increase due to the use of MSCs, with an OR of 1.07 in perianal abscess (P = .87, 95%CI 0.67, 1.72) vs controls, and an OR of 1.10 in proctalgia (P = .47, 95%CI 0.63, 1.92) vs controls. CONCLUSIONS: MSCs seem to be an effective and safe therapy for pfCD. MSCs based therapy has the potential to be used in combination with traditional therapies.

D3 Versus D2 Lymphadenectomy in Right Hemicolectomy: A Systematic Review and Meta-analysis.

PURPOSE: D3 lymphadenectomy for right colon cancer improves oncological outcomes. This meta-analysis aimed to compare operation data, histopathological characteristics, perioperative conditions, and long-term survival after D3 and D2 lymphadenectomy in right hemicolectomy. METHODS: We searched PubMed, Embase, and the Cochrane Library for relevant articles (up to March 31, 2020). Random-effects and fixed-effects meta-analysis models were used. Review Manager (RevMan) version 5.3 and Stata version 15.1 were used for pooled estimates. RESULTS: After screening 714 articles, 7 articles with a total of 1368 patients were eligible for inclusion. Compared with D2, D3 lymphadenectomy improves results in terms of blood loss (weighted mean difference [WMD] = -20.63, 95% confidence interval [CI] -28.19 to -13.16, P < .01), harvested lymph nodes (WMD = 8.86, 95% CI 7.74 to 9.98, P < .01), 3-year overall survival (OS) (hazard ratio [HR] = 2.03, 95% CI 1.20 to 3.43, P < .01), 5-year OS (HR = 2.22, 95% CI 1.15 to 4.30, P = .02), and 5-year disease-free survival (DFS) (HR = 2.16, 95% CI 1.19 to 3.90, P = .01). There was no significant difference regarding operation time, anastomosis leakage, wound infection, overall morbidity, postoperative hospital stay, mortality, length of dissected colon, and 3-year DFS (P >= .05). CONCLUSIONS: It is suggested in this review that D3 lymphadenectomy is superior to D2 lymphadenectomy in terms of blood loss, harvested lymph nodes, 3-year OS, 5-year OS, and 5-year DFS. The conclusion must be drawn with caution due to the limited number of included studies. Further RCTs are needed for stronger evidence.

Epigallocatechin-3 gallate regulates macrophage subtypes and immunometabolism to ameliorate experimental autoimmune encephalomyelitis.

Epigallocatechin-3 gallate (EGCG) is a polyphenolic component of tea and has potential curative effects in patients with autoimmune diseases. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). It remains unknown whether EGCG can regulate macrophage subtypes in MS. Here we evaluated the effects of EGCG in experimental autoimmune encephalomyelitis (EAE), MS mouse model. We found that EGCG treatment reduced EAE severity and macrophage inflammation in the CNS. Moreover, EAE severity was well correlated with the ratio of M1 to M2 macrophages, and EGCG treatment suppressed M1 macrophage-mediated inflammation in spleen. In vitro experiments showed that EGCG inhibited M1 macrophage polarization, but promoted M2 macrophage polarization. These effects were likely to be related to the inhibition of nuclear factor-κB signaling and glycolysis in macrophages by EGCG in macrophages. Overall, these findings provided important insights into the mechanisms through which EGCG may mediate MS.

Identification and validation of a novel angiogenesis-related gene signature for predicting prognosis in gastric adenocarcinoma.

Background: Angiogenesis is a major promotor of tumor progression and metastasis in gastric adenocarcinoma (STAD). We aimed to develop a novel lncRNA gene signature by identifying angiogenesis-related genes to better predict prognosis in STAD patients. Methods: The expression profiles of angiogenesis-related mRNA and lncRNA genes were collected from The Cancer Genome Atlas (TCGA). Then, the "limma" package was used to identify differentially expressed genes (DEGs). The expression profiles of angiogenesis-related genes were clustered by consumusclusterplus. The Pearson correlation coefficient was further used to identify lncRNAs coexpressed with angiogenesis-related clustere genes. We used Lasso Cox regression analysis to construct the angiogenesis-related lncRNAs signature. Furthermore, the diagnostic accuracy of the prognostic risk signature were validated by the TCGA training set, internal test sets and external test set. We used multifactor Cox analysis to determine that the risk score is an independent prognostic factor different from clinical characteristics. Nomogram has been used to quantitatively determine personal risk in a clinical environment. The ssGSEA method or GSE176307 data were used to evaluate the infiltration state of immune cells or predictive ability for the benefit of immunotherapy by angiogenesis-related lncRNAs signature. Finally, the expression and function of these signature genes were explored by RT-PCR and colony formation assays. Results: Among angiogenesis-related genes clusters, the stable number of clusters was 2. A total of 289 DEGs were identified and 116 lncRNAs were screened to have a significant coexpression relationship with angiogenic DEGs (P value<0.001 and |R| >0.5). A six-gene signature comprising LINC01579, LINC01094, RP11.497E19.1, AC093850.2, RP11.613D13.8, and RP11.384P7.7 was constructed by Lasso Cox regression analysis. The multifactor Cox analysis and Nomogram results showed that our angiogenesis-related lncRNAs signature has good predictive ability for some different clinical factors. For immune, angiogenesis-related lncRNAs signature had the ability to efficiently predict infiltration state of 23 immune cells and immunotherapy. The qPCR analysis showed that the expression levels of the six lncRNA signature genes were all higher in gastric adenocarcinoma tissues than in adjacent tissues. The functional experiment results indicated that downregulation of the expression of these six lncRNA signature genes suppressed the proliferation of ASG and MKN45 cells. Conclusion: Six angiogenesis-related genes were identified and integrated into a novel risk signature that can effectively assess prognosis and provide potential therapeutic targets for STAD patients.

Targeting type Iγ phosphatidylinositol phosphate kinase overcomes oxaliplatin resistance in colorectal cancer.

Rationale: Oxaliplatin is a widely used chemotherapy drug for advanced colorectal cancer (CRC) and its resistance is a major challenge for disease treatment. However, the molecular mechanism underlying oxaliplatin resistance remains largely elusive. Methods: An integrative analysis was performed to determine differentially expressed genes involved in oxaliplatin resistance. Loss- and gain-of-function studies were employed to investigate the roles of type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) on oxaliplatin resistance in CRC cells. Exosomes derived from CRC cell lines were assessed for PD-L1 level and the ability to promote oxaliplatin resistance. Quantitative real-time PCR, immunofluorescence, luciferase reporter assay, Western blotting and other techniques were conducted to decipher the molecular mechanism. Results: PIPKIγ was identified as a critical gene related to oxaliplatin resistance in CRC. Genetic manipulation studies revealed that PIPKIγ profoundly facilitated oxaliplatin resistance and affected the expression of DNA damage repair proteins. Mechanistically, PIPKIγ promoted the expression of the immune checkpoint molecule PD-L1 via activation of NF-κB signaling pathway. Genetic silencing of PD-L1 did not affect CRC cell proliferation but significantly sensitized CRC cells to oxaliplatin. Notably, PD-L1 was revealed to be encapsulated in the exosomes, and the addition of exosomal PD-L1 to sh-PD-L1 CRC cells restored oxaliplatin resistance. Pharmacological hijacking PIPKIγ-exosomal PD-L1 axis largely reduced oxaliplatin resistance in CRC cells. In vivo experiments showed that PD-L1 loss significantly blocked oxaliplatin resistance and the addition of PD-L1-enriched exosomes promoted tumor growth and reduced mouse survival time. Conclusion: Our findings reveal a previous unprecedented role of PIPKIγ in oxaliplatin resistance and provide a key mechanism of exosomal PD-L1 in CRC with potential therapeutics.

Laparoscopic bowel resection combined with infliximab treatment (LaRIC) versus infliximab for terminal ileitis in Crohn's disease: a randomised, controlled, open-label trial.

INTRODUCTION: Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract with an increasing incidence and prevalence worldwide. The early use of anti--tumour necrosis factor agents, such as infliximab, in patients with an aggressive form of Crohn's disease has become part of routine practice. However, infliximab has limitations, and early surgery might benefit patients more. The objective of this study was to compare laparoscopic bowel resection with infliximab treatment in patients with moderately or severely active Crohn's disease with respect to endoscopic remission. The laparoscopic bowel resection combined with infliximab treatment trial is the first randomised controlled trial to demonstrate if early surgery can improve the outcome of patients with Crohn's disease with limited non-stricturing disease treated with infliximab. METHODS AND ANALYSIS: This is a randomised, open-label, controlled trial at Renji Hospital. In this study, a total of 106 adult patients aged 18-80 years with moderately or severely active and steroid-dependent or steroid-resistant Crohn's disease of the distal ileum will be randomly assigned in a 1:1 ratio to the control and surgery groups. The primary outcome is 12-month endoscopic remission measured by the Simple Endoscopic Score for Crohn's Disease in the control group and the Rutgeerts score in the surgery group. The secondary outcomes are clinical remission, surgery rate, quality of life, Crohn's disease-related medical costs and Crohn's disease-related morbidity. The patients will be followed up every 6 months after randomisation through intestinal magnetic resonance enterography and colonoscopy for either 3 years or until clinical remission. ETHICS AND DISSEMINATION: All participants will provide informed consent. The protocol has been approved by the Medical Ethical Committee of the Academic Medical Center in Shanghai (No KY2019-180). Results will be disseminated through peer-reviewed journals and scientific conference presentations. TRIAL REGISTRATION NUMBER: ChiCTR2000029323.