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Background Observational studies on the prognostic role of thyroid transcription factor 1 (TTF-1) in non-small-cell lung cancer (NSCLC) are controversial. Methods To clarify the impact of TTF-1 in NSCLC survival, we performed this meta-analysis that included eligible studies. The combined hazard ratios and their corresponding 95% confidence intervals were calculated in terms of overall survival. Results A total of 17 studies with 2235 patients were evaluable for this meta-analysis. The studies were categorized by histology, disease stage and patient race. Our results suggested that TTF-1 overexpression had a favorable impact on survival of patients with NSCLC, the HR (95% CI) was 0.49 (0.42 to 0.55) overall, 0.46 (0.38–0.54) in Asian patients, 0.52 (0.42–0.63) in non-Asian patients, 0.45 (0.38–0.52) in adenocarcinoma, 0.63 (0.39–0.86) in stage I NSCLC, and 0.43 (0.33–0.53) in stage IIIb–IV NSCLC. The data collected were not sufficient to determine the prognostic value of VEGF in patients with squamous cell lung carcinomas. But there was a high heterogeneity between the studies. Conclusion TTF-1 overexpression indicates a favorable prognosis for patients with NSCLC, this effect appears also significant when the analysis is restricted in lung AC patients, stage I and stage IIIb–IV NSCLC. [ABSTRACT FROM AUTHOR]

• Gentianine alleviates the phenotype in DSS-induced ulcerative colitis. • Gentianine inhibits TLR4/NLRP3 inflammasome activation in colitis. • Gentianine inhibits cell inflammation via inhibition of NLRP3-mediated pyroptosis. Ulcerative colitis (UC) is a common inflammatory bowel disorder. Gentiana scabra Bunge is a traditional medicinal plant that is used to treat a variety of diseases. Studies have shown that gentianine (GTN) from Gentiana scabra inhibits the development of inflammatory diseases. The purpose of this study was to investigate the effect and possible mechanism of action of GTN on UC in mice. An animal model of UC was established using dextran sulfate sodium (DSS). Mice were administered intraperitoneally with GTN (12.5, 25, or 50 mg/kg/day) for seven days. Body weight and disease activity index (DAI) were monitored daily during GTN administration. Colon length, pathological changes, and myeloperoxidase (MPO) activity were measured following GTN administration. The signalling pathways regulated by GTN were analysed using machine learning. HT-29 cells were used to verify the effect and mechanism of action of GTN on UC in vitro. GTN suppressed weight loss, shortened colon length, alleviated colon injury, and reduced the DAI score and MPO activity of mice with UC in a dose-dependent manner. Further analysis showed that GTN inhibited the NOD-like receptor (NLR) signalling pathway. GTN markedly decreased the levels of NLR signalling pathway-related proteins. Moreover, GTN decreased the levels of pyroptosis-related proteins, IL-1β and IL-18. The in vitro data were consistent with those of animal experiments. Furthermore, TLR4 and NLRP3 overexpression eliminated the protective effects of GTN in HT-29 cells. Gentianine alleviated DSS-induced UC by inhibiting TLR4/NLRP3-mediated pyroptosis. [ABSTRACT FROM AUTHOR]

Objective: To explore a method for culturing hepatocellular carcinoma and tumor-infiltrating lymphocytes (HCC-TIL) and investigate the mechanism of TIL in killing tumors. Methods: The distribution of regulatory T cells (Treg) in HCC was detected by immunohistochemistry. Conventional TIL and oligoclonal TIL were isolated by the traditional method of enzyme digestion combined with mechanical treatment for whole HCC and micro HCC tissue block culturing method. MTT was used to compare the killing activity of TIL. Flow cytometry was used to analyze the proportion of CD8+ T cells and Treg cells in TIL. Tumor-bearing mice were established, and TIL adoptive immunotherapy was performed. Results: Treg cells were mainly distributed in the stroma of HCC. In vitro experiments showed oligoclonal TIL had higher cytotoxicity to tumor cells which negatively correlated with the proportion of Treg cells. In vivo experiments showed oligoclonal TIL had a higher anti-tumor effect. IFN-γ in peripheral blood and the positive rate of intratumoral lymphocytic infiltration in oligoclonal TIL group were both higher. TGF-β and IL-10 in peripheral blood and the positive rate of intratumoral FoxP3 and IL-17 were both lower than those in conventional TIL group. Conclusion: The oligoclonal TIL culture method could obtain TIL with higher purity, and cytotoxicity to tumor cells was associated with Treg cells. The oligoclonal TIL had cytotoxicity to autologous HCC cells and significant inhibitory effect on the growth of transplanted tumors. The mechanism might be associated with the inhibition of Treg cells proliferation, increase of IFN-γ secretion, and decrease of TGF-β, IL-10, and IL-17 secretion. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine was reported to have good effects in treating functional constipation. This work attempted to prove the effects of aqueous extracts of Herba Cistanche (AEHC) on STC treatment and to determine the possible mechanisms by a loperamide-induced slow transit constipation (STC) model. HPLC was performed for identification and confirmation of the bioactive components in the AEHC. It was found that AEHC attenuated STC responses based on increased fecal quantity, moisture content, and intestinal transit rate, as well as serum levels of GAS, MTL, SS, and CGRP. The protein and mRNA levels of c-kit, a labeling of interstitial cells of Cajal (ICC), also increased. Meanwhile, only the protein level of SCF, a ligand of c-kit, increased. The analysis of our data suggested that AEHC could obviously improve the function of ICC via a signaling pathway involving PI3K, SCF, and c-kit and enhance colonic motility indices such as GAS, MTL, SS, and CGRP. It is interesting to note that AEHC appeared to be effective on constipation, so further experiments are necessary to clarify the exact mechanisms involved. [ABSTRACT FROM AUTHOR]

Anoikis is a form of apoptosis which occurs when anchorage-dependent cells either show loss of adhesion or inappropriate adhesion. Only a few cancer cells that detach from the primary site of the tumor acquire the ability to resist anoikis and form metastasis. The mechanism underlying the resistance of colorectal cancer (CRC) cells to anoikis remains unclear. Interleukin-8 (alternatively known as CXCL8) is associated with CRC angiogenesis and progression. Here, we found that a high abundance of CXCL8 or TOPK strongly correlated with poor overall and disease-free survival of 186 patients with CRC. A combination of high CXCL8 and high TOPK expressions had the worst prognosis. We showed that CXCL8 expression was negatively correlated with anoikis in CRC cells. CXCL8 treatment enhanced the resistance of CRC cells to apoptosis, which was accompanied by the increase of TOPK, and the activation of AKT and ERK. Moreover, we demonstrated that the inhibition of either ERK or AKT by specific chemical inhibitors attenuated the CXCL8-mediated resistance to anoikis. Treatment with AKT inhibitor abolished the effects of CXCL8 on TOPK expression, suggesting that TOPK was downstream of AKT in the process of anoikis. Taken together, we demonstrated that CXCL8 is strongly implicated in the resistance of CRC cells to anoikis, and that the AKT, TOPK and ERK pathway may be a potential therapeutic target for CRC. [ABSTRACT FROM AUTHOR]

Liver metastases represent the major cause of death in patients with colorectal cancer (CRC). Recent studies have suggested that the chemotactic responses of tumor cells are necessary for metastatic spread to the liver, and CCL20 and CXCL8 have a strong association with CRC metastasis. The aim of our study was to identify the mechanisms by which CCL20 and CXCL8 synergize to promote metastatic progression and evaluated their potential as prognostic markers for CRC patients. The abilities of CCL20 and CXCL8 to promote CRC cell progression and epithelial-mesenchymal transition(EMT)phenotype were analyzed in vitro. Possible signaling pathways were investigated with specific pathway inhibitors and small interfering RNA (siRNA). 213 Patients with CRC who underwent surgery were enrolled for analysis of CCL20, CXCL8 and E-cadherin expressions in tumor tissues. Prognostic factors were then identified. CCL20 or CXCL8 alone was not sufficient to induce complete EMT in CRC cells, but both of them could coordinately induce EMT-like phenotype that was required to maintain CRC cell proliferation, migration and invasion. PI3K/AKT-ERK1/2 pathway crosstalk was demonstrated to be responsible for this process. Coexpression of CCL20 and CXCL8 was negatively correlated with E-cadherin expression in human CRC tissues. CRC patients with coexpression of CCL20 and CXCL8 were more likely to develop liver metastases and both coexpression was an independent high-risk factor for a most poor prognosis. CCL20 and CXCL8 synergize to promote CRC metastatic progression by coordinated induction of EMT via PI3K/AKT-ERK1/2 signaling axis. Detection of both coexpressions can be used to predict clinical outcomes in CRC patients. [ABSTRACT FROM AUTHOR]

Abstract: Liver metastases represent the major cause of death in patients with colorectal cancer (CRC). Recent studies have suggested that the chemotactic responses of tumor cells are necessary for metastatic spread to the liver, and CCL20 and CXCL8 have a strong association with CRC metastasis. The aim of our study was to identify the mechanisms by which CCL20 and CXCL8 synergize to promote metastatic progression and evaluated their potential as prognostic markers forCRC patients. The abilities of CCL20 and CXCL8 to promote CRC cell progression and epithelial–mesenchymal transition(EMT)phenotype were analyzed in vitro. Possible signaling pathways were investigated with specific pathway inhibitors and small interfering RNA (siRNA). 213 Patients with CRC who underwent surgery were enrolled for analysis of CCL20, CXCL8 and E-cadherin expressions in tumor tissues. Prognostic factors were then identified. CCL20 or CXCL8 alonewasnotsufficient toinduce complete EMT in CRC cells, but both of them could coordinately induce EMT-like phenotype that was required to maintain CRC cell proliferation, migration and invasion. PI3K/AKT-ERK1/2 pathway crosstalk was demonstrated to be responsible for this process. Coexpression of CCL20 and CXCL8 was negatively correlated with E-cadherin expression in human CRC tissues. CRC patients with coexpression of CCL20 and CXCL8 were more likely to develop liver metastases and both coexpression was an independent high-risk factor for a most poor prognosis. CCL20 and CXCL8 synergize to promote CRC metastatic progression by coordinated induction of EMT via PI3K/AKT-ERK1/2 signaling axis. Detection of both coexpressions can be used to predict clinicaloutcomes inCRC patients. [Copyright &y& Elsevier]