Tumor-secreted IFI35 promotes proliferation and cytotoxic activity of CD8+ T cells through PI3K/AKT/mTOR signaling pathway in colorectal cancer.

BACKGROUND: A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8+ T cells, and to investigate its effect on CAR-T cells against colorectal cancer. METHODS: Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8+ T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. RESULTS: The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8+ T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8+ T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8+ T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8+ T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. CONCLUSION: Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8+ T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells.

Ulinastatin inhibits the metastasis of nasopharyngeal carcinoma by involving uPA/uPAR signaling.

Distant metastasis is the primary reason for treatment failure in patients with nasopharyngeal carcinoma (NPC). In this study, we investigated the effect of ulinastatin (UTI) on NPC metastasis and its underlying mechanism. Highly-metastatic NPC cell lines S18 and 58F were treated with UTI and the effect on cell proliferation, migration, and invasion were determined by MTS and Transwell assays. S18 cells with luciferase-expressing (S18-1C3) were injected into the left hind footpad of nude mice to establish a model of spontaneous metastasis from the footpad to popliteal lymph node (LN). The luciferase messenger RNA (mRNA) was measured by quantitative polymerase chain reaction (qPCR), and the metastasis inhibition rate was calculated. Key molecular members of the UTI-related uPA, uPAR, and JAT/STAT3 signaling pathways were detected by qPCR and immunoblotting. UTI suppressed the migration and infiltration of S18 and 5-8F cells and suppressed the metastasis of S18 cells in vivo without affecting cell proliferation. uPAR expression decreased from 24 to 48 h after UTI treatment. The antimetastatic effect of UTI is partly due to the suppression of uPA and uPAR. UTI partially suppresses NPC metastasis by downregulating the expression of uPA and uPAR.

Analysis and external validation of a nomogram to predict peritoneal dissemination in gastric cancer.

OBJECTIVE: Peritoneal dissemination is difficult to diagnose by conventional imaging technologies. We aimed to construct a nomogram to predict peritoneal dissemination in gastric cancer (GC) patients. METHODS: We retrospectively analyzed 1,112 GC patients in Sun Yat-sen University Cancer Center between 2001 and 2010 as the development set and 474 patients from The Sixth Affiliated Hospital, Sun Yat-sen University between 2010 and 2016 as the validation set. The clinicopathological variables associated with gastric cancer with peritoneal dissemination (GCPD) were analyzed. We used logistic regression analysis to identify independent risk factors for peritoneal dissemination. Then, we constructed a nomogram for the prediction of GCPD and defined its predictive value with a receiver operating characteristic (ROC) curve. External validation was performed to validate the applicability of the nomogram. RESULTS: In total, 250 patients were histologically identified as having peritoneal dissemination. Logistic regression analysis demonstrated that age, sex, tumor location, tumor size, signet-ring cell carcinoma (SRCC), T stage, N stage and Borrmann classification IV (Borrmann IV) were independent risk factors for peritoneal dissemination. We constructed a nomogram consisting of these eight factors to predict GCPD and found an optimistic predictive capability, with a C-index of 0.791, an area under the curve (AUC) of 0.791, and a 95% confidence interval (95% CI) of 0.762-0.820. The results found in the external validation set were also promising. CONCLUSIONS: We constructed a highly sensitive nomogram that can assist clinicians in the early diagnosis of GCPD and serve as a reference for optimizing clinical management strategies.

Comparative Safety, Efficacy and Survival Outcome of Anti-PD-1 Immunotherapy in Colorectal Cancer Patients With vs Without Hepatitis B Virus Infection: A Multicenter Cohort Study.

INTRODUCTION: Antiprogrammed cell death protein-1 (PD-1) immunotherapy has substantially broadened in scope for the treatment of colorectal cancer (CRC). However, comparative safety, efficacy and survival outcome of anti-PD-1 therapy in CRC patients with and without hepatitis B virus (HBV) infection remain unclear. METHODS: This multicenter, retrospective cohort study included 180 advanced-stage CRC patients with available serological markers for HBV infection treated with anti-PD-1 therapy at the Sixth Affiliated Hospital, Sun Yat-sen University and Sun Yat-sen University Cancer Center between December 2016 and December 2019. A propensity score-matched analysis was performed to compare the safety, efficacy, and survival outcome between HBV and non-HBV groups. RESULTS: The incidences of deficient mismatch repair and metastatic disease were significantly different between HBV and non-HBV groups (both P < 0.05). After propensity score-matched analysis, any grade immune-related adverse events and grade ≥ 3 immune-related adverse events were 47% vs 38% (P = 0.25) and 5% vs 6% (P = 1.0) between HBV and non-HBV groups, respectively. The overall response rate was 39% with 17 complete responses and 13 partial responses for the HBV infection cohort and 39% with 11 complete responses and 19 partial responses for the non-HBV infection cohort (P = 1.0). Two-year progression-free survival rates were 38% vs 40% (P = 0.596) and 2-year overall survival rates were 55% vs 63% (P = 0.401) for HBV vs non-HBV infection cohorts. DISCUSSION: The incidences of toxicity, efficacy and survival outcome were similar between patients with HBV infection and non-HBV patients receiving anti-PD-1 therapy, which supports to include CRC patients with HBV in clinical trials of anti-PD-1 therapy.

Association of Peripheral Blood Biomarkers With Response to Anti-PD-1 Immunotherapy for Patients With Deficient Mismatch Repair Metastatic Colorectal Cancer: A Multicenter Cohort Study.

Purpose: Deficient mismatch repair (dMMR) is an established biomarker for the response to the programmed cell death (PD)-1 inhibitors in metastatic colorectal cancer (mCRC). Although patients with dMMR mCRC could achieve a high incidence of disease control and favorable progression-free survival (PFS), reported response rates to PD-1 inhibitors are variable from 28% to 52%. We aimed to explore the additional predictive biomarkers associated with response to anti-PD-1 immunotherapy in patients with dMMR mCRC. Methods: This multicenter cohort study enrolled patients with dMMR mCRC receiving anti-PD-1 immunotherapy at the Sixth Affiliated Hospital of Sun Yat-sen University and Sun Yat-sen University Cancer Center between December 2016 and December 2019. The total information of 20 peripheral blood biomarkers, including T cells (frequency of CD4+ T cell, frequency of CD8+ T cell, and ratio of CD4+/CD8+), carcinoembryonic antigen (CEA), inflammatory markers, and lipid metabolism markers, was collected. The association between response or survival and peripheral blood parameters was analyzed. Results: Among the tested parameters, the ratio of CD4+/CD8+ and frequency of CD4+ T cell were significantly associated with PFS (p = 0.023, p = 0.012) and overall survival (OS; p = 0.027, p = 0.019) in a univariate analysis. A lower level of CD4+/CD8+ ratio or frequency of CD4+ T cell showed a significant association with better overall response rates (ORRs; p = 0.03, p = 0.01). The ratio of CD4+/CD8+ and frequency of CD4+ T cell maintained significance in multivariate Cox model for PFS (HR = 9.23, p = 0.004; HR = 4.83, p = 0.02) and OS (HR = 15.22, p = 0.009; HR = 16.21, p = 0.025). Conclusion: This study indicated that the ratio of CD4+/CD8+ and the frequency of CD4+ T cell might be crucial independent biomarkers within dMMR mCRC to better identify patients for anti-PD-1 immunotherapy. If validated in prospective clinical trials, the ratio of CD4+/CD8+ and the frequency of CD4+ T cell might aid in guiding the treatment of PD-1 inhibitors among patients with dMMR mCRC.

Effects of hormone replacement therapy on magnetic resonance imaging of brain parenchyma hyperintensities in postmenopausal women.

AIM: To apply 3.0 magnetic resonance imaging (MRI) to study the effects of long-term, low dose hormone replacement therapy (HRT) on the brain parenchyma of postmenopausal women. METHODS: A total of 155 postmenopausal healthy female medical staff members from Peking Union Medical College Hospital were enrolled. The HRT group was composed of 71 subjects who had been given a low dose of HRT for over 4 years, while 84 women who had never been given HRT were enrolled in the control group. The Mini-Mental State Examination (MMSE) was used to evaluate mental state, and an Enzyme-Linked ImmunoSorbent Assay (ELISA) was used to detect plasma levels of sex hormones. In addition, all participants were subjected to an MRI, including axial T2 weighted imaging (T2WI), fluid-attenuated inversion recovery (FLAIR), T1 weighted imaging (T1WI, oblique coronal, vertical to the hippocampus, slice thickness 3 mm without gaps), and a 3D image of the whole brain. RESULTS: The ELISA showed that the plasma level of estradiol in the HRT group was significantly higher than that in the control group (P<0.05). No differences were observed in the MMSE between the two groups. In participants older than 70 years of age, the number of deep white matter hyperintensities (DWMHs) in the control group was significantly higher than that in the HRT group (P=0.0013); however, in other age subgroups, no statistical differences were observed. Finally, no significant difference in periventricular hyperintensity (PVH) between the two groups was observed. CONCLUSION: We found that a high plasma level of estradiol in postmenopausal women receiving long-term HRT was correlated with the survival of brain parenchyma.Acta Pharmacologica Sinica (2009) 30: 1065-1070; doi: 10.1038/aps.2009.81.

Postoperative complications and nutritional status between uncut Roux-en-Y anastomosis and Billroth II anastomosis after D2 distal gastrectomy: a study protocol for a multicenter randomized controlled trial.

BACKGROUND: Gastric cancer is the fourth most common malignant disease worldwide, with lower one-third gastric cancer the most common type. Distal gastrectomy with D2 lymph node dissection was recommended as a standard surgery for distal gastric cancer patients. However, some controversy remains about the anastomosis of the residual stomach and the intestine. The objectives of this trial are to test the hypothesis that uncut Roux-en-Y anastomosis can reduce postoperative complications and improve nutritional status more effectively than Billroth II anastomosis in gastric cancer patients after D2 gastrectomy. METHODS/DESIGN: This multi-center, prospective, phase III, randomized controlled trial will compare the efficacy of uncut Roux-en-Y anastomosis versus Billroth II anastomosis in phase I-III patients with initial treatment of radical distal gastrectomy. Patients will be randomized to undergo either the intervention (uncut Roux-en-Y anastomosis) or the control (Billroth II anastomosis). We will recruit 832 patients who meet the trial eligibility criteria and will follow the patients after surgery to observe postoperative complications and nutrition status for 5 years. The primary assessment indices of the study are reflux gastritis, esophagitis, bile regurgitation, and anastomotic ulcer. The secondary assessment indices are nutritional status, quality of life, perioperative complications, overall survival rate, and others. When the number of cases reaches 400, an interim analysis will be performed to identify any evidence of definite superiority of the experimental intervention. DISCUSSION: We aim to test the hypothesis that uncut Roux-en-Y anastomosis can reduce postoperative complications and improve nutritional status more than Billroth II anastomosis in gastric cancer patients after D2 gastrectomy. The results of the trial will contribute to the best evidence on which to base the reconstruction of distal gastrectomy. TRIAL REGISTRATION: Chinese Southern Gastric Cancer Conference CSGC002 Trial. ClinicalTrials.gov, NCT02763878 . Registered on 5 May 2016.

The Development and Future of Digestive Tract Reconstruction after Distal Gastrectomy: A Systemic Review and Meta-Analysis.

Background: Billroth I, Billroth II, Roux-en-Y, and Un-cut Roux-en-Y are common reconstruction techniques of distal gastrectomy. Which of these techniques is better has yet to be established. We performed an indirect comparison to evaluate which technique was optimal for preventing reflux symptoms. Methods: The PubMed, Cochrane Collaboration, Embase, ClinicalTrials.gov and Web of Science databases were searched to identify clinical trials that compared at least two of the reconstruction skills among Billroth I, Billroth II, Roux-en-Y, and Un-cut Roux-en-Y. Data on reflux gastritis, intraoperative blood loss, bile reflux and postoperative hospital stays were extracted from the included clinical trials for meta-analysis using a random-effects model. Results: Twenty-four articles that included 5419 individuals were assessed as eligible for meta-analysis. The indirect comparison suggested that Roux-en-Y reconstruction significantly reduces reflux gastritis, and it tended to rank first and had the highest probability of preventing bile reflux. No significant differences were found in intraoperative blood loss and postoperative hospital stays. Conclusion: This indirect comparison suggested some superiority of Roux-en-Y reconstruction after distal gastrectomy. Further perspective clinical trials are required to provide evidence for the optimal reconstruction skill.