Clinical activity and safety of sintilimab, bevacizumab, and TMZ in patients with recurrent glioblastoma.

PURPOSE: There are limited and no standard therapies for recurrent glioblastoma. We herein report the antitumour activity and safety of sintilimab, bevacizumab and temozolomide (TMZ) in recurrent glioblastoma. METHODS: We retrospectively analysed eight patients with recurrent glioblastoma treated with sintilimab (200 mg) every three weeks + bevacizumab (10 mg/kg) every three weeks + TMZ (200 mg/m²orally) (5 days orally every 28 days for a total of four weeks). The primary objective was investigator-assessed median progression-free survival(mPFS). Secondary objectives were to assess the 6-month PFS, objective response rate (ORR) and duration of response (DOR) accroding to RANO criteria. RESULTS: The mPFS time for 8 patients was 3.340 months (95% CI: 2.217-4.463), The longest PFS was close to 9 months. Five patients were assessed to have achieved partial response (PR), with an overall remission rate of 62.5%, Four patients experienced a change in tumour volume at the best response time of greater than 60% shrinkage from baseline, and one patient remained progression free upon review, with a DOR of more than 6.57 months. The 6-month PFS was 25% (95% CI: 5.0-55.0%). Three patients had a treatment-related adverse events, though no grade 4 or 5 adverse events occurred. CONCLUSION: In this small retrospective study, the combination regimen of sintilimab, bevacizumab and TMZ showed promising antitumour activity in treatment of recurrent glioblastoma, with a good objective remission rate.

LHX2 facilitates the progression of nasopharyngeal carcinoma via activation of the FGF1/FGFR axis.

BACKGROUND: Distant metastasis and recurrence remain the main obstacle to nasopharyngeal carcinoma (NPC) treatment. However, the molecular mechanisms underlying NPC growth and metastasis are poorly understood. METHODS: LHX2 expression was examined in NPC cell lines and NPC tissues using quantitative reverse transcription-polymerase chain reaction, western blotting and Immunohistochemistry assay. NPC cells overexpressing or silencing LHX2 were used to perform CCK-8 assay, colony-formation assay, EdU assay, wound-healing and invasion assays in vitro. Xenograft tumour models and lung metastasis models were involved for the in vivo assays. The Gene Set Enrichment Analysis (GSEA), ELISA assay, western blot, chromatin immunoprecipitation (ChIP) assay and Luciferase reporter assay were applied for the downstream target mechanism investigation. RESULTS: LIM-homeodomain transcription factor 2 (LHX2) was upregulated in NPC tissues and cell lines. Elevated LHX2 was closely associated with poor survival in NPC patients. Ectopic LHX2 overexpression dramatically promoted the growth, migration and invasion of NPC cells both in vitro and in vivo. Mechanistically, LHX2 transcriptionally increased the fibroblast growth factor 1 (FGF1) expression, which in turn activated the phosphorylation of STAT3 (signal transducer and activator of transcription 3), ERK1/2 (extracellular regulated protein kinases 1/2) and AKT signalling pathways in an autocrine and paracrine manner, thereby promoting the growth and metastasis of NPC. Inhibition of FGF1 with siRNA or FGFR inhibitor blocked LHX2-induced nasopharyngeal carcinoma cell growth, migration and invasion. CONCLUSIONS: Our study identifies the LHX2-FGF1-FGFR axis plays a key role in NPC progression and provides a potential target for NPC therapy.

CMTM6 promotes migration, invasion, and EMT by interacting with and stabilizing vimentin in hepatocellular carcinoma cells.

BACKGROUND: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) has been associated with the development in many kinds of cancers. However, the roles of CMTM6 in hepatocellular carcinoma (HCC) are largely unknown. Thus, the present study aimed to investigate the function of CMTM6 in HCC. METHODS: We analysed CMTM6 levels and functions using human HCC cell lines, paired HCC and adjacent non-tumorous tissues, and a tissue microarray. CMTM6 expression was silenced using short hairpin RNAs and its was overexpressed from a lentivirus vector. CMTM6 mRNA and protein levels were determined using quantitative real-time reverse transcription PCR and western blotting, respectively. Proliferation, colony formation, migration, and invasion were assessed using a Cell counting kit-8, colony formation, wound-healing, and Matrigel invasion assays, respectively. Immunohistochemistry was used to score the expression of CMTM6 in tissue samples. The localization and binding partners of CMTM6 were investigated using immunofluorescence and coimmunoprecipitation experiments, respectively. A mouse xenograft model was used for in vivo studies. RESULTS: Compared with that in adjacent, non-cancerous tissue, Here, CMTM6 levels were increased in HCC tissue samples. Silencing of CMTM6 suppressed the proliferation, migration, and invasion of HCC cells. Conversely, CMTM6 overexpression enhanced HCC cell invasion, migration, and proliferation. Mechanistically, CMTM6 physically interacts with and stabilizes vimentin, thus inducing epithelial-mesenchymal transition (EMT), which promotes proliferation, migration and invasion. Importantly, in HCC tissues, CMTM6 expression correlated positively with vimentin levels. Poor prognosis of HCC was associated significantly with higher CMTM6 expression. CONCLUSIONS: CMTM6 has an important function in HCC proliferation, migration, and invasion, via its interaction with and stabilization of vimentin. CMTM6 might represent a potential biomarker and therapeutic target to treat HCC.

Pan-cancer analyses reveal genomics and clinical characteristics of the melatonergic regulators in cancer.

Melatonin, an endogenous hormone, plays protective roles in cancer. In addition to regulating circadian rhythms, sleep, and neuroendocrine activity, melatonin functions in various survival pathways. However, the mechanisms of melatonin regulation in cancer remain unknown. In the present study, we performed a comprehensive characterization of melatonin regulators in 9125 tumor samples across 33 cancer types using multi-omic data from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia. In the genomic landscape, we identified the heterozygous amplification of AANAT and GPR50, and heterozygous deletion of PER3, CYP2C19, and MTNR1A as the dominant alteration events. Expression analysis revealed methylation-mediated downregulation of melatonergic regulator expression. In addition, we found that melatonergic regulator expression could be used to predict patient survival in various cancers. In depth, microRNA (miRNA) analysis revealed an miRNA-mRNA interaction network, and the deregulated miRNAs were involved in melatonin secretion and metabolism by targeting circadian clock genes. Pathway analysis showed that melatonergic regulators were associated with inhibition of apoptosis, the cell cycle, the DNA damage response, and activation of RAS/MAPK and RTK signaling pathways. Importantly, by mining the Genomics of Drug Sensitivity in Cancer database, we discovered a number of potential drugs that might target melatonergic regulators. In summary, this study revealed the genomic alteration and clinical characteristics of melatonergic regulators across 33 cancers, which might clarify the relationship between melatonin and tumorigenesis. Our findings also might provide a novel approach for the clinical treatment of cancers.

A signature based on circadian rhythm-associated genes for the evaluation of prognosis and the tumour microenvironment in HNSCC.

The morbidity and mortality rates of head and neck squamous cell carcinoma (HNSCC) remain high worldwide. Therefore, there is an urgent need to identify a new prognostic biomarker to guide the personalized treatment of HNSCC patients. Increasing evidence suggests that circadian rhythm genes play an important role in the development and progression of cancer. We aimed to explore the value of circadian rhythm genes in predicting prognosis and guiding the treatment of HNSCC. We first obtained a list of circadian rhythm genes from previous research. The sequencing data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Finally, univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox proportional hazard analysis were performed to develop a prognostic signature (Circadian Rhythm-Related Gene Prognostic Index, CRRGPI) consisting of nine circadian rhythm genes. The signature exhibited good performance in predicting overall survival. Patients with low CRRGPI scores had lower metabolic activities and an active antitumour immunity ability. Additionally, a clinical cohort was used to further evaluate the ability of the CRRGPI to predict the efficacy of immune checkpoint inhibitors. In conclusion, the novel circadian rhythm-related gene signature can provide a precise prognostic evaluation with the potential capacity to guide individualized treatment regimens for HNSCC patients.

Causal association between metabolites and upper gastrointestinal tumors: A Mendelian randomization study.

Upper gastrointestinal (UGI) tumors, notably gastric cancer (GC) and esophageal cancer (EC), are significant global health concerns due to their high morbidity and mortality rates. However, only a limited number of metabolites have been identified as biomarkers for these cancers. To explore the association between metabolites and UGI tumors, the present study conducted a comprehensive two­sample Mendelian randomization (MR) analysis using publicly available genetic data. In the present study, the causal relationships were examined between 1,400 metabolites and UGI cancer using methods such as inverse variance weighting and weighted medians, along with sensitivity analyses for heterogeneity and pleiotropy. Functional experiments were conducted to validate the MR results. The analysis identified 57 metabolites associated with EC and 58 with GC. Key metabolites included fructosyllysine [EC: Odds ratio (OR)=1.450, 95% confidence interval (CI)=1.087­1.934, P=0.011; GC: OR=1.728, 95% CI=1.202­2.483, P=0.003], 2'­deoxyuridine to cytidine ratio (EC: OR=1.464, 95% CI=1.111­1.929, P=0.007; GC: OR=1.464, 95% CI=1.094­1.957, P=0.010) and carnitine to protonylcarnitine (C3) ratio (EC: OR=0.655, 95% CI=0.499­0.861, P=0.002; GC: OR=0.664, 95% CI=0.486­0.906, P=0.010). Notably, fructosyllysine levels and the 2'­deoxyuridine to cytidine ratio were identified as risk factors for both EC and GC, while the C3 ratio served as a protective factor. Functional experiments demonstrated that fructosyllysine and the 2'­deoxyuridine to cytidine ratio promoted the proliferation of EC and GC cells, whereas carnitine inhibited their proliferation. In conclusion, the present findings provide insights into the causal factors and biomarkers associated with UGI tumors, which may be instrumental in guiding targeted dietary and pharmacological interventions, thereby contributing to the prevention and treatment of UGI cancer.

Phosphate-to-alanine ratio and bilirubin-to-androsterone glucuronide ratio are the hub metabolites in upper gastrointestinal cancers: a Mendelian randomisation (MR) study.

Objective: Upper gastrointestinal (UGI) cancers, particularly esophageal cancer (EC) and gastric cancer (GC) represent a significant health burden with complex etiologies. Metabolic alterations are known to play a crucial role in cancer development and progression. Identifying key metabolic biomarkers may offer insights into the pathophysiology of UGI cancers and potential therapeutic targets. This study aimed to investigate the causal associations between 1,400 types of metabolites, specifically phosphate-to-alanine and bilirubin-to-androsterone glucuronide, and the risk of developing UGI cancers using Mendelian randomisation (MR) analysis. Method: We conducted a two-sample MR study utilising genetic instruments identified from large-scale genome-wide association studies (GWASs) for metabolic traits. The outcomes were derived from GWAS datasets of UGI cancer patients, including EC and GC. Several MR methods were employed to ensure the robustness of the findings, including inverse variance weighted (IVW), MR-Egger and weighted median approaches. Results: Our analysis found a total of 44 metabolites associated with EC and 15 metabolites associated with GC. The MR analyses revealed a significant causal relationship between the phosphate-to-alanine ratio (EC: OR = 1.002,95% CI = 1.00034-1.0037, p = 0.0037; GC: OR = 1.24,95% CI = 1.046-1.476, p = 0.01) and increased risk of UGI cancers. In contrast, the bilirubin-to-androsterone glucuronide ratio (EC: OR = 0.998,95% CI = 0.997-0.999, p = 0.03; GC: OR = 0.80,95% CI = 0.656-0.991, p = 0.04) was inversely associated with the risk, suggesting a potential protective effect. Conclusion: Our findings suggest that the phosphate-to-alanine ratio and bilirubin-to-androsterone glucuronide ratio are key hub metabolites in the etiology of UGI cancers. These metabolic ratios could serve as potential biomarkers for early detection or targets for therapeutic intervention. Further research is warranted to elucidate the underlying biological mechanisms and to validate the clinical utility of these associations.

Cancer-Associated Fibroblasts Promote Radioresistance of Breast Cancer Cells via the HGF/c-Met Signaling Pathway.

PURPOSE: Cancer-associated fibroblasts (CAFs) are an integral part of the tumor microenvironment (TME), which is involved in therapy resistance. This study aimed to investigate the role of CAFs in radiosensitivity of breast cancer cells. METHODS AND MATERIALS: The CAFs were isolated from the breast cancer tissues, and the conditioned medium was collected to culture breast cancer cells. Radiation-induced DNA damage was evaluated by immunofluorescence and western blotting. Cytokine array and enzyme-linked immunosorbent assay were performed to analyze the secretion of cytokines and growth factors. An in vitro clonogenic survival assay and in vivo xenograft mouse model were performed to determine the radiosensitivity of breast cancer cells. Finally, the expression of hepatocyte growth factor (HGF) and c-Met in the breast cancer tissues were detected by immunohistochemistry. RESULTS: The CAFs were found to secrete HGF to activate the c-Met signaling pathway, which induced epithelial-to-mesenchymal transition, growth, and radioresistance of breast cancer cells. Furthermore, radiation was observed to enhance HGF secretion by CAFs and increase c-Met expression in breast cancer cells, which led to HGF/c-Met signaling pathway activation. Moreover, radiation-induced tumor necrosis factor α (TNFα) secretion by breast cancer cells promoted CAF proliferation and HGF secretion. Additionally, HGF and c-Met high expression were associated with worse recurrence-free survival in patients with breast cancer who had received radiation therapy. CONCLUSIONS: The findings revealed that HGF and TNFα are critical for the crosstalk between breast cancer cells and CAFs in the TME and that the HGF/c-Met signaling pathway is a promising therapeutic target for radiosensitizing breast cancer.

PD-L1 expression as biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in metastatic triple negative breast cancer: A systematic review and meta-analysis.

Background: Inhibitors of programmed cell death 1 (PD-1)/programmed cell death ligand 1(PD-L1) checkpoint have been approved for metastatic triple negative breast cancer (mTNBC) in patients positive for PD-L1 expression. Negative results from the recent phase III trials (IMPassion131 and IMPassion132) have raises questions on the efficacy of PD-1/PD-L1 checkpoint inhibitors and the predictive value of PD-L1 expression. Here we attempt to systematically analyze the biomarker value of PD-L1 expression for predicting the response of PD-1/PD-L1 checkpoint inhibitors in mTNBC. Materials and methods: PubMed database was searched until Dec 2021 for studies evaluating PD-1/PD-L1 checkpoint inhibitors plus/minus chemotherapy in mTNBC. Outcome of interest included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Review Manager (RevMan) version 5.4. was used for data-analysis. Results: In total, 20 clinical trials comprising 3962 mTNBC patients (ICT: 2665 (67%); CT: 1297 (33%) were included in this study. Overall ORR was 22% (95%CI, 14-30%) and significant improvement was observed for PD-L1+ patients (ORR 1.78 [95%CI, 1.45-2.19], p<0.00001) as compared to PD-L1- cohort. Pooled outcome also indicated a significant 1-year PFS and 2-year OS advantage for patients with PD-L1 expression (1-year PFS: ORR 1.39 [95%CI, 1.04-1.85], p=0.02; I2 = 0%; 2-year OS: (ORR 2.47 [95%CI, 1.30-4.69], p=0.006; I2 = 63%). Subgroup analysis indicated that PD-L1 expression can successfully predict tumor response and 2-year OS benefit in mTNBC patients regardless of the type of investigating agent, line of treatment administration, and to some extent the type of treatment. Biomarker ability of PD-L1 expression to predict 1-year PFS was slightly better with pembrolizumab (p=0.09) than atezolizumab (p=0.18), and significantly better when treatment was administered in the first-line setting (OR 1.38 [95%CI, 1.02-1.87], p=0.04) and chemotherapy was added (OR 1.38 [95%CI, 1.02-1.86], p=0.03). Immune-related toxicity of any grade and grade≥3 was 39% (95%CI, 26%-52%) and 10% (95%CI, 8%-13%), respectively. Conclusions: PD-L1 expression can predict objective response rate and 2-year OS in mTNBC patients receiving PD-1/PD-L1 checkpoint inhibitors. One-year PFS is also predicted in selected patients. PD-L1 expression can be a useful biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in mTNBC.

A Meta-analysis of Total Neoadjuvant Therapies Combining Chemoradiotherapy with Induction or Consolidated Chemotherapy for Locally Advanced Rectal Cancer.

OBJECTIVE: Total neoadjuvant therapy (TNT) combining chemoradiotherapy (CRT) with chemotherapy (CT) was a novel pre-surgical approach to cancer treatment. This meta-analysis aimed to compare the clinical outcomes between neoadjuvant CRT (nCRT) with induction CT and nCRT with consolidated CT in locally advanced rectal cancer (LARC) patients. METHOD: In July 2022, a literature search was conducted using the following public databases: PubMed, MEDLINE, Embase, the Cochrane Library, and Web of Science, retrieved all relevant articles comparing nCRT-combining induction CT with nCRT-combining-consolidated CT treatments for LARC patients. RESULTS: Four eligible studies were identified, including a total of 995 LARC patients: 473 in the nCRT with consolidated CT group and 522 in the nCRT with induction CT group. The organ preservation (OP) rate of the nCRT with consolidated CT group was higher than that of the nCRT with induction CT group (RR [relative risk]: 1.53; 95% CI (confidence interval): 1.09-2.14). The pathological complete response (PCR, RR: 1.22; 95% CI 0.37-2.17), the 3-year disease-free survival (DFS, RR 1.02; 95% CI 0.71-1.46), the local recurrence (LR, RR 0.98; 95% CI 0.52-1.85), rates of R0 resection (RR 0.74; 95% CI 0.55-1.10), compliance (RR 0.52; 95% CI 0.12-2.26), and grade 3--4 toxicities (RR 0.78; 95% CI 0.57-1.06) were all similar between the two groups. CONCLUSION: In this meta-analysis of TNT regimens for rectal cancer, consolidative CT following nCRT was associated with similar PCR, 3-year DFS, LR, R0 resection, compliance, and grade 3-4 toxicities compared to induction CT prior to nCRT but a higher rate of organ preservation.

Efficacy of adjuvant chemotherapy/maintenance chemotherapy after induction chemotherapy and concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Experiences of two centers.

BACKGROUND AND OBJECTIVE: In general, there are not many studies exploring the clinical value of adjuvant chemotherapy or maintenance chemotherapy (AC/MC) after induction chemotherapy and concurrent chemoradiotherapy (IC+CCRT+AC/MC). The purpose of this study was to establish a clinical nomogram for the use of AC/MC in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). MATERIAL AND METHODS: Two centers (Guangzhou Medical University Cancer Center [N = 1226] and Zhongshan People's Hospital [N = 150]) recruited 1376 patients with LA-NPC. All the patients underwent IC+CCRT; 560 patients received AC with cisplatin/nedaplatin plus docetaxel/paclitaxel (TP) or cisplatin/nedaplatin plus fluorouracil (PF), and 81 patients received MC with S-1. Multivariate Cox regression was used to confirm optimal predictors of progression-free survival (PFS), and a nomogram was established to identify patients into low-risk and high-risk cohorts. Additionally, bootstrap internal validation was performed to further verify our nomogram. RESULTS: After propensity score matching (PSM), the survival curves were not statistically different between IC+CCRT+AC/MC and IC+CCRT (all p > 0.05). Then, a nomogram was developed based on variables that were screened by univariate and multivariate Cox regression, including N stage, cumulative platinum dose during CCRT, body mass index (BMI), IC cycles, IC regimen and cervical lymph node (CLN) necrosis and infiltration of adjacent tissues. The results of the nomogram showed that the high-risk cohort had greatly worse 5-year DMFS, LRFS, PFS and OS compared to low-risk cohort (all p < 0.05), and subgroup analysis found that the 5-year DMFS, PFS and OS of patients treated with IC+CCRT+AC/MC were better than those treated with IC+CCRT in high-risk cohort (all p < 0.05). Notably, the incidence of adverse effects for IC+CCRT+AC cohort was higher than that for IC+CCRT+MC cohort, especially leukocytopenia and neutropenia. IC+CCRT and IC+CCRT+MC were associated with similar incidences of adverse effects. CONCLUSIONS: The addition of AC or MC to IC+CCRT could improve the DMFS of patients with high-risk NPC and prolong their survival. Additionally, our findings suggest a potential role of AC/MC following IC plus CCRT in the treatment of high-risk LA-NPC.

Comparative analysis of immune checkpoint inhibitors in first-line treatment of esophageal squamous cell carcinoma: a network meta-analysis.

Aim: To evaluate the efficacy and safety of first-line immunochemotherapy in the treatment of advanced esophageal squamous cell carcinoma (CRD42021287033). Methods: PubMed, Embase, Cochrane Library and Web of Science were systematically searched to obtain randomized controlled trials, and the outcome indicators of the reports were compared and analyzed. Results: A total of 3163 patients from five reported randomized controlled trials were included in the meta-analysis. The results showed the comprehensive benefits of toripalimab combined with chemotherapy, in terms of overall survival (hazard ratio: 0.59; 95% CI: 0.43-0.81) and progression-free survival (hazard ratio: 0.58; 95% CI: 0.46-0.73). Conclusion: Toripalimab combined with chemotherapy may be a better choice for first-line immunochemotherapy, although this needs to be verified by clinical studies.

The treatment of cancer is an issue of importance to the general public. A number of drugs are available to treat cancer, including those that enhance the body's natural defense. Such drugs are also the first choice for cancer of the esophagus, which cannot be removed surgically. In this study, we analyzed five different first-choice drugs in different ways, including how long the patient survives and how long the patient lives without their disease getting worse. We found that toripalimab, which strengthens the body's natural defense, may be the best combination choice for use in combination with chemotherapy. Although further studies are needed to increase the reliability of the conclusions, we preliminarily consider that this drug is particularly promising.

Adjuvant chemotherapy following combined induction chemotherapy and concurrent chemoradiotherapy improves survival in N2-3-positive nasopharyngeal carcinoma patients.

OBJECTIVE: This study aimed to explore the clinical value of adjuvant chemotherapy (ACT) following concurrent chemo-radiotherapy (CCRT) and induction chemotherapy (ICT) in loco-regionally advanced nasopharyngeal carcinoma (LANC). METHODS: We included 839 newly diagnosed LANC patients in this study. ICT plus CCRT (ICT + CCRT group) was administered to 443 patients, and 396 patients received ACT after ICT plus CCRT (ICT + CCRT + ACT group). Univariate and multivariate Cox regression analyses were carried out. Furthermore, propensity score matching (PSM) was applied to balance the study and control groups. RESULTS: A total of 373 pairs of LANC patients were obtained after PSM analysis. We found that ACT following ICT + CCRT has no significant effect on improving the survival of LANC patients. By further exploring the ICT + CCRT + ACT treatment protocol, we excluded N0-1-positive patients and re-performed PSM in the ICT + CCRT and ICT + CCRT + ACT groups. Each group consisted of 237 patients. Kaplan-Meier analysis revealed that there were differences between the ICT + CCRT and ICT + CCRT + ACT groups in terms of the 5-year overall survival (OS) (78.9% vs. 85.0%, P = 0.034), disease-free survival (DFS) (73.4% vs. 81.7%, P = 0.029), and distant metastasis-free survival (DMFS) (84.9% vs. 76.0%, P = 0.019). In addition, the ICT + CCRT + ACT group had a higher incidence of grade 3/4 acute leukocytopenia/neutropenia. CONCLUSION: Compared with ICT + CCRT, ACT following ICT plus CCRT can reduce distant metastasis of N2-3-positive LANC and improve the OS and DFS. The results demonstrated the feasibility and clinical utility of ACT following ICT plus CCRT.

Integrative Pan-Cancer Analysis Confirmed that FCGR3A is a Candidate Biomarker Associated With Tumor Immunity.

Background: Fc gamma receptor 3A (FCGR3A) encodes a receptor for the Fc portion of immunoglobulin G, which plays a significant role in the immune response. However, the role of FCGR3A in cancers remains unclear. This study aimed to visualize the prognostic landscape of FCGR3A in pan-cancer and investigate the relationship between FCGR3A expression and tumor microenvironment. Method: Based on the TCGA database, GTEx database, and GDSC database, we analyzed the expression of FCGR3A in pan-cancers and adjacent normal tissues and its relationship with prognosis, immune cells infiltration, immune-related genes, DNA mismatch repair (MMR) genes, DNA methylation, and drugs sensitivity. The gene alteration frequency of FCGR3A was acquired on the cBioportal website. Moreover, we constructed PPI networks, performed GO and KEGG analysis to illustrate the function, and signaling pathways of FCGR3A-related genes, and conducted gene set enrichment analysis (GSEA) of FCGR3A to further explore its potential biological functions. Result: The differential analysis results of the publicly available databases showed that FCGR3A was generally highly expressed in pan-cancer. Survival analysis revealed that FCGR3A predominated as a risk prognostic factor in most cancers. Additionally, the expression of FCGR3A was confirmed to be associated with several immune cells infiltration, multiple immune checkpoint genes, and DNA mismatch repair genes expression in generalized carcinoma. We also identified a negative correlation between FCGR3A and DNA methylation levels. Through GO/KEGG and GESA, we found that FCGR3A was involved in many pathologic and physiological processes, and was most closely related to tumor immune-related pathways. Drug sensitivity analysis showed that higher FCGR3A expression predicts a low IC50 value for the vast majority of drugs. Conclusions: FCGR3A may be an immune-oncogenic molecule that correlates with tumor immune infiltration levels and affects drug sensitivity, thus it can be served as a promising biomarker for cancer detection, prognosis, therapeutic design, and follow-up.

A Metabolism-Related Gene Prognostic Index Bridging Metabolic Signatures and Antitumor Immune Cycling in Head and Neck Squamous Cell Carcinoma.

Background: In the era of immunotherapy, predictive or prognostic biomarkers for head and neck squamous cell carcinoma (HNSCC) are urgently needed. Metabolic reprogramming in the tumor microenvironment (TME) is a non-negligible reason for the low therapeutic response to immune checkpoint inhibitor (ICI) therapy. We aimed to construct a metabolism-related gene prognostic index (MRGPI) for HNSCC bridging metabolic characteristics and antitumor immune cycling and identified the immunophenotype, genetic alternations, potential targeted inhibitors, and the benefit of immunotherapy in MRGPI-defined subgroups of HNSCC. Methods: Based on The Cancer Genome Atlas (TCGA) HNSCC dataset (n = 502), metabolism-related hub genes were identified by the weighted gene co-expression network analysis (WGCNA). Seven genes were identified to construct the MRGPI by using the Cox regression method and validated with an HNSCC dataset (n = 270) from the Gene Expression Omnibus (GEO) database. Afterward, the prognostic value, metabolic activities, genetic alternations, gene set enrichment analysis (GSEA), immunophenotype, Connectivity map (cMAP), and benefit of immunotherapy in MRGPI-defined subgroups were analyzed. Results: The MRGPI was constructed based on HPRT1, AGPAT4, AMY2B, ACADL, CKM, PLA2G2D, and ADA. Patients in the low-MRGPI group had better overall survival than those in the high-MRGPI group, consistent with the results in the GEO cohort (cutoff value = 1.01). Patients with a low MRGPI score display lower metabolic activities and an active antitumor immunity status and more benefit from immunotherapy. In contrast, a higher MRGPI score was correlated with higher metabolic activities, more TP53 mutation rate, lower antitumor immunity ability, an immunosuppressive TME, and less benefit from immunotherapy. Conclusion: The MRGPI is a promising indicator to distinguish the prognosis, the metabolic, molecular, and immune phenotype, and the benefit from immunotherapy in HNSCC.

Diblock Copolymers Containing Titanium-Hybridized Polyhedral Oligomeric Silsesquioxane Used as a Macromolecular Flame Retardant for Epoxy Resin.

In this paper, the 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO)-containing diblock copolymer poly[(p-hydroxybenzaldehyde methacrylate)m-b-(2-((6-oxidodibenzo[c,e][1,2]oxaphosphinin-6-yl)oxy)ethyl methacrylate)n] (abbrev. poly(HAMAm-b-HEPOMAn)) was synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. When it was continued to react with titanium-hybridized aminopropyl-polyhedral oligomeric silsesquioxane (Ti-POSS) through a Schiff-base reaction, new grafted copolymers poly[(Ti-POSS-HAMA)m-b-HEPOMAn] (abbrev. PolyTi) were obtained. Then, they were used as macromolecular flame retardant to modify epoxy resin materials. The thermal, flame retardant and mechanical properties of the prepared EP/PolyTi composites were tested by TGA, DSC, LOI, UL-94, SEM, Raman, DMA, etc. The migration of phosphorus moiety from epoxy resin composites was analyzed by immersing the composites into ethanol/H2O solution and recording the extraction solution by UV-Vis spectroscopy. The results showed that the added PolyTi enhanced the glass transition temperature, the carbon residue, the graphitization of char, LOI, and mechanical properties of the EP/PolyTi composites when compared to pure cured EP. Furthermore, the phosphorus moieties were more likely to migrate from EP/DOPO composites than that from EP/PolyTi composites. Obviously, compared with small molecular flame retardant modified EP, the macromolecular flame retardant modified EP/PolyTi composites exhibited better thermal stability, flame retardancy, and resistance to migration.

A Multi-Omics Pan-Cancer Analysis of 4EBP1 in Cancer Prognosis and Cancer-Associated Fibroblasts Infiltration.

Background: Eukaryotic Translation Initiation Factor 4E Binding Protein 1 (4EBP1) involved in inhibition of protein translation and synthesis. However, the phosphoprotein of 4EBP1 (p-4EBP1) promotes the translation and synthesis of several proteins, including multiple classic oncogenic proteins. The prognostic significance of 4EBP1 mRNA, 4EBP1 protein, and p-4EBP1 in Pan-cancer are still unclear. Methods: In this study, we provided a multi-Omics investigation for the prognostic value of 4EBP1 mRNA, 4EBP1 protein, and different 4EBP1 phosphoproteins in a Pan-cancer manner based on the TCGA projects. We explored the correlation between 4EBP1 expression and the cancer-associated fibroblast (CAFs) infiltration, respectively using the EPIC, MCPCOUNTER, and TIDE algorithms. The functional states of 4EBP1 were explored using single-cell sequencing analysis in Pan-Cancer. Immunohistochemistry staining was used to detect and verify the expression of 4EBP1 in several cancers. Results: 4EBP1 mRNA was aberrantly overexpressed in most cancers, and was associated with the poor prognosis in ten cancers. Notably, increased 4EBP1 mRNA expression significantly correlated with tumor staging and worse prognosis in BRCA, KIRC, and KIRP, while having the opposite effect in STAD. 4EBP1 expression was associated with the CAFs infiltration level in ten cancer types. Interestingly, the correlation between 4EBP1 and CAFs infiltration had pronounced heterogeneity in digestive system tumors and urinary system tumors. In BLCA, KIRC, and ACC as well as BRCA, 4EBP1 was significantly positively correlated with CAFs infiltration and was associated with a poor prognosis. In STAD and COAD, 4EBP1 is negatively correlated with CAFs infiltration and was associated with a better prognosis. Lastly, the expression and prognostic significance of 4EBP1 protein and different p-4EBP1 varied enormously among cancers. Conclusion: Our multi-omics study indicates that 4EBP1-driven CAFs infiltration is associated with cancer prognosis and 4EBP1 mRNA, 4EBP1 protein, and p-4EBP1 proteins may serve as potential prognostic biomarkers and therapeutic targets in diverse cancer.

Exosomal B7-H4 from irradiated glioblastoma cells contributes to increase FoxP3 expression of differentiating Th1 cells and promotes tumor growth.

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor. Although numerous postoperative therapeutic strategies have already been developed, including radiotherapy, tumors inevitably recur after several years of treatment. The coinhibitory molecule B7-H4 negatively regulates T cell immune responses and promotes immune escape. Exosomes mediate intercellular communication and initiate immune evasion in the tumor microenvironment (TME). OBJECTIVE: This study aimed to determine whether B7-H4 is upregulated by radiation and loaded into exosomes, thus contributing to immunosuppression and enhancing tumor growth. METHODS: Iodixanol density-gradient centrifugation and flow cytometry were used to verify exosomal B7-H4. Naïve T cells were differentiated into Th1 cells, with or without exosomes. T cell-secreted cytokines and markers of T cell subsets were measured. Mechanistically, the roles of B7-H4, and ALIX in GBM were analyzed using databases and tissue samples. Co-immunoprecipitation, and pull-down assays were used to tested the direct interactions between ATM and ALIX or STAT3. In vitro ATM kinase assays, western blotting, and site-directed mutation were used to assess ATM-mediated STAT3 phosphorylation. Finally, the contribution of exosomal B7-H4 to immunosuppression and tumor growth was investigated in vivo. RESULTS: Exosomes from irradiated GBM cells decreased the anti-tumor immune response of T cell in vitro and in vivo via delivered B7-H4. Mechanistically, irradiation promoted exosome biogenesis by increasing the ATM-ALIX interaction. Furthermore, the ATM-phosphorylated STAT3 was found to directly binds to the B7-H4 promoter to increase its expression. Finally, the radiation-induced increase in exosomal B7-H4 induced FoxP3 expression during Th1 cell differentiation via the activated STAT1 pathway. In vivo, exosomal B7-H4 decreased the radiation sensitivity of GBM cells, and reduced the survival of GBM mice model. CONCLUSION: This study showed that radiation-enhanced exosomal B7-H4 promoted immunosuppression and tumor growth, hence defining a direct link between irradiation and anti-tumor immune responses. Our results suggest that co-administration of radiotherapy with anti-B7-H4 therapy could improve local tumor control and identify exosomal B7-H4 as a potential tumor biomarker.

Pyroptosis relates to tumor microenvironment remodeling and prognosis: A pan-cancer perspective.

Background and aim: Pyroptosis is an inflammatory form of programmed cell death implicated in inflammation and disease. Moreover, inducing pyroptosis has been appreciated as anti-cancer therapy for its ability to unleash anti-cancer immune responses. Methods: Utilizing the data available in The Cancer Genome Atlas (TCGA), pyroptosis-related genes' (PRGs) expression, genomic aberrations, and clinical significance were systematically analyzed in pan-cancer. A GSVA score was obtained to rate pyroptosis level and divide the cancers into pyroptosis-low and pyroptosis-high groups. Immunohistochemistry (IHC) was used to evaluate the differential expression of major PRGs (GSDMC, GSDMD, GSDME, NLRP3, NLRC4, IL1B) in selected tumor types (COAD, HNSC, KIRC, LIHC, LUAD, LUSC). Selection of tumors for immunohistochemistry (IHC) was based on their expression pattern in TCGA cancers, clinical relevance, tumor epidemiology, and sample availability. Results: Differential expression of PRGs was evident in various cancers and associated with prognosis which was driven by genomic variations and epigenetic abnormalities, such as single nucleotide variations (SNVs), copy number variation (CNV) and DNA methylation level. For example, methylation of PRGs in lower grade glioma (LGG), uveal melanoma (UVM) and kidney renal clear cell carcinoma (KIRC) were predictive of improved survival as upregulation of PRGs was risky in these cancers. Pyroptosis level significantly differentiated tumor from normal samples in 15 types of cancers, exhibited a progressive trend with cancer stage, observed variation among cancer subtypes, and showed a significant association with cancer prognosis. Higher pyroptosis level was associated with worst prognosis in majority of the cancers in terms of OS (KIRC, LGG, and UVM), PFS (GBM, KIRC, LGG, PRAD, THCA, and THYM) and DSS (KIRC and LGG) as estimated by Kaplan-Meier survival curves. Moreover, Pyroptosis level was strongly indicative of a hot tumor immune microenvironment with high presence of CD8+ T cell and other T cell subtypes. Several oncogenic pathways, such as P53 pathway, DNA repair, KRAS signaling, epithelial-mesenchymal transition (EMT), IL6 JAK STAT3 signaling, IL2 STAT5 signaling, PI3K AKT MTOR signaling and angiogenesis, were enriched in pyroptosis-hi subgroups across cancers. Conclusions: Genetic alterations in PRGs greatly influence the pyroptosis level and cancer prognosis. A relatively hot tumor immune microenvironment was associated with pyroptosis irrespective of the cancer prognosis. Overall, our study reveals the critical role of pyroptosis in cancer and highlights pyroptosis-based therapeutic vulnerabilities.