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.

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.

Inhibition of sphingolipid metabolism in osteosarcoma protects against CD151-mediated tumorigenicity.

Osteosarcoma is the most common primary bone tumor, with a poor prognosis owing to the lack of efficient molecular-based targeted therapies. Previous studies have suggested an association between CD151 and distinct consequences in osteosarcoma tumorigenicity. However, the potential of CD151 as a therapeutic target has not yet been sufficiently explored. Here, we performed integrated transcriptomic and metabolomic analyses of osteosarcoma and identified sphingolipid metabolism as the top CD151-regulated pathway. CD151 regulates sphingolipid metabolism primarily through SPTCL1, the first rate-limiting enzyme in sphingolipid biosynthesis. Mechanistically, depletion of CD151 enhanced c-myc polyubiquitination and subsequent degradation. c-myc is vital for the transcriptional activation of SPTLC1. Functionally, sphingolipid synthesis and the SPTLC1 inhibitor, myriocin, significantly suppressed the clonogenic growth of CD151-overexpression cells. Importantly, myriocin selectively restrained CD151-high expression tumor growth in preclinical patient-derived xenograft models. Collectively, these data establish that CD151 is a key mediator of sphingolipid metabolism and provide a new approach to developing novel CD151-based targeted therapies for osteosarcoma.

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.

MYLK4 promotes tumor progression through the activation of epidermal growth factor receptor signaling in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary bone cancer in adolescents and lung metastasis is the leading cause of death in patients with OS. However, the molecular mechanisms that promote OS growth and metastasis remain unknown. METHODS: We investigated the expression of myosin light chain kinase family members between metastasis and non-metastasis patients in the TARGET database and ensured that only myosin light chain kinase family member 4 (MYLK4) had higher expression in metastatic osteosarcoma patients. Then we confirmed the results by immunohistochemistry (IHC) and Western blotting (WB) of OS tissues. The effect of MYLK4 on the metastasis and proliferation of OS cells was investigated by wound healing, Transwell and colony-formation assays. Mass spectrum analysis was used to ensure the new binding protein of MYLK4. Tissue microarrays analysis was used to show the correlation between MYLK4 and pEGFR (Y1068). A series of in vivo experiments were conducted to reveal the mechanisms by which MYLK4 modulated the metastasis and proliferation of OS. RESULTS: Myosin Light Chain Kinase Family Member 4 (MYLK4) was significantly upregulated in metastatic human OS tissues. Growth and metastasis of OS could be accelerated by MYLK4 overexpression, whereas silencing MYLK4 expression resulted in decreased cell growth and metastasis. Mechanistically, mass spectrum analysis showed that MYLK4 interacted with the epidermal growth factor receptor (EGFR) in osteosarcoma cells and promoted growth and metastasis via the EGFR signaling pathway. Tissue microarrays analysis also showed that MYLK4 expression had a positive correlation with the expression of pEGFR (Y1068). Moreover, the EGFR inhibitor gefitinib could partially reverse the effect of cell proliferation and metastasis caused by MYLK4 overexpression. Importantly, the combination of MYLK4 and EGFR inhibitors had synergistic effects on growth and metastasis of OS in vitro and in vivo. CONCLUSION: Our results indicate that MYLK4 promotes OS growth and metastasis by activating the EGFR signaling pathway and can be a novel therapeutic target for the treatment of OS patients.

Her4 promotes cancer metabolic reprogramming via the c-Myc-dependent signaling axis.

Despite the growing recognition of metabolic reprogramming as an important hallmark of cancer in the past few years, the molecular mechanisms underlying metabolic alterations during tumorigenesis remain unclear. In this study, we identified a critical role of Her4 in rewiring cancer metabolism toward tumor-promoting metabolic processes, including increased glycolysis, glutaminolysis, mitochondrial biogenesis, and oxidative phosphorylation, which may in part cooperate to promote tumorigenesis. We found that overexpression of Her4 promoted the stabilization of c-Myc through a CIP2A-mediated increase in c-MycS62 phosphorylation and GSK3ß-mediated decrease in c-MycT58 phosphorylation, both of which decreased c-Myc degradation. Furthermore, Her4 was found to increase glucose uptake and tumor growth in an osteosarcoma xenograft model. Overall, these findings provide a better understanding of the involvement of Her4 in tumorigenesis and document its potential role in metabolic reprogramming for the first time. We believe that our study might lead to promising opportunities for targeted metabolic therapy for cancer.