BackgroundUnderstanding common and unique mechanisms driving oncogenic processes in human tumors is indispensable to develop efficient therapies. Recent studies have proposed Twinfilin Actin Binding Protein 1 (TWF1) as a putative driver gene in lung cancer, pancreatic cancer and breast cancer, however a systematic pan-cancer analysis has not been carried out.MethodsHere, we set out to explore the role of TWF1 in 33 tumor types using TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus) dataset, Human Protein Atlas (HPA), and several bioinformatic tools.ResultsAs part of our analysis, we have assessed TWF1 expression across tumors. We found that over-expression of TWF1 generally predicted poor OS for patients with tumors with high TWF1 expression, such as mesothelioma, lung adenocarcinoma, cervical cancer and pancreatic adenocarcinoma. We also assessed the mutation burden of TWF1 in cancer and the TWF1-associated survival of cancer patients, compared the phosphorylation of TWF1 between normal and primary tumor tissues and explored putative functional mechanisms in TWF1-mediated oncogenesis.ConclusionsOur pan-cancer analysis provides a comprehensive overview of the oncogenic roles of TWF1 in multiple human cancers.

Poly(ADP‐ribose) glycohydrolase (PARG) as a main enzyme hydrolyzing poly(ADP‐ribose) in eukaryotes, and its silencing can inhibit benzo(a)pyrene (BaP)‐induced carcinogenesis. A thorough understanding of the mechanism of PARG silenced inhibition of BaP‐induced carcinogenesis provides a new therapeutic target for the prevention and treatment of environmental hazard induced lung cancer. We found that the expression of several subtypes of the histone H2B was downregulated in BaP‐induced carcinogenesis via PARG silencing as determined by label‐free proteomics and confirmed by previous cell line‐ and mouse model‐based studies. Analysis using the GEPIA2 online tool indicated that the transcription levels of H2BFS, HIST1H2BD, and HIST1H2BK in lung adenocarcinoma (LUAD) tissues and squamous cell lung carcinoma (LUSC) tissues were higher than those in normal lung tissues, while the transcription levels of HIST1H2BH in LUSC tissues were higher than those in normal lung tissues. The expression levels of HIST1H2BB, HIST1H2BH, and HIST1H2BL were significantly different in different lung cancer (LC) stages. Moreover, the expression of H2BFS, HIST1H2BD, HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H2BO, HIST2H2BE, and HIST2H2BF was positively correlated with that of PARG in LC tissues. Analysis of the Kaplan‐Meier plotter database indicated that high H2B levels predicted low survival in all LC patients suggesting that H2B could be a new biomarker for determining the prognosis of the LC, and that its expression can be inhibited by PARG silencing in BaP‐induced carcinogenesis.

This study evaluates the impact of the use of antibiotics on the effectiveness of nivolumab in the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). A literature search was conducted in various electronic databases to identify studies, which evaluated the impact of antibiotic use on the survival of patients with advanced/metastatic NSCLC who have been treated with nivolumab. Six studies, comprising a total of 787 patients with 37.2% females and of age range 30–90 years, were included in the study. A lack of smoking history was reported in 14.4% of the patients. A meta-analysis was conducted in 678 and 713 patients for PFS and OS, respectively. The pooled HR was 1.95 (95% CI: 1.13–3.37, P = 0.016) for PFS and 2.70 (95% CI: 1.81–4.02, P < 0.001) for OS. Among patients exposed to antibiotics, the median PFS and OS were reduced by 1.6 months (95% CI: 1.5–1.7) and 8.8 months (95% CI: 8.5–9.1), respectively. Our study indicates that, among patients with advanced/metastatic NSCLC, the use of antibiotics with nivolumab led to a decrease in the median OS by more than 8 months. Studying the mechanism of the effect of antibiotics on the efficacy of nivolumab in patients with NSCLC should also be prioritized.

Cisplatin is a first-line chemotherapy drug for lung adenocarcinoma (LUAD). However, its therapeutic efficacy is limited because of serious side effects and acquired drug resistance. Targeting HER2 has been proven to be a viable therapeutic strategy against LUAD. Moreover, inetetamab, an innovative anti-HER2 monoclonal antibody, has a more potent antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing effect than trastuzumab, which has been shown to be an effective and rational strategy in the clinic when combined with multiple chemotherapeutic agents. Thus, the present study aimed to explore the synergistic effects of cisplatin (DDP) and inetetamab in LUAD cells and investigate the detailed underlying mechanisms. Here, in vitro and in vivo , we found that the combination of inetetamab and cisplatin induced synergistic effects, including induction of pyroptosis, in LUAD. Mechanistic studies revealed that inetetamab combined with cisplatin inhibited HER2/AKT/Nrf2 signaling to increase ROS levels, which triggered NLRP3/caspase-1/GSDMB-mediated pyroptosis to synergistically enhance antitumor efficacy in LUAD cells. In addition, cisplatin enhanced the PBMC-killing ability of inetetamab by inducing GSDMB-mediated pyroptosis, which can be explained by increased secretion of IFN-γ. Our study reveals that the anti-HER2 monoclonal antibody inetetamab may be an attractive candidate for LUAD therapy, which opens new avenues for therapeutic interventions for LUAD.

Novel promising strategies for combination with sorafenib are urgently needed to enhance its clinical benefit and overcome toxicity in hepatocellular carcinoma (HCC). the molecular and immunomodulatory antitumor effects of sorafenib alone and in combination with the new immunotherapeutic agent R848 are presented. Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage‐to‐FTH1high M1 macrophage transition. The close interaction between neutrophils/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8+ T cell‐mediated antitumor immunity. Additionally, low‐dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low‐dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment.