Background: Although several key molecules have been identified to modulate SARS-CoV-2 invasion of human host cells, the molecules correlated with outcomes in COVID-19 caused by SARS-CoV-2 infection remain insufficiently explored.Methods: This study analyzed three RNA-Seq gene expression profiling datasets for COVID-19 and identified differentially expressed genes (DEGs) between COVID-19 patients and normal people, commonly in the three datasets. Furthermore, this study explored the correlation between the expression of these genes and clinical features in COVID-19 patients.Results: This analysis identified 13 genes significantly upregulated in COVID-19 patients’ leukocyte and SARS-CoV-2-infected nasopharyngeal tissue compared to normal tissue. These genes included OAS1, OAS2, OAS3, OASL, HERC6, SERPING1, IFI6, IFI44, IFI44L, CMPK2, RSAD2, EPSTI1, and CXCL10, all of which are involved in antiviral immune regulation. We found that these genes’ downregulation was associated with worse clinical outcomes in COVID-19 patients, such as intensive care unit (ICU) admission, mechanical ventilatory support (MVS) requirement, elevated D-dimer levels, and increased viral loads. Furthermore, this analysis identified two COVID-19 clusters based on the expression profiles of the 13 genes, termed COV-C1 and COV-C2. Compared with COV-C1, COV-C2 more highly expressed the 13 genes, had stronger antiviral immune responses, were younger, and displayed more favorable clinical outcomes.Conclusions: A strong antiviral immune response is essential in reducing severity of COVID-19.

The roles of the microbiome in human beings have become clearer with the development of next-generation sequencing techniques. Several pieces of evidence showed strong correlations between the microbiome and human health and disease, such as metabolic disorders, infectious diseases, digestive system diseases, and cancers. Among these diverse microbiomes, the role of bacteria in human cancers, especially in cancer cells, has received extensive attention. Latest studies found that bacteria widely existed in cancers, mainly in cancer cells and immune cells. In this review, we summarize the latest advances in understanding the role of bacteria in human cancer cells. We also discuss how bacteria are transported into cancer cells and their physiological significance in cancer progression. Finally, we present the prospect of bacterial therapy in cancer treatment.

Background: Immune checkpoint inhibitor (ICI) plus chemotherapy is effective in advanced gastric or gastroesophageal junction (G/GEJ) cancer. This study aims to evaluate the clinical effect of first-line immunotherapy in combination with chemotherapy for advanced G/GEJ cancer. Methods: PubMed, Web of Science, Embase and Cochrane databases were systematically searched from the inception of the databases to December 2021. Randomized trials comparing ICI plus chemotherapy with chemotherapy in first-line treatment for advanced G/GEJ cancer were included. The outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Analyses were performed in Stata 14.0 software. The study protocol was registered with PROSPERO, number CRD42022300907. Results: Five trials were included for analysis, involving 2, 814 patients. ICI plus chemotherapy can significantly improve OS (hazards ratio [HR], 0.86; 95% CI 0.78-0.94; P = .002), PFS (HR, 0.79; 95% CI 0.63-0.99; P ＜ .001) and ORR (relative ratio [RR], 1.20; 95% CI 1.11-1.30; P < .001). In safety analyses, there were no significant differences in incidence of all AEs, treatment-related adverse event (TRAE), TRAE of grade 3 or higher, serious TRAE and TRAE leading to death between two arms ( P > .05). Conclusions: ICI plus chemotherapy is more effective first-line treatment for advanced G/GEJ cancer in contrast to chemotherapy regrading to improving OS, PFS and ORR, without increasing TRAE risk. This study will redefine the role of ICI in combination with chemotherapy in the first-line setting for G/GEJ cancer, and provide reference for clinical treatment.

Background: Brigatinib is approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Despite its superior efficacy, the dermal toxicities caused by brigatinib cannot be overlooked. However, its underlying mechanism remains unknown.Methods: The effects of brigatinib on the proliferation ability of human immortalized keratinocyte (HaCaT) cells were evaluated using Cell Counting Kit-8 (CCK-8) proliferation, colony formation, and 5-ethynyl-2′-deoxyuridine (EdU) incorporation assays. The effects of brigatinib on apoptosis were detected using Annexin FITC/PI and Acridine Orange (AO) staining assays. Cell cycle was assessed with flow cytometry. An analysis of transcriptome by RNA sequencing procedures (RNA-seq) was performed to reveal the key regulatory genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to find out the biological function and related signal pathways. The expressions of amphiregulin, epiregulin and transforming growth factor alpha (TGFA) and the protein levels of Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and Cleaved-Caspase three were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot assay.Results: Brigatinib inhibits cell proliferation with an IC₅₀ value of 2.9 μmol/L and significantly increases apoptosis rates. Transcriptome sequencing (RNA-seq) indicates that brigatinib could significantly downregulate the expression of amphiregulin, epiregulin and TGFA. In addition, we demonstrated that brigatinib reduced the protein expression of amphiregulin, epiregulin, TGFA, PI3K, AKT and phosphorylated AKT (p-AKT).Conclusion: This study confirms the inhibition of HaCaT cells growth and progression by brigatinib and highlights the potential value of the PI3K/AKT pathway as a therapeutic target for brigatinib-induced dermal toxicities.

Background: The tyrosine receptor kinase inhibitor (TRKi) entrectinib is used to treat neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumors and ROS1-positive patients. Despite its impressive efficacy against cancer, the clinical application is still limited by the central nervous system (CNS)-related toxicities. However, the precise mechanism of such CNS-related toxicities remains elusive.Methods: The effect of entrectinib-induced nerve cell damage was evaluated by the nerve cells (PC12, HT22 and SK-N-SH) based in vitro models. Various assays, including CCK-8, colony formation and EdU incorporation assays were utilized to estimate the cellular viability and proliferation ability. Cell apoptosis was measured by flow cytometry. Next, transcriptome sequencing technology was performed to identify differentially expressed genes (DEGs). Gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG) analysis and gene set enrichment analysis (GSEA) were applied to predict the potential functions of DEGs. Quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting assays were performed to measure the expressions of thrombospondin-1 (THBS1), TGF-β1, PI3K, AKT and phosphorylated AKT (p-AKT) in the entrectinib-treated nerve cells. Additionally, we Preliminary observed and validated whether THBS1 overexpression could rescue nerve cell damage and the abnormalities in PI3K-AKT and TGF-β signaling pathways.Results: Entrectinib significantly inhibited the nerve cells proliferation and colony formation, and induced nerve cells apoptosis. Transcriptome sequencing analysis and qRT-PCR revealed that THBS1 was downregulated within entrectinib treatment. KEGG and GSEA analysis also suggested that entrectinib directly caused the abnormalities in proliferation-related signaling pathway like PI3K-AKT pathway, and apoptosis-related signaling pathway including TGF-β pathway. We further demonstrated that THBS1, TGF-β1, PI3K, AKT and p-AKT were downregulated by entrectinib. Meanwhile, pretreatment with THBS1 overexpression plasmids significantly rescued nerve cells (PC12, HT22 and SK-N-SH) from cell death and the abnormalities in PI3K-AKT and TGF-β signaling pathways.Conclusion: These results identified a critical role of entrectinib in promoting nerve cell damage by downregulating the expression of THBS1 while also inhibiting PI3K-AKT and TGF-β signaling pathways. Our findings will provide potential therapeutic targets for CNS-related toxicities.