Bioinformatics analysis identified RGS4 as a potential tumor promoter in glioma.

Gliomas is the most common type of intracranial primary malignant tumor and it accounts for ∼80% of primary malignant tumors of the central nervous system. At present, surgical resection with adjuvant radiotherapy and temozolomide adjuvant chemotherapy combined with radiotherapy are the only standard treatments for glioma. However, but overall survival of patients is only 15 months. Glioma is resistant to radiotherapy and chemotherapy, and this malignant behavior leads to a high recurrence rate. Therefore, the use of therapeutics is usually ineffective. As a result, patients with glioma do not significantly benefit from standard treatment. There is therefore an urgent need to develop novel diagnostic approaches and, in particular, more effective treatment strategies. The application of gene expression microarrays provides a feasible and effective way to study gliomas. The present study therefore aimed to identify the key protein-coding genes of glioma using bioinformatics methods and thereby search, for novel biomarkers and therapeutic targets for the treatment of glioma. First, mRNA microarray datasets were selected and obtained from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) between gliomas and normal tissues. The DEGs were clarified using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), Protein-Protein Interaction (PPI) network and statistical analysis. Subsequently, reverse transcription-quantitative PCR (RT-qPCR)and western blot were used to verify the results of the bioinformatics analysis. A total of 400 DEGs were identified in glioma and they were enriched in several cancer-related GO and KEGG pathways. In the PPI network, it was observed that G-protein signal regulatory protein 4 (RGS4), thymidine phosphorylase, collagen type VI alpha-1, Src homology 2 domain-containing transforming protein1(SHC1) and ring finger protein 135 exhibited a strong protein-protein interaction. Furthermore, . Subsequently, brain damaged tissues and glioma cell lines were selected for RT-qPCR and western blotting analysis. The results demonstrated that RGS4 was highly expressed in glioma cell lines. In conclusion, RGS4 may be a key protein-coding gene in glioma. RGS4 should therefore be studied further to verify its feasibility and effectiveness as a potential glioma biomarker and therapeutic target.

Opposite regulation of F508del-CFTR biogenesis by four poly-lysine ubiquitin chains In vitro.

As a misfolding protein, almost all of F508del-CFTR is degraded by the ubiquitin-proteasome system before its maturation, which results in no membrane expression of cystic fibrosis transmembrane conductance regulator (CFTR) and therefore, no chloride secretion across epithelial cells of cystic fibrosis (CF) patients. The conjugation of ubiquitin (Ub) chains to protein substrates is necessary for the proteasomal degradation of F508del-CFTR. Ubiquitin contains seven lysine (K) residues, all of which can be conjugated to one another, forming poly-ubiquitin chains on substrates, either by mixing together, or by only one type of lysine providing sorting signals for different pathways. Here, we report that four lysine-linked poly-Ub chains (LLPUCs) were involved in F508del-CFTR biogenesis: LLPUCs linked by K11 or K48 facilitated F508del-CFTR degradation, whereas the other two linked by K63 and K33 protected F508del-CFTR from degradation. LLPUC K11 is more potent for F508del-CFTR degradation than K48. F508del-CFTR utilizes four specific lysine-linked poly-Ub chains during its biogenesis for opposite destiny through different identification by proteasomal shuttle protein or receptors. These findings provide new insights into the CF pathogenesis and are expected to facilitate the development of therapies for this devastating disease.

Current status and development of anti-PD-1/PD-L1 immunotherapy for lung cancer.

Lung cancer is the leading cause of cancer deaths worldwide, mainly because it is usually in the advanced stage at the time of diagnosis. Although great progress has been made in the diagnosis and treatment of lung cancer in the past 25 years, the prognosis of lung cancer patients remains unsatisfactory. Agents targeting immune checkpoints have shown potential to improve therapeutic outcomes in patients with lung cancer. Inhibitors of PD-1/PD-L1 have been approved for the treatment of different types of lung cancer by FDA. Nevertheless, with the increasing number of clinical trails, the adverse events have emerged. Therefore, attention has been paid to finding out the factors influencing the therapeutic effect of anti-PD-1/PD-L1 therapy and reducing the occurrence of adverse events. Combination therapy may be an effective strategy to reduce the adverse events and improve the therapeutic effect. In this review, we summarized the current status and progress of anti-PD1/PD-L1 agents in lung cancer treatment.

Chimeric antigen receptor (CAR)-modified NK cells against cancer: Opportunities and challenges.

NK cells may have great potential in tumor immunotherapy because they can kill tumor cells directly and quickly. Chimeric antigen receptor is a fusion protein composed of extracellular antigen recognition domain, transmembrane domain and intracellular signal domain. Rapid development of CAR-modified T cells has made tremendous achievements in the treatment of malignancies, especially hematological malignancies. However, there are many deficiencies in clinical application of CAR-T cell therapy. Car-modified NK cells have attracted much attention because they may avoid these shortcomings. At present, preclinical and clinical studies have shown that CAR-NK cell therapy may play significant anti-tumor role and it is safer than CAR-T cell therapy. Nevertheless, CAR-NK cell therapy still faces some challenges, such as the expansion and activation of primary NK cells in vitro, the difficulty to store and ship NK cell products and the low transduction efficiency. Thus further research is still needed to optimize CAR-NK cell therapy. Building better CAR-NK cells is important to improve the treatment efficacy and combination therapy offers a novel direction of NK-cell based immunotherapy.

Chimeric antigen receptor T cell therapy and other therapeutics for malignancies: Combination and opportunity.

Chimeric antigen receptor T (CAR-T) cell therapy provides possibility for the treatment of malignancies since clinical trials have shown that CAR-T therapy has a significant anti-tumor effect. Although many efforts have been made to improve the efficacy and reduce the side effects of CAR-T therapy, there are still many problems to solve. With the rapid development of this field, combination immunotherapy has been proved to improve the efficacy of CAR-T therapy. Studies have shown that radiotherapy, chemotherapy, oncolytic virotherapy, BTK inhibitors and immune checkpoint blockade-based therapy may further enhance the efficacy of CAR-T therapy while CRISPR/Cas9 technology and IL-1 blockade may improve the safety. In this review, we summarized the advantages and the mechanisms of the combination immunotherapy based on CAR-T cell therapy.

Identification of key protein-coding genes in lung adenocarcinomas based on bioinformatic analysis.

BACKGROUND: Lung cancer is one of the most common cancers and the primary cause of cancer-related deaths in the world. The 5-year survival of lung cancer patients is lower than 15%. As a common subtype of lung cancer, lung adenocarcinoma still has a high morbidity and mortality, although many strategies have been made, such as surgical operation, chemotherapy, targeted therapy. The use of gene expression microarray has provided a feasible and effective approach for the study on lung cancer. However, the biomarkers and potential therapeutic targets of lung adenocarcinomas are still not completely identified. Our study is aimed to find biomarkers and therapeutic targets of lung adenocarcinomas by identifying the key protein-coding gene in lung adenocarcinomas by bioinformatical approaches. METHODS: We selected and obtained messenger RNA microarray datasets from Gene Expression Omnibus database to identify differentially expressed genes between lung adenocarcinomas and normal lung tissue. The differentially expressed genes were clarified by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, the protein-protein interaction (PPI) network and statistical analyses. Subsequently, quantitative real-time PCR was used to verify the results of bioinformatic analysis. RESULTS: We obtained 1,264, 896 and 408 differentially expressed genes from GSE32863, GSE43458 and GSE63459, respectively. The 242 common differentially expressed genes in three datasets were related to cell adhesion molecules, ECM-receptor interaction, leukocyte transendothelial migration according to KEGG analysis. GO analysis showed that these common differentially expressed genes were enriched in tumor-related functions. ASPM, CCNB2, CDC20, CDC45, MELK, TOP2A and UBE2T and KIAA0101 have the strongest protein-protein interaction relationships based on protein-protein interaction networks. Survival analysis showed that these nine genes were closely related to the survival of lung adenocarcinomas. The further qRT-PCR assays indicated that seven key genes (ASPM, CCNB2, CDC20, CDC45, MELK, TOP2A and UBE2T) display differential profile between clinical lung adenocarcinoma specimens and their matched normal tissues. CONCLUSIONS: ASPM, CCNB2, CDC20, CDC45, MELK, TOP2A and UBE2T may be key protein coding genes in lung adenocarcinoma, and deserve further study to verify their feasibility and effectiveness as biomarkers and therapeutic targets for lung adenocarcinomas.