Immunological checkpoint inhibitors have been immensely successfully applied in the treatment of cancer, however, a portion of tumor patients can't benefit from checkpoint therapy. The low PD-1/CTLA-4 positive rate and involvement of multiple immunosuppressive pathways are thought to be one of the reasons for treatment failure in non-responding patients. A new immune checkpoint molecule, HHLA2, which was widely expressed in PD-1 negative human tumors, may be a promising target for the improvement of recent immune therapy. Yet, the prognostic value and transcriptional regulatory mechanisms of HHLA2 remains unclear. In this study, we aimed to evaluate the prognostic value and transcriptional regulation mechanism of HHLA2 according to clinical and experimental data from multiple databases, including cBioPortal, TCGA, Cistrome, TIMER, Oncomine, Kaplan-Meier, GeneXplain. It was found that the expression of HHLA2 was significantly elevated in renal tumors, and significantly decreased in colorectal tumors. Pan-cancer survival analysis indicates that HHLA2 was an independent prognostic factor in 9/20 of human cancers. Especially in renal clear cell carcinoma ( P = 3.0E-7). Through plotting survival curve in Kaplan-Meier Plotter, it was found that hypomethylation of HHLA2 DNA was a favorable prognostic factor for KIRC patients. Yet, the copy number variant of HHLA2 was not significantly correlated with the overall survival of KIRC patients. Finally, by analyzing the motif of HHLA2 co-expression genes, we identified 15 transcription factors that may be involved in the regulation of the HHLA2 co-expression network. Among these transcription factors, BATF in B lymphocyte and SMAD in monocyte were confirmed to be able to directly bind to HHLA2 DNA according to chip-seq experimental data from Cistrome database.
The success of immunotherapy was overshadowed by its low response rate, and the hot or cold tumor microenvironment was reported to be responsible for it. However, due to the lack of an appropriate method, it is still a huge challenge for researchers to understand the molecular differences between hot and cold tumor microenvironments. Further research is needed to gain deeper insight into the molecular characteristics of the hot/cold tumor microenvironment. A large-scale clinical cohort and single-cell RNA-seq technology were used to identify the molecular characteristics of inflamed or noninflamed tumors. With single-cell RNA sequencing technology, we provided a novel method to dissect the tumor microenvironment into a hot/cold tumor microenvironment to help us understand the molecular differences between hot and cold tumor microenvironments. Compared with cold tumors, hot tumors highly expressed B cell-related genes, such as MS4A1 and CXCR5, neurogenesis-related miRNA such as MIR650, and immune molecule-related lncRNA such as MIR155HG and LINC00426. In cold tumors, the expression of genes related to multiple biological processes, such as the neural system, was significantly upregulated, and methylome analysis indicated that the promoter methylation level of genes related to neurogenesis was significantly reduced. Finally, we investigated the pan-cancer prognostic value of the cold/hot microenvironment and performed pharmacogenomic analysis to predict potential drugs that may have the potential to convert the cold microenvironment into a hot microenvironment. Our study reveals the multiomics characteristics of cold/hot microenvironments. These molecular characteristics may contribute to the understanding of immune exclusion and the development of microenvironment-targeted therapy.
Ewing sarcoma (ES) is a highly malignant pediatric tumor with a low survival rate and a high rate of metastasis. However, there have been limited reports on the exploration of new biomarkers of ES. Therefore, the aim of the present study was to identify the potential hub genes associated with overall vital survival (OVS) and metastasis in ES. Traditional methods for identifying differentially expressed genes lack the in-depth information of mechanistic studies. In this study, a weighted co-expression network for ES was constructed through weighted gene co-expression network analysis to identify co-expression modules associated with clinical phenotypes. The hub genes in the metastasis- and OVS-related co-expression modules were extracted, and the association between the hub genes and patient OVS was verified in another independent Gene Expression Omnibus dataset. Functional annotations and protein-protein interaction analysis of co-expression modules were also used to understand the potential regulatory mechanisms. The results of the functional enrichment analysis revealed that the OVS-associated module was mainly enriched in the cell cycle and immune response, and the metastasis-associated module was enriched in metabolism. A total of four genes (proteasome subunit α4, L1 cell adhesion molecule, serine/threonine kinase receptor-associated protein and cytotoxic T-lymphocyte-associated protein 4) in the OVS-related module and two genes (calcium voltage-gated channel auxiliary subunit γ2 and γ-aminobutyric acid type B receptor subunit 2) in the metastasis-related module were selected as hub genes. Further research on the hub genes identified in the present study may contribute to the understanding of the mechanism of ES metastasis and progression.
Background: The recent clinical success of immunotherapy represents a turning point in cancer management. But the response rate of immunotherapy is still limited. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, due to the lack of appropriate experimental methods, the reason why the immunotherapeutic resistance still existed on the inflamed tumor microenvironment remains unclear. Materials and Methods: Here, based on single-cell RNA sequencing, we classified the tumor microenvironment into inflamed immunotherapeutic responsive and inflamed non-responsive. Then, phenotype-specific genes were identified to show mechanistic differences between distant microenvironment phenotypes. Finally, we screened for some potential drugs that can convert an unfavorable microenvironment phenotype to a favorable one to aid current immunotherapy. Results: Multiple signaling pathways were phenotypes-specific dysregulated. Compared to non-inflamed microenvironment, the expression of interleukin signaling pathways-associated genes was upregulated in inflamed microenvironment. Compared to inflamed responsive microenvironment, the PPAR signaling pathway-related genes and multiple epigenetic pathways-related genes were, respectively, suppressed and upregulated in the inflamed non-responsive microenvironment, suggesting a potential mechanism of immunotherapeutic resistance. Interestingly, some of the identified phenotype-specific gene signatures have shown their potential to enhance the efficacy of current immunotherapy. Conclusion: These results may contribute to the mechanistic understanding of immunotherapeutic resistance and guide rational therapeutic combinations of distant targeted chemotherapy agents with immunotherapy.
[Background] Various bone grafting have been reported to achieve anterior column support and bone fusion after one stage posterior debridement in the treatment of lumbar tuberculosis. However, nonstructural bone grafting has been rarely studied. This study aimed to compare the efficacy of nonstructural bone grafting versus structural bone grafting in the treatment of lumbar tuberculosis.[Patients and methods] We retrospectively reviewed patients with nonstructural (n=27) and structural (n=22) bone grafting after single-stage posterior debridement and instrumentation for lumbar tuberculosis with at least 24 months of follow-up. Plain radiographs, magnetic resonance imaging, computed tomography scans, and health-related outcomes (e.g. Visual Analog Scale for back pain, the Oswestry Disability Index) were collected before surgery and at follow-up. [Results] Both nonstructural and structural bone grafting were associated with significant improvements in the quality of life parameters, the laboratory tests and the Cobb angle of local kyphosis. A slight loss of Cobb angle correction was observed in two groups. Nonstructural bone grafting resulted in the significantly less operation duration, blood loss and lower bone fusion rate than structural bone grafting group. There were three complications in the nonstructural bone grafting and four complications in the structural bone grafting group, with no significant difference between two groups.[Conclusions] Nonstructural bone grafting can achieve anterior column support with less surgical trauma and simpler surgical procedure than structural bone grafting, but the lower rate of grafted bone fusion should be taken into consideration when choosing nonstructural bone grafting.
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