The survival prognosis of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) is largely different, and little is known about the anti-tumor mechanism of tumor-infiltrated exhausted CD8+ T cells (Tex) in HNSCC. We performed cell-level multi-omics sequencing on human HNSCC samples to decipher the multi-dimensional characteristics of Tex cells. A proliferative exhausted CD8+ T cell cluster (P-Tex) which was beneficial to survival outcomes of patients with HPV-positive HNSCC was identified. Interestingly, P-Tex cells expressed CDK4 genes as high as cancer cells, which could be simultaneously inhibited by CDK4 inhibitors and might be a potential reason for the ineffectiveness of CDK4 inhibitors in treating HPV-positive HNSCC. P-Tex cells could aggregate in the antigen-presenting cell niches and activate certain signaling pathways. Together, our findings suggest a promising role for P-Tex cells in the prognosis of patients with HPV-positive HNSCC by providing modest but persistent anti-tumor effects.
Background
Dilated cardiomyopathy (DCM) is a serious cardiac heterogeneous pathological disease, which may be caused by mutations in the LMNA gene. Lamins interact with not only lamina-associated domains (LADs) but also euchromatin by alone or associates with the lamina-associated polypeptide 2 alpha (LAP2α). Numerous studies have documented that LMNA regulates gene expression by interacting with LADs in heterochromatin. However, the role of LMNA in regulating euchromatin in DCM is poorly understood. Here, we determine the differential binding genes on euchromatin in DCM induced by LMNA mutation by performing an integrated analysis of bioinformatics and explore the possible molecular pathogenesis mechanism.
Results
Six hundred twenty-three and 4484 differential binding genes were identified by ChIP-seq technology. The ChIP-seq analysis results and matched RNA-Seq transcriptome data were integrated to further validate the differential binding genes of ChIP-seq. Five and 60 candidate genes involved in a series of downstream analysis were identified. Finally, 4 key genes (CREBBP, PPP2R2B, BMP4, and BMP7) were harvested, and these genes may regulate LMNA mutation-induced DCM through WNT/β-catenin or TGFβ-BMP pathways.
Conclusions
We identified four key genes that may serve as potential biomarkers and novel therapeutic targets. Our study also illuminates the possible molecular pathogenesis mechanism that the abnormal binding between LMNA or LAP2α-lamin A/C complexes and euchromatin DNA in LMNA mutations, which may cause DCM through the changes of CREBBP, PPP2R2B, BMP4, BMP7 expressions, and the dysregulation of WNT/β-catenin or TGFβ-BMP pathways, providing valuable insights to improve the occurrence and development of DCM.
Graphic abstract
Numerous studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect host cells through binding to Angiotensin I Converting Enzyme 2 (ACE2) expressing in various tissues and organs. In this study, we deeply analyzed the single-cell expression profiles of ACE2 in fetal and adult human hearts to explore the potential mechanism of SARS-CoV-2 harming the heart. The molecular docking software was used to simulate the binding of SARS-CoV-2 spike protein with ACE2. The genes closely related to ACE2 in renin-angiotensin system (RAS) were identified by constructing a protein-protein interaction network. Through the analysis of single-cell transcription profiles at different stages of human embryos, we found that the expression level of ACE2 in ventricular myocytes was increased with embryonic development. The results of single-cell sequencing analysis showed that the expression of ACE2 in ventricular myocytes was up-regulated in heart failure induced by dilated cardiomyopathy compared with normal hearts. The up-regulation of ACE2 increases the risk of infection with SARS-CoV-2 in fetal and adult human hearts. In addition, the pathway analysis revealed that ACE2 may regulate the differently expressed genes in heart failure through calcium signaling pathway and Wnt signaling pathway.
ObjectivesTo explore the prognostic effects of previous cancer history on patients with major salivary gland cancer (SGC).Subjects and MethodsSGC patients with (sec‐SGC) and without (one‐SGC) a previous cancer from the SEER database were identified. Cox proportional hazards regression (CoxPH) models were used to compare the prognosis between sec‐SGC and one‐SGC patients. Subgroup analyses for sec‐SGC patients by gender, previous cancer types, previous cancer histology, and cancer diagnosis interval (CDI) were performed. Two CoxPH models were constructed to distinguish sec‐SGC patients with different prognostic risks.Results9098 SGC patients were enrolled. Overall, sec‐SGC patients (adjusted HR [aHR] = 1.26, p < 0.001), especially those with a CDI ≤ 5 years (aHR = 1.47, p < 0.001), had worse overall survival (OS) than one‐SGC patients. In subgroup analysis, only sec‐SGC patients with a previous head and neck cancer who were female (aHR = 2.38, p = 0.005), with a CDI ≤ 5 years (aHR = 1.65, p = 0.007) or with a previous squamous cell carcinoma (aHR = 6.52, p < 0.001) had worse OS. Our models successfully differentiated all sec‐SGC patients into high‐, intermediate‐ and low‐risk groups with different prognosis.ConclusionsSec‐SGC patients with different previous cancer types, gender, CDI and previous cancer histology had varied prognosis. The models we constructed could help differentiate the prognosis of sec‐SGC patients with different risks.
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