RESUMEN
Background: A growing body of evidence suggests that immunological processes have a significant role in developing idiopathic sudden sensorineural hearing loss (SSHL). However, few studies have examined the association between immune cell phenotype and SSHL using Mendelian Randomization (MR). Methods: The online genome-wide association studies (GWAS) database was used to compile data from GWAS covering 731 immunophenotypes and SSHL. Inverse variance weighted (IVW) analysis was primarily used for MR study, and single nucleotide polymorphisms (SNPs) associated with immunophenotypes served as dependent variables. A sensitivity study and the false discovery rate (FDR) correction were used to examine the MR hypothesis. In addition, the possibility of reverse causality between immunophenotype and SSHL was validated by reverse MR. Reverse MR was analyzed in a manner consistent with forward MR. Results: After FDR correction and sensitivity analysis, we screened 7 immunophenotypes, including IgD+ CD38dim %lymphocyte (95% CI: 1.0019, 1.0742, p = 3.87 × 10-2, FDR = 1.15 × 10-2); Unsw mem AC (95% CI: 1.004, 1.2522, p = 4.23 × 10-2, FDR = 2.25 × 10-2); CD86+ myeloid DC AC (95% CI: 1.0083, 1.1147, p = 2.24 × 10-2, FDR = 4.27 × 10-2); CD33dim HLA DR- AC (95% CI: 1.0046, 1.0583, p = 2.12 × 10-2, FDR = 4.69 × 10-2); SSC-A on CD8br (95% CI: 1.0028, 1.1461, p = 4.12 × 10-2, FDR = 4.71 × 10-2); CD45RA- CD4+ %T cell (95% CI: 1.0036, 1.0503, p = 2.32 × 10-2, FDR = 4.82 × 10-2); DP (CD4+CD8+) AC (95% CI: 1.011, 1.2091, p = 2.78 × 10-2, FDR = 4.97 × 10-2). There was a strong causal relationship with SSHL onset, and the reliability of the results was verified. Furthermore, the immunological cell profile and SSHL did not appear to be closely associated, as shown by reverse MR analysis. Conclusion: Our study provides more support for the current hypothesis that immunophenotypes and the pathophysiology of SSHL are closely associated. Further validation is needed to assess the role of these immunophenotypes in SSHL.
RESUMEN
Pancreatic adenocarcinoma (PAAD) was characterized by dense fibrotic stroma and immunosuppressive tumor microenvironment (TME). TGFß signaling pathways are highly activated in human cancers. However, the role of TGFß2 in TME of PAAD remains to be elucidated. In this study, we showed that TGFß2 was expressed at a relatively high level in PAAD tissues or cancer cells. Moreover, its high expression predicted unfavorable prognosis. In PAAD, gene set enrichment analysis showed that TGFß2 correlated positively with leukocyte transendothelial migration, but negatively with aerobic metabolism, including oxidative phosphorylation. Results in Tumor and Immune System Interaction Database showed that TGFß2 correlated with the infiltration of tumor-associated macrophages (TAMs), which could be attributed to that TGFß2 promote CCL2 expression in PAAD. Moreover, correlation analysis showed that TGFß2 could trigger cancer-associated fibroblasts (CAFs) activation in PAAD. The drug sensitivity analysis may indicate that patients with TGFß2 high expression have higher sensitivity to chemotherapeutics, but the sensitivity to targeted drugs is still controversial. TGFß2 could promote expansion of CAFs and infiltration of TAMs, thus participating in the construction of a fibrotic and immunosuppressive TME in PAAD. Targeting TGFß2 could be a promising therapeutic approach, which needs to be elucidated by clinical and experimental evidences.
RESUMEN
Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis.