Causal effect of age first had sexual intercourse and lifetime number of sexual partners on cervical cancer.

Objective: In this study, we aimed to investigate whether age first had sexual intercourse (AFSI) and lifetime number of sexual partners (LNSP) have a direct causal effect on cervical cancer by Mendelian randomization (MR) analysis. Methods: Four approaches were used for MR Analysis, including MR-Egger, weighted method, weighted median, and inverse variance weighted (IVW). MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) as well as MR-Egger regression analysis were conducted to detect whether there was pleiotropy between IVs and outcome, and the outlier SNPs can be detected by MR-PRESSO. The presence or absence of heterogeneity among IVs was suggested according to Cochran's Q statistic. Leave-one-out sensitivity analysis was performed to identify and remove SNPs which could independently change the results. We corrected the results using Bonferroni correction. Results: From the results of IVW, AFSI had a negative effect on cervical cancer (OR = 0.996, 95 % CI: 0.995, 0.998 P = 1.70E-07), which still persisted after Bonferroni correction. However, no causal effect of LNSP on cervical cancer was found according to the IVW results (OR = 1.003, 95 % CI: 1.000, 1.007, P = 0.071). From the results of MR-PRESSO and MR-Egger, no SNP with horizontal pleiotropy between cervical cancer was detected and no SNP was identified as an outlier SNP. Cochran's Q statistic suggested that no heterogeneity existed among IVs of AFSI and LNSP. According to Leave-one-out analysis, the results of MR did not change after excluding any single IV. Conclusion: This MR study reveals that early AFSI has a causal effect on cervical cancer.

Immune checkpoint inhibitors in advanced and recurrent/metastatic cervical cancer.

Cervical cancer (CC) poses a serious threat to women's health. Although many early-stage patients have a good prognosis, there are still a lack of effective therapies for advanced and recurrent/metastatic CC. In this context, immunotherapy and immune checkpoint inhibitors (ICIs) are particularly likely to play a role in the treatment of cervical tumors in a variety of disease settings. Some promising immune checkpoints include programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), which exert immunomodulatory effects as negative regulators of T-cell activation and suppress immune responses in cervical cancer through cancer cell immune evasion. Initial trials of ICIs for CC have shown encouraging results in terms of objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), both monotherapy and combination strategies. Meanwhile, human papillomavirus, vaginal microecology and intestinal microenvironment play an important role in CC, which provides new treatment directions. This review analyzed a number of completed or ongoing clinical trials of ICIs in the treatment of advanced and recurrent/metastatic CC. And we also analyzed the important relationship between vaginal microecology and intestinal microecology with CC and their related immunotherapy prospects.

Effects of targeting signal mutations in a mitochondrial presequence on the spatial distribution of the conformational ensemble in the binding site of Tom20.

The 20-kDa TOM (translocase of outer mitochondrial membrane) subunit, Tom20, is the first receptor of the protein import pathway into mitochondria. Tom20 recognizes the mitochondrial targeting signal embedded in the presequences attached to mature mitochondrial proteins, as an N-terminal extension. Consequently, ~1,000 different mitochondrial proteins are sorted into the mitochondrial matrix, and distinguished from non-mitochondrial proteins. We previously reported the MPRIDE (multiple partial recognitions in dynamic equilibrium) mechanism to explain the structural basis of the promiscuous recognition of presequences by Tom20. A subset of the targeting signal features is recognized in each pose of the presequence in the binding state, and all of the features are collectively recognized in the dynamic equilibrium between the poses. Here, we changed the volumes of the hydrophobic side chains in the targeting signal, while maintaining the binding affinity. We tethered the mutated presequences to the binding site of Tom20 and placed them in the crystal contact-free space (CCFS) created in the crystal lattice. The spatial distributions of the mutated presequences were visualized as smeared electron densities in the low-pass filtered difference maps obtained by X-ray crystallography. The mutated presequence ensembles shifted their positions in the binding state to accommodate the larger side chains, thus providing positive evidence supporting the use of the MPRIDE mechanism in the promiscuous recognition by Tom20.

Tumor mutation burden in connection with immune-related survival in uterine corpus endometrial carcinoma.

BACKGROUND: UCEC is the most common gynecological malignancy in many countries, and its mechanism of occurrence and development is related to tumor mutation burden (TMB) and immune cell infiltration. Therefore, it is necessary to systematically explore the TMB-related gene profile in immune cells to improve the prognosis of UCEC. METHODS: We integrated TMB-related genes with basic clinical information of UCEC patients based on TCGA dataset. Differentially expressed genes (DEGs) were selected through differential expression screening, PPI, and enrichment analysis. Additionally, we analyzed the components of immune cell infiltration of the DEGs to obtain the differential immunity-related genes. A single factor and multifactor Cox regression analyses were conducted to establish new prognostic indicators of OS and DFS based on TMB-related immune genes. To further study the correlation between survival and immune cell infiltration, a Cox model based on these immune infiltration compositions was built. Using the clinical variables, we established nomograms for OS and DFS. RESULTS: 393 DEGs were significantly associated with clinical outcomes and the immune component in patients with UCEC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, Genomes (KEGG) pathway and protein-protein interaction network (PPI) analyses revealed the role of these genes and information on related pathways. Then, two prognostic models were established based on the differential immune genes for OS (GFAP and MX2) and DFS (MX2, GFAP, IGHM, FGF20, and TRAV21). In DFS, the differential immune genes were related to CD4+ T cell, CD8+ T cell, macrophage, and neutrophil (all P < 0.05). B cell and CD8+ T cell were independent prognostic factors from among the immune cell elements in UCEC. Finally, the risk scores of these models were combined with the clinical elements-based nomogram models, and the AUC values were all over 0.7. CONCLUSIONS: Our results identified several clinically significant differential immune genes and established relevant prognostic models, providing a basis for the molecular analysis of TMB and immune cells in UCEC, and identified potential prognostic and immune-related genes for UCEC. We added clinical related conditions for further analysis to confirm the identity of the genes and clinical elements-based models.

Lymphadenectomy and prognosis for elderly females with stage I endometrioid endometrial cancer.

PURPOSE: The potential therapeutic benefits of lymphadenectomy in endometrial cancer (EC) patients are still ambiguous. Therefore, a population-based retrospective analysis was conducted to determine the association between lymphadenectomy and survival in elderly female patients with stage I endometrioid EC. METHODS: The Surveillance, Epidemiology, and End Results (SEER) program database was retrospectively analyzed, and data of 63,372 female patients with early-stage type I EC from 1988 to 2013 were collected. The main patient and tumor characteristics included marital status, age, ethnicity, time of diagnosis, tumor grade, radiotherapy, and lymphadenectomy status. Kaplan-Meier and Cox proportional hazard regression analyses were performed to determine the association between lymph node dissection and the overall survival (OS) and cancer-specific survival in women older than 50 years with stage I endometrioid EC. RESULTS: The majority (83.7%) of the patients who met the inclusion criteria for the study were older than 50 years. In both grade 1 and 2 patients aged over 50 years, lymph node conservation was associated with a higher mortality risk compared to lymphadenectomy (all P < 0.005). Multivariate analysis indicated that lymphadenectomy was an independent predictor of improved OS in early-stage type 1 EC patients, with hazard ratios of 0.893 and 0.827 for the grade 1 and grade 2 patients, respectively (P < 0.0001). CONCLUSIONS: Lymphadenectomy could improve long-term OS in women older than 50 years with grade 1 and 2 endometrioid EC.

General Self-Template Synthesis of Transition-Metal Oxide and Chalcogenide Mesoporous Nanotubes with Enhanced Electrochemical Performances.

The development of a general strategy for synthesizing hierarchical porous transition-metal oxide and chalcogenide mesoporous nanotubes, is still highly challenging. Herein we present a facile self-template strategy to synthesize Co3 O4 mesoporous nanotubes with outstanding performances in both the electrocatalytic oxygen-evolution reaction (OER) and Li-ion battery via the thermal-oxidation-induced transformation of cheap and easily-prepared Co-Asp(cobalt-aspartic acid) nanowires. The initially formed thin layers on the precursor surfaces, oxygen-induced outward diffusion of interior precursors, the gas release of organic oxidation, and subsequent Kirkendall effect are important for the appearance of the mesoporous nanotubes. This self-template strategy of low-cost precursors is found to be a versatile method to prepare other functional mesoporous nanotubes of transition-metal oxides and chalcogenides, such as NiO, NiCo2 O4 , Mn5 O8 , CoS2 and CoSe2 .