TOP2A modulates signaling via the AKT/mTOR pathway to promote ovarian cancer cell proliferation.

Ovarian cancer (OC) is a form of gynecological malignancy that is associated with worse patient outcomes than any other cancer of the female reproductive tract. Topoisomerase II α (TOP2A) is commonly regarded as an oncogene that is associated with malignant disease progression in a variety of cancers, its mechanistic functions in OC have yet to be firmly established. We explored the role of TOP2A in OC through online databases, clinical samples, in vitro and in vivo experiments. And initial analyses of public databases revealed high OC-related TOP2A expression in patient samples that was related to poorer prognosis. This was confirmed by clinical samples in which TOP2A expression was elevated in OC relative to healthy tissue. Kaplan-Meier analyses further suggested that higher TOP2A expression levels were correlated with worse prognosis in OC patients. In vitro, TOP2A knockdown resulted in the inhibition of OC cell proliferation, with cells entering G1 phase arrest and undergoing consequent apoptotic death. In rescue assays, TOP2A was confirmed to regulate cell proliferation and cell cycle through AKT/mTOR pathway activity. Mouse model experiments further affirmed the key role that TOP2A plays as a driver of OC cell proliferation. These data provide strong evidence supporting TOP2A as an oncogenic mediator and prognostic biomarker related to OC progression and poor outcomes. At the mechanistic level, TOP2A can control tumor cell growth via AKT/mTOR pathway modulation. These preliminary results provide a foundation for future research seeking to explore the utility of TOP2A inhibitor-based combination treatment regimens in platinum-resistant recurrent OC patients.

The Clinicopathological Significance and Prognostic Value of Androgen Receptor in Endometrial Carcinoma: A Meta-Analysis.

Background: The role of androgen receptor (AR) in evaluating the prognosis of patients with endometrial cancer (EC) remains controversial. Here, we performed a meta-analysis to assess whether AR expression improves EC survival outcomes. Methods: We searched related articles published before August 2021 in PubMed, EMBASE, and Web of Science. The association between AR expression and patient prognosis was estimated with hazard ratios (HRs) and odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs). The review is registered on PROSPERO, registration number: CRD42021268591. Results: Ten studies including 1,485 patients were enrolled in the meta-analysis. The results showed that AR expression in EC tissues was associated with a better survival in crude analyses (HR = 1.63, 95% CI = 1.32-2.02, P < 0.001). However, no significant relation was found after the adjustment of the confounding factors (HR = 1.68, 95% CI = 0.75-3.75, P = 0.205). In subgroup analyses, grade 1-2 disease, stage I-II disease, negative lymph node status, and lack of the lymphovascular invasion were more common in AR-positive groups (OR = 0.47, 0.48, 0.37, and 0.57; 95% CI = 0.45-0.62, 0.35-0.65, 0.24-0.56, and 0.37-0.89). Furthermore, AR expression was more common in endometrioid cancers (OR = 2.39, 95% CI = 1.79-3.20). Conclusions: AR expression is significantly associated favorable characteristics including low-grade disease, early-stage disease, negative lymph node status, and lack of the lymphovascular invasion and a specific histology-endometrioid cancer. However, AR is not an independent prognostic factor.

Tuberculosis infection screening in children with close contact: a hospital-based study.

BACKGROUND: Identifying and prioritizing at-risk populations is critical for pediatric tuberculosis control. We aimed to identify a latent tuberculosis infection (LTBI) screening strategy that is appropriate for the Chinese context among children with different TB exposure levels and to explore its clinical importance. METHODS: During 2013-2015, we enrolled hospitalized children with suspected respiratory infectious disease (RID) for LTBI screening using the tuberculin skin test (TST) and interferon-γ release assay (IGRA) T-SPOT.TB as part of a work up for their RID. Participants with confirmed diagnosis were classified into three subgroups according to level of exposure to TB: no reported contact risk, with household contact risk, and with non-household contact risk. RESULTS: A total 6202 children (median age: 4.76 years; interquartile range: 1.0-8.0 years) were enrolled. Children with no reported contact risk had the lowest proportions of positive results for the IGRA (0.7%) and TST (3.3%). The proportion of positive results for each test was higher for household contacts than non-household contacts. The TST positive proportion was much higher than that for the IGRA in all three groups. Children with IGRA+/TST+ results had larger indurations than those with IGRA- /TST+ results (15 mm vs. 13 mm, P = 0.02). For IGRA, older age (> 5 years) and non-household or household contact risk were associated with a positive result. CONCLUSIONS: Positive IGRA results in children with a contact risk can serve as a critical reference for LTBI management. IGRA can be used, in preference to TST, for Chinese children with a TB exposure risk.

The Proportion and Prognostic Significance of T-Regulatory Cells in Patients with Gynecological Cancers: A Systematic Review and Meta-Analysis.

Objective: Multiple reports have described the proportion of T-regulatory cells (Tregs) in peripheral blood (PB) and tissues in patients with gynecological cancers (GCs) with controversial results. Thus, the aim of this study was to investigate the proportion of Tregs and its prognostic survival role in GCs patients. Methods: We performed a comprehensive search from database inception for all studies presenting changes of Tregs in GCs patients versus controls to evaluate the pooled standardized mean differences (SMD) with 95% confidence intervals (95% CI). And hazard ratios (HRs) with 95% CI were recorded if available to determine the prognostic significance of Tregs. Results: Totally, 22 studies were included. Compared with controls, GCs patients had a higher proportion of Tregs in PB (SMD = 2.32, 95% CI = 1.47 to 3.17, P = 0.000) as well as in tissues (SMD = 3.47, 95% CI = 0.77 to 6.18, P = 0.012). Furthermore, more significant elevated frequency of Tregs was observed in GCs patients with advanced stage than those in the early stage in both PB and tissues. However, no association was found between Tregs and survival of GCs patients with an HR of 1.34 (95% CI = 0.96 to 1.88, P = 0.09). Conclusions: Compared to controls, proportion of Tregs in PB and tissues was both higher among GCs patients, and it can be considered as a clinical biomarker for screening and prediction of clinical characteristics of GCs patients. But larger researches with rigorous design should be carried to explore the deep mechanisms of Tregs in GCs.

Toll-like receptor 1(TLR1) Gene SNP rs5743618 is associated with increased risk for tuberculosis in Han Chinese children.

Toll-like receptor 1 (TLR1) recognizes lipopeptides with TLR2, and affects immune response to Mycobacterium tuberculosis infection. Here, we report results of the first case-control pediatric study of the TLR1 single-nucleotide polymorphisms and susceptibility to tuberculosis (TB). A pediatric case-control study enrolled 340 TB patients and 366 healthy controls, all Han Chinese from North China. Significant differences of the allelic and genotypic distributions of rs5743618 in TLR1 gene were observed between TB group and control group and, G allele of rs5743618 was associated with increased risk for TB (OR: 2.40, 95%CI: 1.41-4.07, P = 0.0009). TLR1 rs5743618 -GT genotype was related to reduction in surface expression of TLR1 in monocytes and granulocytes regardless of stimulation with inactivated H37Rv. In addition, after stimulated with inactivated lysate of M. tuberculosis strain H37Rv, samples of peripheral blood mononuclear cells (PBMCs) from children with the rs5743618 GT genotypes showed a decreased level of Tumor Necrosis Factor-a (TNF-a) and CXC chemokine ligand 10 (CXCL10) production, invariable production of interleukin-6 (IL-6) and IL-8 and increased production of IL-10 ex vivo. To conclude, TLR1 rs5743618 G allele was found associated to susceptibility to TB in Han Chinese pediatric population. TLR1 rs5743618-GT genotype carriers may have reduced immune response to MTB infection although further study is warranted to test this conclusion.

Tag SNP polymorphism of CCL2 and its role in clinical tuberculosis in Han Chinese pediatric population.

BACKGROUND: Chemokine (C-C motif) ligand 2 CCL2/MCP-1 is among the key signaling molecules of innate immunity; in particular, it is involved in recruitment of mononuclear and other cells in response to infection, including tuberculosis (TB) and is essential for granuloma formation. METHODOLOGY/PRINCIPAL FINDINGS: We identified a tag SNP for the CCL2/MCP-1 gene (rs4586 C/T). In order to understand whether this SNP may serve to evaluate the contribution of the CCL2 gene to the expression of TB disease, we further analysed distribution of its alleles and genotypes in 301 TB cases versus 338 non-infected controls (all BCG vaccinated) representing a high-risk pediatric population of North China. In the male TB subgroup, the C allele was identified in a higher rate (P = 0.045), and, acting dominantly, was found to be a risk factor for clinical TB (P = 0.029). Homozygous TT genotype was significantly associated with lower CSF mononuclear leukocyte (ML) counts in patients with tuberculous meningitis (TBM) (P = 0.001). CONCLUSIONS/SIGNIFICANCE: The present study found an association of the CCL2 tag SNP rs4586 C allele and pediatric TB disease in males, suggesting that gender may affect the susceptibility to TB even in children. The association of homozygous TT genotype with decreased CSF mononuclear leukocyte (ML) count not only suggests a clinical significance of this SNP, but indicates its potential to assist in the clinical assessment of suspected TBM, where delay is critical and diagnosis is difficult.

Polymorphism of 3'UTR region of TNFR2 coding gene and its role in clinical tuberculosis in Han Chinese pediatric population.

Genetic factors of human susceptibility to tuberculosis (TB) are multiple and their effect may be ethnic- and age-dependent. TNFR2 encoded by the TNFRSF1B gene is one of the important TNF-α receptors; its polymorphisms were previously suggested as potential markers of host susceptibility to TB. Here, genotyping of three SNPs in TNFRSF1B 3'UTR (rs1061624, rs5030792, rs3397) was performed in Han Chinese pediatric population (229 TB patients and 233 control subjects). rs5030792 was found homozygous (TT genotype) in all studied individuals. The rs3397-T allele was almost equally represented in both gender groups in this study; in particular, it was detected in 33.9% and 35.2% in female cases and controls, respectively (P=0.8). This latter result differs strikingly from an African study where rs3397-T was found in only 12.8 and 16.2% of Ghanaian female cases and controls, respectively (P=0.007 [Möller et al., 2010. Am. J. Respir. Crit. Care. Med. 181, 388-393]). In contrast, rs1061624-A allele, acting recessively, was found to be a possible risk factor for clinical TB in females (P=0.03). The rs1061624 heterozygotes were overdominant in controls versus patients (P=0.015) that warrants further study of their hypothetical advantage in TB. Neither of the common haplotypes was associated with susceptibility to TB. Compared to the published contrasting data on African (7-15%) and European (57%) populations, GTT haplotype was found in an intermediate frequency (26%). Further studies on both adult and pediatric populations in ethnically diverse settings are needed to elucidate the functionality of these 3'UTR SNPs of the TNFR2 gene.