Objective: MicroRNAs (miRNAs) play a vital role in pathogenesis and progression of many cancers, including cervical cancer.However, importance of serum level of miR-101 in cervical cancer has rarely been studied.In the present study, clinical significance and prognostic value of serum miR-101 for cervical cancer was investigated.Methods: Association between miR-101 level in cervical cancer tissues and prognosis of patients was analyzed by using data retrieved from The Cancer Genome Atlas (TCGA) database, which was followed with our clinical study in which miR-101 serum level comparison between cervical cancer patients and healthy controls was conducted by realtime quantitative polymerase chain reaction (PCR).Results: TCGA database demonstrated that miR-101 was down-regulated in cervical cancer tissues compared with normal cervical tissues, and univariate Cox regression analysis indicated that decreased miR-101 expression was a highly significant negative risk factor.Similar trend was found in the serum miR-101.Serum level of miR-101 was associated with International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.003),lymph node metastasis (p=0.001), and serum squamous cell carcinoma antigen (SCC-Ag) level >4 (p=0.007).The overall survival time of cervical cancer patients with a higher level of serum miR-101 was significantly longer than that of patients with a lower level of serum miR-101.Moreover, multivariate Cox regression analysis indicated that the down-regulated serum level of miR-101 was an independent predictor for the unfavorable prognosis of cervical cancer.Conclusion: Serum level of miR-101 is closely associated with metastasis and prognosis of cervical cancer; and, hence could be a potential biomarker and prognostic predictor for cervical cancer.
To analyze the clinicopathologic features of mucinous cervical adenocarcinoma (ADC) and supply some reference for its diagnosis, treatment and prognosis.Totally 88 cases with primary mucinous ADC diagnosed between January 2003 and December 2007 in Jiangxi Maternal and Child Health Hospital were retrieved. Their clinical and pathological data were reviewed and analyzed.Among 88 patients, 70 cases of them were endocervical ADC, 11 cases were minimal deviation adenocarcinoma (MDA), 2 cases were intestinal subtype and 5 cases were villoglandular ADC. The positive rate of cervical Pap smear cytology was only 28% (10/36). There were 10 cases were performed several times of cervical Pap smear cytology test and biopsies, while still no abnormality was found. Finally, 7 cases of them were diagnosed by cervical excisional biopsy and endocervical curettage, including 5 cases with endocervical ADC and 2 cases with MDA; 2 cases (1 case with stage Ib1 endocervical ADC and 1 case with Ib1 MDA) were diagnosed by cold knife conization, and 1 case with stageIb1 endocervical were diagnosed by uteroscopically directed biopsy. The overall 5-year survival rate was 60.0%. Using univariate analysis results showed that age (P = 0.046), stage (P = 0.007), tumor size (P = 0.007) and therapeutic methods (P = 0.009) were significant prognostic factors. Multivariate analysis showed that therapeutic methods was an independent predictor for survival (P = 0.013). Stage IIb-IIIb MDA patients occupied 7/11 of all MDA patient, while there was only one such patient of 5 cases with villoglandular ADC. The overall HPV infection rate was 65% (57/88), and there was no obvious differences about the HPV infection rates among different types of mucinous ADC.Cervical smear cytology is of little significance to the diagnosis of mucinous cervical adenocarcinoma. Early stage mucinous ADC is difficult to be detected, especially for MDA. Cervical excisional biopsy, endocervical curettage, cold knife conization, uteroscope are beneficial to its diagnosis. Therapeutic methods is an important prognostic factor for mucinous ADC and comprehensive treatment should be given to those patients with risky postsurgical factors.
ABSTRACT We have investigated the functional organization of active and silent integrated luciferase transgenes in zebrafish, with the aim of accounting for the variegation of transgene expression in this species. We demonstrate the enrichment of transcriptionally active transgenes in acetylated histone H4 and the dynamic association of the transgenes with splicing factor SC35 and RNA Pol II. Analysis of interphase nuclei and extended chromatin fibers by immunofluorescence and in situ hybridization reveals a co-localization of transgenes with acetylated H4 in luciferase-expressing animals only. Enrichment of expressed transgenes in acetylated H4 is further demonstrated by their co-precipitation from chromatin using anti-acetylated H4 antibodies. Little correlation exists, however, between the level of histone acetylation and the degree of transgene expression. In transgene-expressing zebrafish, most transgenes co-localize with Pol II and SC35, whereas no such association occurs in non-expressing individuals. Inhibition of Pol II abolishes transgene expression and disrupts association of transgenes with SC35, although inactivated transgenes remains enriched in acetylated histones. Exposure of embryos to the histone deacetylation inhibitor TSA induces expression of most silent transgenes. Chromatin containing activated transgenes becomes enriched in acetylated histones and the transgenes recruit SC35 and Pol II. The results demonstrate a correlation between H4 acetylation and transgene activity, and argue that active transgenes dynamically recruit splicing factors and Pol II. The data also suggest that dissociation of splicing factors from transgenes upon Pol II inhibition is not a consequence of changes in H4 acetylation.
Abstract Objective The aim of this study was to compare the therapeutic value and treatment-related complications of radical hysterectomy with those of concurrent chemoradiotherapy (CCRT) for locally resectable (T1a2–T2a1) stage IIIC1r cervical cancer. Methods A total of 213 patients with locally resectable stage IIIC1r cervical cancer who had been treated at Jiangxi Maternal and Child Health Care Hospital between January 2013 and December 2021 were included in the study and classified into two groups: surgery (148 patients) and CCRT (65 patients). The disease-free survival (DFS) rate, overall survival (OS) rate, side effects, and economic costs associated with the two groups were compared. Results 43.9% (65/148) patients in the surgical group had no pelvic lymph node metastasis, and 21of them did not require supplementary treatment after surgery due to a low risk of postoperative pathology. The median follow-up time was 46 months (range: 7–108 months). The five-year DFS and OS rates of the surgery group were slightly higher than those of the CCRT group (80.7% vs. 75.1% and 81.6% vs. 80.6%, respectively; p > 0.05). The incidences of grade III–IV gastrointestinal reactions in the surgery and CCRT groups were 5.5% and 9.2%, respectively ( p = 0.332). Grade III–IV myelosuppression was identified in 27.6% of the surgery group and 26.2% of the CCRT group ( p = 0.836). The per capita treatment cost was higher for the surgery group than for the CCRT group (RMB 123, 918.6 0 vs. RMB 101, 880.90, p = 0.001). Conclusion The therapeutic effects and treatment-related complications of hysterectomy and CCRT are equivalent in patients with locally resectable stage IIIC1r cervical cancer, but surgery can provide accurate lymph node information and benefit patients with unnecessary radiation.
Form-finding is one of the key steps in the whole design process of cable-membrane structures. Traditional form-finding methods are usually complicated and have poor accuracy or stability. Thus, form-finding of cable-membrane structures based on particle swarm optimization (PSO) algorithm is proposed. The shape and loading characteristics of cable-membrane structures are optimized. The optimization objective is to minimize the maximum support reaction, and the initial prestress on the membrane surface is taken as the optimization variable. The main constraints are material strength limitation, structural stress, and displacement of the cable and membrane. A program is given based on the proposed PSO, and the optimization model and calculation process are implemented based on MATLAB and ANSYS platforms. Form-finding of three typical cable-membrane structures including rotating catenary surface, saddle surface, and rhombic hyperboloid is carried out. The results compare well with those from the force density method. The initial prestresses of the three membrane structures are obtained while the form-finding result is optimal, respectively. The proposed PSO shows a more accurate method in form-finding of cable-membrane structures in a simpler way.
The development of vehicles driving foreign DNA into the cell nucleus is essential for effective cellular gene transfer applications. We report that noncovalent binding of nuclear localization signal (NLS) peptides to plasmid DNA enhances nuclear uptake of the DNA and promotes germline integration, inheritance, and expression of a single copy of a luciferase reporter gene in zebrafish. As few as 10 DNA-NLS complexes (0.06 fg plasmid DNA) cytoplasmically injected are sufficient to produce germline-transgenic zebrafish bearing a single copy of the transgene. This corresponds to a 10(5)-fold reduction in DNA concentration compared to commonly used procedures. Use of 10(3) or 10(4) DNA-NLS complexes augments the number of transgene integrations, which occur mostly within 1-4 distinct insertion sites in the genome. In situ hybridization analyses and transmission studies show that transgene integration into the germline and somatic tissues is mosaic, and that the extent of mosaicism is negatively correlated with the amount of DNA-NLS injected. In addition, a larger proportion of zebrafish harboring a single copy of the transgene expresses luciferase, albeit at a 10-fold lower level than those containing numerous transgene insertions. The data demonstrate the potential use of nuclear targeting peptides noncovalently bound to vector DNA to enhance the efficiency of biotechnological nonviral gene transfer applications.
To investigate the role of P16 (INK4a)-extracellular signal related kinase 1/2 (ERK1/2) signaling pathway in cisplatin (DDP) resistance induced by multidrug resistance protein 1 (MDR1), also known as P-glycoprotein (P-gp), in cervical adenocarcinoma.A human DDP-resistant HeLa cell line (HeLa/DDP) was constructed using the combination of incremental and intermittent administration of DDP. Cell Counting Kit-8 (CCK-8) assay was used to measure the IC50 and resistance index (RI) of cells. The morphological changes and population doubling time were observed under an inverted microscope. Plate cloning formation assay was performed to evaluate the cell proliferation and tumorigenic ability. Cell invasion and migration were determined by transwell assays. Besides, the expression of P16, phosphorylated extracellular signal related kinase 1 and 2 (pERK1/2), total ERK1/2 and MDR1 were measured using western blot analysis. The ERK-specific inhibitor U0126 and agonist TPA was used to explore the role of ERK.The DDP-resistant cervical adenocarcinoma HeLa/DDP cell line was successfully established, which showed stronger cell growth, invasion, and migration. In the HeLa/DDP cells, pERK1/2 was downregulated, P-gp was upregulated and P16 was downregulated. Overexpression of P16 led to a significant decrease in the proliferation rate, migration ability, and invasion ability of the HeLa/DDP cells. Furthermore, overexpression of P16 increased and the decreased expression of pERK1/2 and P-gp in the HeLa/DDP cells, respectively. Treatment of HeLa/DDP cells transfected with P16 plasmid with ERK-specific inhibitor U0126 significantly decreased the expression of pERK1/2 and increased the expression of P-gp from 6 h to 48 h. Moreover, after 72 h, the expression of pERK1/2 was up-regulated and the expression of P-gp was inhibited.Overexpression of P16 could partially reverse the MDR1-mediated DDP resistance in the cervical adenocarcinoma by the enhancement of phosphorylation of ERK signaling pathway, which provided a theoretical basis for the treatment of DDP resistance in cervical adenocarcinoma.
Suppressor of fused is essential for the maximal activation of Sonic Hedgehog signaling in development and tumorigenesis. However, the role of Sufu in cervical carcinoma remains unknown. Here, we report new findings of Sufu in regulating the epithelial-to-mesenchymal transition through the FoxM1 transcriptional modulation by 14-3-3ζ protein in cervical carcinoma. Sufu is overexpressed in cervical squamous cell carcinoma and its level in clinical tumor tissues is positively correlated with 14-3-3ζ. Functionanlly, siSufu remarkably prevents the cancer cell migration and invasion. We further demonstrate that the transcriptional activity of Sufu is increased by FoxM1, of which stability is promoted by 14-3-3ζ. Knockdown FoxM1 decreases the invasion of SiHa cells and reconstitution of Sufu rescues the invasion of these cells.Finally, overexpression of Sufu is significantly associated with differentiation grade, FIGO stage, Depth of stromal invasion and vascular cancer embolus. Our findings highlight a novel role for Sufu in cervical carcinogenesis.
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