USP18 promotes cell proliferation and suppressed apoptosis in cervical cancer cells via activating AKT signaling pathway.

BACKGROUND: The deubiquitinating (DUB) enzyme ubiquitin-specific protease 18 (USP18), also known as UBP43, is an ubiquitin-specific protease linked to several human malignancies. However, USP18's underlying function in human cervical cancer remains unclear. In the current study, we aimed to analyse the role of USP18 and its signalling pathways in cervical cancer. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to analyse USP18 levels in cervical cancer and matched to adjacent normal tissues. Moreover, RNA interference (RNAi) and lentiviral-mediated vector transfections were performed to silence and overexpress USP18, respectively, in cervical cancer cells. Further, Cell Counting Kit-8 (CCK-8) and Annexin V/PI staining assays were used to assess its biological function in cell proliferation and apoptosis, respectively. A xenograft model was used to examine USP18's function in vivo. RESULTS: The present findings demonstrated that USP18 was overexpressed in cervical cancer specimens and cell lines. Silencing USP18 in SiHa and Caski cervical cancer cell lines inhibited cell proliferation, induced apoptosis, and promoted cleaved caspase-3 expression. In contrast, USP18 overexpression showed the opposite effects in human HcerEpic cells. A Gene Set Enrichment Analysis revealed that USP18 was enriched in the PI3K/AKT signalling pathway in cervical cancer. Hence, the PI3K/AKT inhibitor LY294002 was used to determine the relationship between USP18 and AKT in cervical cancer cells. Importantly, LY294002 significantly abolished the effects of USP18 overexpression in cervical cancer cells. In vivo, USP18 silencing inhibited human cervical cancer cells' tumorigenicity. CONCLUSIONS: The current study indicates that USP18 is an oncogenic gene in cervical cancer. Our findings not only deepened the understanding of USP18's biological function in cervical cancer pathogenesis, but we also provided novel insight for cervical cancer therapy. TRIAL REGISTRATION: Retrospectively registered.

Application of a diagnosis flow draft based on appearance impression for detection of vulvar disease.

OBJECTIVES: The aims of this retrospective study were to evaluate the clinical applicability of the latest International Society for the Study of Vulvovaginal Disease (ISSVD) and International Federation for Cervical Pathology and Colposcopy (IFCPC) terminology for vulvar diseases, and to explore a new evaluation flow to optimize decision-making on diagnosis. METHODS: A total of 1,068 patients with 5,340 qualified vulvar images were evaluated by observers using 2011 ISSVD and 2011 IFCPC terminology systems. The sensitivity, specificity, positive predictive value, negative predictive value, Youden Index and Overall Diagnostic Value (ODV) were calculated for each finding in the two systems. Then the disease diagnosis order and a diagnosis flow draft (DFD) were obtained. RESULTS: A total of 15 kinds of vulvar diseases were diagnosed. The proportion of patients accompanied with cervical or vaginal intraepithelial neoplasia was highest (83.3 %) in vulvar Paget's disease group (p<0.001). Total area of lesions was larger in vulvar Paget's disease, lichen simplex chronicus and lichen sclerosus group (p<0.001). Among the top five findings of ODV, some findings inferred several (≥6) kinds of diseases, while some findings only exist in a certain disease. When the DFD was used, the agreement between the initial impression and histopathology diagnosis was 68.8 %, higher than those when ISSVD an IFCPC terminology systems used (p=0.028), and it didn't change with the experience of the observer (p=0.178). CONCLUSIONS: Based on the findings in ISSVD and IFCPC terminology systems, we explored a DFD for observers with different experience on the detection of vulvar disease.

[Study on relationship between endogenous androgens and insulin resistance at the different stages of postmenopause].

OBJECTIVE: To investigate the relationship between insulin resistance and endogenous androgens at early and late phase of postmenopause. METHODS: A total of 105 women with early postmenopause ( ≤ 5 years since menopause) and 107 women with late postmenopause ( ≥ 10 years since menopause) were enrolled in this study.In the mean time, those women were classified into normal weight[body mass index (BMI), BMI <24 kg/m(2)] group and overweight (BMI ≥ 24 kg/m(2)) group.Sex hormone-binding globulin (SHBG), testosterone (T) , dehydroepiandrosterone-sulfate (DHEA-S) , fasting blood glucose(FBG), fasting insulin (FINS) levels were measured and then calculated free androgen index (FAI) and homeostatic model assessment of insulin resistance (HOMA-IR) . The relationship between sex hormones and insulin resistance was analyzed by partial correlation and multiple linear regression analyses. RESULTS: Compared to early postmenopausal women, late postmenopausal women had higher FINS [(7.9 ± 6.6) mU/L versus (6.6 ± 4.0) mU/L] and HOMA-IR(2.1 ± 1.9 versus 1.7 ± 1.1), but they had lower DHEA-S[(0.9 ± 0.5) mg/L versus (1.1 ± 0.5) mg/L, all P < 0.05) ]. Both in early postmenopausal and late postmenopausal groups, overweight women had higher HOMA-IR (early group, 2.2 ± 1.0 versus 1.2 ± 0.9;late group, 2.8 ± 2.6 versus 1.6 ± 1.1) and FINS early group[(6.9 ± 2.9) mU/L versus (4.6 ± 2.0) mU/L];late group[(10.2 ± 9.3) mU/L versus (6.4 ± 3.6) mU/L] than those at women with normal weight group (all P < 0.05) .In early postmenopausal group, overweight women had lower SHBG[ (52 ± 37) nmol/L versus (71 ± 37) nmol/L] and higher FAI (2.5 ± 2.1) versus (1.3 ± 1.1) than those at normal weight women group (all P < 0.05) .In late postmenopausal group, overweight women had higher DHEA-S (1.0 ± 0.5) mg/L versus (0.8 ± 0.4) mg/L (P < 0.05) . The analyses suggested that in early postmenopausal group, SHBG was correlated negatively with FINS and HOMA-IR (ß = -0.386, P < 0.05;ß = -0.553, P < 0.05) , DHEA-S was correlated positively with FBG (ß = 0.348, P < 0.05) in early postmenopausal group.FAI was correlated positively with FBG in late postmenopausal group (ß = 0.505, P < 0.05) . CONCLUSIONS: The increased androgenic activities are associated with insulin resistance after of menopause. These correlations are different at different stages of postmenopause, which SHBG levels correlate with high risk of insulin resistance and DHEA-S levels correlates with high blood glucose levels at early postmenopause and FAI correlates with high blood glucose levels at late postmenopause.

Preparation and Microstructure of High-Activity Spherical TaNbTiZr Refractory High-Entropy Alloy Powders.

High-activity spherical TaNbTiZr refractory high-entropy alloy (REHA) powders were successfully prepared by electrode induction melting gas atomization (EIGA) and plasma rotating electrode process (PREP) methods. Both the EIGAed and PREPed TaNbTiZr RHEA powders have a single-phase body-centered cubic (BCC) structure and low oxygen content. Compared with the EIGAed powders, the PREPed powders exhibit higher sphericity and smoother surface, but larger particle size. The average particle sizes of the EIGAed and PREPed powders are 51.8 and 65.9 µm, respectively. In addition, both the coarse EIGAed and PREPed powders have dendritic structure, and the dendrite size of the EIGAed powders is larger than that of the PREPed powders. Theoretical calculation indicates that the cooling rate of the PREPed powders is one order of magnitude higher than that of the EIGAed powders during the solidification process, and the dendritic structure has more time to grow during EIGA, which is the main reason for the coarser dendrite size of the EIGAed powders.

Effect of Si on Microstructure and Mechanical Properties of FeCrNi Medium Entropy Alloys.

FeCrNi medium entropy alloy (MEA) has been widely regarded for its excellent mechanical properties and corrosion resistance. However, insufficient strength limits its industrial application. Intermetallic particle dispersion strengthening is considered to be an effective method to improve strength, which is expected to solve this problem. In this work, microstructural evolution and mechanical behavior of FeCrNi MEA with different Si content were investigated. We found that the precipitation of fine σ particles can be formed in situ by thermomechanical treatment of Si doping FeCrNi MEAs. The FeCrNiSi0.15 MEA exhibits a good combination of strength and ductility, with yield strength and tensile elongation of 1050 MPa and 7.84%, respectively. The yield strength is almost five times that of the as-cast FeCrNi MEA. The strength enhancement is mainly attributed to the grain-boundary strengthening and precipitation strengthening caused by fine σ particles.

In Situ Buildup of Zinc Anode Protection Films with Natural Protein Additives for High-Performance Zinc Battery Cycling.

The uncontrolled growth of dendrites and serious side reactions, such as hydrogen evolution and corrosion, significantly hinder the industrial application and development of aqueous zinc-ion batteries (ZIBs). This article presents ovalbumin (OVA) as a multifunctional electrolyte additive for aqueous ZIBs. Experimental characterizations and theoretical calculations reveal that the OVA additive can replace the solvated sheath of recombinant hydrated Zn2+ through the coordination water, preferentially adsorb on the surface of the Zn anode, and construct a high-quality self-healing protective film. Notably, the OVA-based protective film with strong Zn2+ affinity will promote uniform Zn deposition and inhibit side reactions. As a result, Zn||Zn symmetrical batteries in ZnSO4 electrolytes containing OVA achieve a cycle life exceeding 2200 h. Zn||Cu batteries and Zn||MnO2 (2 A g-1) full batteries show excellent cycling stability for 2500 cycles, demonstrating promising application prospects. This study provides insights into utilizing natural protein molecules to modulate the kinetics of Zn2+ diffusion and enhance the stability of the anode interface.

[Retracted] Tripartite motif­containing 14 regulates cell proliferation and apoptosis in cervical cancer via the Akt signaling pathway.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the GAPDH control western blotting data shown in Fig. 2B were strikingly similar to data appearing in different form in Fig. 1E in another article written by different authors at different research institutes [Liang T, Ye X, Liu Y, Qiu X, Li Z, Tian B and Yan D: FAM46B inhibits cell proliferation and cell cycle progression in prostate cancer through ubiquitination of ß­catenin. Exp Mol Med 50: 1­12, 2018]. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 22: 5145­5154, 2020; DOI: 10.3892/mmr.2020.11634].

Microstructure and Mechanical Properties of Novel Lightweight TaNbVTi-Based Refractory High Entropy Alloys.

A series of novel lightweight TaNbVTi-based refractory high entropy alloys (RHEA) were fabricated through ball-milling and spark plasma sintering (SPS). The reinforced phase of TiO precipitates were in-situ formed due to the introduction of Al2O3 ceramic particles. The RHEA with 15% Al2O3 exhibits a high compressive yield strength (1837 MPa) and a low density (7.75 g/cm3) with an adequate ductility retention. The yield strength and density are 32% higher and 15% lower, respectively, compared to the RHEA without Al2O3 addition. The specific yield strength (237 MPa cm3/g) of the RHEAs is much higher than that of other reported RHEAs, and is mainly ascribed to the introduction of high volume fraction of Al2O3 additives, resulting in solid solution strengthening and precipitation strengthening. Meanwhile, the ductile matrix is responsible for the good compressive plasticity.

A K-nearest Neighbor Model to Predict Early Recurrence of Hepatocellular Carcinoma After Resection.

Background and Aims: Patients with hepatocellular carcinoma (HCC) surgically resected are at risk of recurrence; however, the risk factors of recurrence remain poorly understood. This study intended to establish a novel machine learning model based on clinical data for predicting early recurrence of HCC after resection. Methods: A total of 220 HCC patients who underwent resection were enrolled. Classification machine learning models were developed to predict HCC recurrence. The standard deviation, recall, and precision of the model were used to assess the model's accuracy and identify efficiency of the model. Results: Recurrent HCC developed in 89 (40.45%) patients at a median time of 14 months from primary resection. In principal component analysis, tumor size, tumor grade differentiation, portal vein tumor thrombus, alpha-fetoprotein, protein induced by vitamin K absence or antagonist-II (PIVKA-II), aspartate aminotransferase, platelet count, white blood cell count, and HBsAg were positive prognostic factors of HCC recurrence and were included in the preoperative model. After comparing different machine learning methods, including logistic regression, decision tree, naïve Bayes, deep neural networks, and k-nearest neighbor (K-NN), we choose the K-NN model as the optimal prediction model. The accuracy, recall, precision of the K-NN model were 70.6%, 51.9%, 70.1%, respectively. The standard deviation was 0.020. Conclusions: The K-NN classification algorithm model performed better than the other classification models. Estimation of the recurrence rate of early HCC can help to allocate treatment, eventually achieving safe oncological outcomes.

[Research on phytoestrogenic effect of formononetin].

OBJECTIVE: Research on the phytoestrogenic effect and its possible mechanism of formononetin. METHOD: To evaluate the estrogenic effect and mechanisms of formononetin through the test of its influence on proliferation and ER subtype expression of T47D cells. RESULT: The proliferation rates of T47D cells treated with 1 x 10(-7) -1 x 10(-6) mol x L(-1) formononetin were not increased. On the influence of ICI182, 780, the proliferation rates of T47D cells treated with 1 x 10(-7) 1 x 10(-6) mol x L(-1) formononetin were decreased. Formonenetin could induce the augment of ERalpha expression significantly of T47D. CONCLUSION: Formonenetin has phytoestrogenic effect Formonenetin can not accelerate ER(+) T47D cell proliferation. But the expression level of ERalpha subtype in T47D cells change significantly with certain concentrations of formonenetin.

The effects of a new, improved Chinese medicine, Gengnianchun formula granules, on hot flushes, depression, anxiety, and sleep in Chinese peri- and postmenopausal women: a randomized placebo-controlled trial.

OBJECTIVE: The aim of the study was to investigate the effectiveness and safety of a new, improved herbal formula of a traditional Chinese medicine, improved Gengnianchun (I-GNC), on hot flushes, depression, anxiety, and sleep in peri- and postmenopausal women in China. METHODS: A randomized, single-blind, placebo-controlled trial of peri- and postmenopausal women with Kupperman Index (KMI) scores of 15 or higher was conducted for 12 weeks. Hot flush frequencies, KMI scores, Hamilton depression scale scores, Hamilton anxiety scale scores, and Pittsburgh Sleep Quality Index scores were evaluated. Each outcome was evaluated every 4 weeks. RESULTS: Ninety-eight participants completed the study. The I-GNC formula significantly reduced the mean (SD) frequency of hot flushes from 7 (4.554) to 1.2 (1.675) in the I-GNC group and from 6.74 (3.43) to 3.66 (2.635) in the placebo group (P < 0.01). The KMI (P < 0.01), Hamilton depression scale (P < 0.01), and Hamilton anxiety scale (P < 0.01) scores decreased in both groups after treatment, and significant differences were observed between the two groups (P < 0.01); however, no significant difference in the Pittsburgh Sleep Quality Index score was observed. I-GNC had no effect on serum follicle-stimulating hormone or E2 levels. There were no obvious adverse effects. CONCLUSIONS: The traditional Chinese medicine herbal formula I-GNC can alleviate the symptoms of menopausal syndrome and improve quality of life among peri- and postmenopausal women. I-GNC is safe and has no notable adverse effects.

Tripartite motif­containing 14 regulates cell proliferation and apoptosis in cervical cancer via the Akt signaling pathway.

Tripartite motif­containing (TRIM) 14 is a protein of the TRIM family. Studies have indicated that TRIM14 may be used as an oncogene in tumor cells, such as osteosarcoma, non­small cell lung cancer and breast cancer through different pathways. However, the functions of TRIM14 in cervical cancer cells remain unclear. Therefore, this study aimed to investigate the functions of TRIM14 in cervical cancer cells and its underlying mechanism. Caski cells stably expressing TRIM14 and SiHa, and HeLa cells stably expressing TRIM14 short hairpin RNA were constructed by lentivirus­mediated overexpression or knockdown systems. The effects of TRIM14 on proliferation and apoptosis of cervical cancer cells were detected by Cell Counting Kit­8 (CCK­8) assay and flow cytometry, respectively. In addition, reverse transcription­quantitative (RT­q) PCR and western blotting were used to investigate the expression levels of TRIM14 and of signaling pathway marker protein including P21, caspase­3, cleaved caspase­3, Akt and phosphorylated Akt. The results of RT­qPCR and western blotting revealed that TRIM14 was highly expressed in human cervical cancer tissues and cell lines compared with adjacent normal tissues and normal cervical epithelial cells. TRIM14 also regulated cell proliferation and apoptosis of human SiHa, HeLa and Caski cervical cancer cell lines through the Akt signaling pathway. Additionally, TRIM14 protein levels were related to the clinical and pathological features of cervical cancer. CCK­8 assay and flow cytometry demonstrated that TRIM14 expression could promote cervical cancer cell proliferation and autophagy suppression. Taken together, TRIM14­induced cell proliferation and apoptosis inhibition may by evoked by the activation of the Akt pathway. This study demonstrated the role of TRIM14 in cervical cancer, and reveals its mechanism of action as a potential therapeutic target for cervical cancer.

High Temperature Deformation Behavior of In-Situ Synthesized Titanium-Based Composite Reinforced with Ultra-Fine TiB Whiskers.

A TiB/Ti-6Al-4V composite reinforced with ultra-fine TiB whiskers (UF-TiB) was prepared by the powder metallurgy method. High temperature compression tests were carried out to study the hot deformation behavior of the UF-TiB/Ti-6Al-4V composite. The compressive deformation was performed in the temperature range of 900⁻1200 °C and the strain rate range of 0.001⁻10 s-1. The results showed that stable flow occurred at the condition of 900⁻1200 °C/0.001⁻0.01 s-1. The optimum working condition was 900 °C/0.001 s-1, with the deformation mechanism of dynamic recrystallization (DRX). Instable flow occurred when the strain rate was higher than 0.01 s-1, where the failure modes included adiabatic shear deformation, whisker breakage and whisker/matrix debonding. The deformability of the UF-TiB/Ti-6Al-4V composite was much better than the traditional casted and the pressed + sintered TiB/Ti-6Al-4V composites, which are typically reinforced with coarse-grained TiB whiskers. The high deformability was primarily attributed to the ultra-fine reinforcements, which could coordinate the deformation more effectively. In addition, a fine matrix microstructure also had a positive effect on deformability because the fine matrix microstructure could improve the grain boundary sliding.

Initiation of GnRH agonist treatment on 3-5 days postoperatively in endometriosis patients: a randomized controlled trial.

Seventy patients with stage III or IV endometriosis were randomly assigned to 2 groups after conservative surgery. Group O (n = 35) received 3 cycles of a 28-day gonadotropin-releasing hormone agonist (GnRH-a) treatment (goserelin, 3.6 mg) starting 3-5 days postoperatively. Group M (n = 35) received the same treatment starting on days 1-5 of menstruation. Groups were further subdivided according to add-back treatment. Pre- and posttreated levels of estradiol (E2 ), follicle stimulating hormone (FSH), and luteinizing hormone (LH) and visual analog scale (VAS), Kupperman menopausal index (KMI), and bone mineral density (BMD) scores were recorded. The incidence of uterine bleeding was assessed. In both groups, serum levels of E2 , FSH, and LH and VAS scores decreased significantly after treatment. Spotting was the most frequent bleeding pattern. During cycle 1, the bleeding time in group M was much longer that than that in group O (P =.001), and the bleeding rate in group M was significantly higher than that in group O (P =.024, RR = 1.185). In patients with stage III or IV endometriosis, the efficacy of GnRH-a initiated 3-5 days postoperatively was equivalent to that of GnRH-a initiated on days 1-5 of menstruation. Female patients who initiated GnRH-a treatment 3-5 days postoperatively experienced less uterine bleeding during the first cycle of treatment.

The relationship between endogenous androgens and body fat distribution in early and late postmenopausal women.

OBJECTIVES: To investigate the relationship between endogenous androgens and body fat distribution in early and late postmenopausal women. MATERIALS AND METHODS: We enrolled postmenopausal women consisting of an early group (≤ 5 years since menopause, n = 105) and a late group (≥ 10 years since menopause, n = 107). Each group was subdivided into normal weight (BMI <24 kg/m(2)) group, overweight and obese (BMI ≥ 24 kg/m(2)) group. Fasting total testosterone (T), dehydroepiandrosterone-sulfate (DHEA-S) and sex hormone-binding globulin (SHBG) levels were measured. Body fat distribution was evaluated by dual-energy X-ray absorptiometry (DEXA). RESULTS: Late postmenopausal women had a higher proportion of body fat than early postmenopausal women. The body fat of the overweight and obese women had a greater tendency to accumulate in the abdomen compared with the normal weight women both in early and late postmenopausal groups. The overweight and obese women had a higher free testosterone (FT) than the normal weight women in early postmenopausal women (P<0.05). In late postmenopausal women, the overweight and obese women had higher DHEA-S levels than normal weight women (P<0.05). No direct relationship was observed between the T levels and body fat distribution both in early and late postmenopausal groups (P>0.05).The FT in early postmenopausal women and the DHEA-S levels in late postmenopausal women correlated positively with the trunk/leg fat ratio (T/L) and the proportion of android fat whereas correlated negatively with the proportion of gynoid fat in the partial correlation and multiple linear regression analyses (all P<0.05). CONCLUSIONS: Serum T levels do not correlate directly with body fat distribution, the FT in early postmenopausal women and DHEA-S levels in late postmenopausal women correlate positively with abdominal fat accumulation.

Correction: The Relationship between Endogenous Androgens and Body Fat Distribution in Early and Late Postmenopausal Women.

[This corrects the article DOI: 10.1371/journal.pone.0058448.].

Marker gene screening for human mesenchymal stem cells in early osteogenic response to bone morphogenetic protein 6 with DNA microarray.

AIMS: Microarray data were analyzed using bioinformatic tools to screen marker genes of human mesenchymal stem cells (hMSC) in response to bone morphogenetic protein 6 (BMP6). RESULTS: A total of 190 differentially expressed genes were identified. The interaction network was divided into three functional modules. These genes were connected with BMP signaling pathways and regulation of cell processes, while NOG and BMPR2 participated in the transforming growth factor-beta signal pathway. Besides, several related small molecules were acquired. CONCLUSION: Marker genes in osteogenic responses to BMP6 treatment for hMSC were screened with microarray data along with elaborate function analysis by bioinformatics. NOG and BMPR2 showed potential to become indicators to monitor the directed differentiation of hMSC into osteoblasts, which can be used for bone disease treatment. Moreover, small molecules such as W-13 were retrieved and provided directions for future drug design.