Factors Correlated with the Accuracy of Colposcopy-Directed Biopsy: A Systematic Review and Meta-Analysis.

PURPOSE/AIM OF THE STUDY: Colposcopy-directed cervical biopsy has played a major role in diagnosing cervical lesions. The precision of colposcopy-guided biopsy has been questioned. We analyzed several factors that may be correlated with the accuracy of biopsy. METHODS: PubMed, EMBASE were searched from January 1, 1998 to March 1, 2020. Odds ratio with 95% confidence intervals (CIs) were calculated. SELECTION CRITERIA: Included studies evaluated factors correlated with the accuracy of biopsy and patients' final diagnosis was established by histological examination of the specimen obtained by conization, loop electrosurgical excision procedure (LEEP), or colpohysterectomy. RESULTS: A total of 10 studies were selected for the systematic review and meta-analysis. The pooled analysis indicated that the diagnostic inaccuracies of colposcopy-directed cervical biopsy were magnified in women who were 50 years of age or older. Postmenopausal status and transformation zone 3 type were also associated with the diagnostic inaccuracies of colposcopy-directed biopsy. High-grade squamous intraepithelial lesions had better concordance rates than low-grade squamous intraepithelial lesions. The number of vaginal deliveries, number of biopsies, and HPV type were associated with biopsy underdiagnosis and biopsy overestimation. CONCLUSIONS: This meta-analysis found that the correlation between the histological findings at biopsy and after surgical treatment was influenced by women's age, menopausal status, and the transformation zone type. The diagnostic efficacy was also better for high-grade squamous intraepithelial lesions than for low-grade squamous intraepithelial lesions. Further large-scale randomized clinical trials are required to analyze the factors correlated with biopsy underdiagnosis and biopsy overestimation.

miR-145 attenuates cardiac fibrosis through the AKT/GSK-3ß/ß-catenin signaling pathway by directly targeting SOX9 in fibroblasts.

Myocardial infarction (MI) will inevitably result in cardiac fibrosis. In this study, we investigated the effect of microRNA-145 (miR-145) and transcription factor sex-determining region Y box 9 (SOX9) in the production of cardiac fibrosis induced by MI. MI rat models were established by left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD, the cardiac fibrosis level was assessed by Masson's trichrome staining. Cardiac fibroblasts (CFs) exposed to hypoxia were used to simulate MI-induced fibrosis. Flow cytometry, cell counting kit-8, and transwell assays were used to examine changes in CF apoptosis, proliferation, and migration, respectively. miR-145 expression was measured by quantitative real-time polymerase chain reaction. Immunofluorescence and Western blot analysis were performed to determine the relative expression of proteins. In comparison to the sham-operated group, the expression of miR-145 was significantly downregulated in the infarction peripheral area, whereas, SOX9 was upregulated. In the infarcted heart, the overexpression of miR-145 significantly ameliorated cardiac fibrosis and cardiac function, and there was a negative correlation between miR-145 and SOX9 expressions in hypoxic CFs in vitro. In addition, SOX9 was verified to be a functional target of miR-145. Overexpression of miR-145 or inhibition of SOX9 decreased CF proliferation, migration, and fibrosis, but augmented their apoptotic rate. Moreover, the upregulation of miR-145 or suppression of SOX9 inhibited AKT and ß-catenin signaling in hypoxic CFs. Taken together, this study highlights a potential treatment for cardiac fibrosis through the targeted regulation of SOX9 by miR-145, and our findings indicate that miR-145 exerts anti-fibrotic effects in MI via the negative regulation of SOX9 and its downstream AKT/GSK-3ß/ß-catenin pathways.

Over-expression of Kv4.3 gene reverses cardiac remodeling and transient-outward K+ current (Ito) reduction via CaMKII inhibition in myocardial infarction.

OBJECTIVE: Previous study has shown that Kv4.3, a main coding subunit generating cardiac transient-outward K+ current (Ito), can inhibit Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. Based on these observations, we speculate that over-expression of Kv4.3 gene could reverse not only Ito reduction but also cardiac remodeling in the rat myocardial infarction (MI) model. METHODS AND RESULTS: Healthy male Sprague-Dawley (SD) rats were used to establish MI model by ligation of left anterior descending coronary artery, and adenovirus integrated with Kv4.3 gene (AD-Kv4.3) was delivered in infarct border zone by intramyocardial injection. The hearts were harvested for histological analysis (HE or Masson trichrome staining), western blot or patch clamp 4 weeks after MI. Our data showed that the application of AD-Kv4.3 could reduce myocardial infarct size and fibrosis, and its cardioprotective effects were similar with medicine therapy (combination of metoprolol and captopril). Moreover, Kv4.3 over-expression significantly improved MI-induced cardiac dysfunction and enhanced Ito density while decreasing corrected QT (QTc) intervals and cardiac electrophysiological instability. Western blot showed that Kv4.3 transfection reduced CaMKII, PLB-17 and ryanodine receptor2 (RyR2 Ser2814) phosphorylation level, at same time increased SERCA2 expression dramatically. CONCLUSION: Over-expression of Kv4.3 can not only attenuate cardiac electrophysiological instability and cardiac performance, but also reduce myocardial infarct area and cardiac fibrosis. Like traditional anti-remodeling therapy-angiotensin converting enzyme inhibitor (ACEI) combined with ß-adrenergic receptor blocker, over-expression of Kv4.3 seems to be an effective and safe therapy for both structural and electrical remodeling induced by MI via CaMKII inhibition.

Association between tumor mutation burden and immune infiltration in ovarian cancer.

BACKGROUND: It remains unclear whether the tumor mutation burden (TMB) or a TMB-related signature could be prognostic indicators in ovarian cancer (OC), as potential correlations with immune infiltrates and immunotherapy responsiveness remains poorly understood. METHODS: Data of 941 OC patients were collected from three datasets, including 587, 260, and 94 patients from The Cancer Genome Atlas (TCGA), GSE32062, and the International Cancer Genome Consortium (ICGC), respectively. TMB was calculated and correlations with clinical outcomes, immune infiltrates, and immunotherapy responsiveness were investigated in the TCGA OC cohort. Weighted gene co-expression network analysis was performed to identify TMB-related genes. A TMB-related signature was constructed and validated. RESULTS: Higher TMB was associated with better survival in the TCGA and ICGC OC cohorts. The high-TMB group had higher CD8+ T-cell infiltration than the low-TMB group. No significant correlation was found between TMB and immunotherapy response. Furthermore, we selected 8 prognostic and TMB-related genes to construct a TMB-related signature that could distinguish between the high- and low-risk patients; its predictive power was validated in the GSE32062 and ICGC datasets. SubMap analysis suggested that patients in the low-risk group might have a better response to anti-PD1 therapy. CONCLUSIONS: We examined the prognostic value of TMB and its potential association with immune cell infiltration and immunotherapy responsiveness in OC. A TMB-related prognostic signature consisting of 8 genes was developed and verified, which might be a promising prognostic signature for the prognosis of OC patients.

Propranolol induced apoptosis and autophagy via the ROS/JNK signaling pathway in Human Ovarian Cancer.

Propranolol has a significant anti-cancer effect towards various cancers. Our study aimed at investigating the underlying mechanism of Propranolol's therapeutic effect towards ovarian cancer. Specifically, Propranolol significantly reduced the viability of human ovarian cancer cell lines SKOV-3 and A2780 in a dose- and time-dependent manner. Flow cytometry analysis revealed that Propranolol induced the cell cycle arrest at G2/M phase therefore leading to apoptosis. Moreover, autophagy inhibitor 3-MA markedly enhanced the Propranolol-induced apoptosis. In addition, reactive oxygen species (ROS) increased dramatically after Propranolol treatment and Propranolol activated the phosphorylation of JNK. What is more, p38 inhibitor SB203580 and JNK inhibitor SP600125 attenuated the upregulated expression of LC3-II and cleaved-caspase-3 by the effect of Propranolol. ROS exclusive inhibitor antioxidant N-acetyl cysteine (NAC) weakens the phosphorylation of JNK proteins induced by Propranolol. In summary, these results suggested that Propranolol induced cell apoptosis and protective autophagy through the ROS/JNK signaling pathway in human ovarian cancer cells.

Over-expression of microRNA-145 drives alterations in ß-adrenergic signaling and attenuates cardiac remodeling in heart failure post myocardial infarction.

BACKGROUND: Numerous studies have highlighted the crucial role of microRNA-145 (miR-145) in coronary atherosclerosis and myocardial ischemia reperfusion injury. However, effects of miR-145 on ß-adrenergic signaling and cardiac remodeling in heart failure (HF) remains unclarified. METHODS AND RESULTS: We established HF model in rats with left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD ligation, rats showed substantial aggravation of cardiac dilation and electrophysiological instability. Up-regulation of miR-145 ameliorated HF-induced myocardial fibrosis and prolonged action potential duration. Echocardiography revealed increased basal contractility and decreased left ventricular inner-diameter in miR-145 over-expressed heart, while cardiac response to ß-adrenergic receptor (ßAR) stimulation was reduced. Furthermore, miR-145 increased L-type calcium current (ICa) density while decreased ICa response to ß-adrenergic stimulation with isoproterenol. The alterations in ßAR signaling might be predominant due to miR-145-mediated activation of Akt/CREB cascades. At high frequency pacing, Ca2+ transient, cell shortening and frequency of Ca2+ waves were significantly improved in AD-miR-145 group. Western blotting revealed that increased expression of Cav1.2, Ca2+-ATPase, ß2AR, GNAI3 and decreased level of CaMKII might be attributed to the cardioprotective effects of miR-145. CONCLUSION: miR-145 effectively alleviates HF-related cardiac remodeling by improving cardiac dilation, fibrosis, intracellular Ca2+ mishandling and electrophysiological instability.

Circular RNA circGSE1 Promotes Cervical Cancer Progression Through miR-138-5p/Vimentin.

BACKGROUND: A growing number of studies have identified that circular RNAs (circRNAs) play a vital role in the progression of various tumors. However, the underlying functions and mechanisms of circRNAs in cervical cancer have not been clarified. METHODS: qRT-PCR was used to detect the level of circGSE1 in cervical cancer tissues and matched normal tissues. In vitro cell wound healing, transwell migration and invasion assays were employed to assess the effects of circGSE1 on cell mobility. The pull-down, luciferase reporter, RIP and rescue assays were performed to evaluate the interaction between circGSE1and miR-138-5p and the regulation of miR-138-5p on Vimentin. RESULTS: We found that circGSE1 was significantly higher in cervical cancer tissues than that in matched normal tissues. Further analyses revealed that the level of circGSE1 was positively correlated with tumor differentiation, FIGUREO stage, depth of stromal invasion, lymph node metastasis and infiltration of parauterine organ. Kaplan-Meier survival analysis showed that high circGSE1 predicted worse overall survival and disease-free survival. Down-regulated circGSE1 evidently inhibited cell migration and metastasis of cervical cancer, while up-regulated circGSE1 significantly promoted cell migration and metastasis. The pull-down, luciferase reporter and RIP assays revealed that circGSE1 directly bound to and sponge miR-138-5p. MiR-138-5p inhibited the expression of Vimentin through directly binding to 3'UTR of Vimentin mRNA. In addition, miR-138-5p suppressed cell migration and invasion through inhibiting Vimentin expression, and circGSE1 promoted cell migration and invasion through sponging miR-138-5p and enhancing Vimentin expression. CONCLUSION: CircGSE1 promotes the progression and may act as a novel diagnostic biomarker for disease progression of cervical cancer.

The novel circCLK3/miR-320a/FoxM1 axis promotes cervical cancer progression.

As a new class of non-coding RNA, circular RNAs (circRNAs) play crucial roles in the development and progression of various cancers. However, the detailed functions of circRNAs in cervical cancer have seldom been reported. In this study, circRNA sequence was applied to detect the differentially expressed circRNAs between cervical cancer tissues and adjacent normal tissues. The relationships between circCLK3 level with clinicopathological characteristics and prognosis were analyzed. In vitro CCK-8, cell count, cell colony, cell wound healing, transwell migration and invasion, and in vivo tumorigenesis and lung metastasis models were performed to evaluate the functions of circCLK3. The pull-down, RNA immunoprecipitation (RIP), luciferase reporter and rescue assays were employed to clarify the interaction between circCLK3 and miR-320a and the regulation of miR-320a on FoxM1. We found that the level of circCLK3 was remarkably higher in cervical cancer tissues than in adjacent normal tissues, and closely associated with tumor differentiation, FIGO stage and depth of stromal invasion. Down-regulated circCLK3 evidently inhibited cell growth and metastasis of cervical cancer in vitro and in vivo, while up-regulated circCLK3 significantly promoted cell growth and metastasis in vitro and in vivo. The pull-down, luciferase reporter and RIP assays demonstrated that circCLK3 directly bound to and sponge miR-320a. MiR-320a suppressed the expression of FoxM1 through directly binding to 3'UTR of FoxM1 mRNA. In addition, FoxM1 promoted cell proliferation, migration, and invasion of cervical cancer, while miR-320a suppressed cell proliferation, migration, and invasion through suppressing FoxM1, and circCLK3 enhanced cell proliferation, migration and invasion through sponging miR-320a and promoting FoxM1 expression. In summary, circCLK3 may serve as a novel diagnostic biomarker for disease progression and a promising molecular target for early diagnoses and treatments of cervical cancer.

MicroRNA-145 Protects against Myocardial Ischemia Reperfusion Injury via CaMKII-Mediated Antiapoptotic and Anti-Inflammatory Pathways.

MicroRNA-145 (miR-145) has been shown to play an important role in cardiovascular system disorders; however, the underlying mechanism is not completely understood. The purpose of this study was aimed at elucidating the cardioprotective effects of miR-145 against myocardial ischemia/reperfusion (I/R) injury. We established a rat myocardial I/R model with 45 min left anterior descending coronary artery (LAD) occlusion and 2 h reperfusion. The levels of myocardial enzymes, apoptotic, inflammatory, and oxidative indices were determined. The arrhythmia score was assessed by programmed electrical stimulation (PES). Quantitative real-time PCR and western blot were applied to evaluate the expression levels of miR-145 and related target proteins, respectively. I/R injury decreased the expression of miR-145; however, upregulated miR-145 markedly reduced the elevation of ST segment, decreased corrected QT (QTc) intervals, and attenuated I/R-induced electrophysiological instability. Furthermore, miR-145 suppressed myocardium apoptotic, inflammatory, and oxidative response as well as the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), ryanodine receptor2 (RyR2 Ser2814), apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinases (JNK), and nuclear translocation of nuclear factor kappa-B (NF-κB) p65. In summary, overexpression of miR-145 alleviates I/R-induced myocardial electrophysiological instability and apoptotic and inflammatory response via inhibition of the CaMKII-mediated ASK1 antiapoptotic pathway and NF-κB p65 anti-inflammatory pathways.

Association of the G-250A promoter polymorphism in the hepatic lipase gene with the risk of type 2 diabetes mellitus.

OBJECTIVE: Variants in hepatic lipase (HL) gene which is a lipolytic enzyme involved in the metabolism of plasma lipoprotein and regulating lipid and lipoprotein metabolism are potential candidate genes for type 2 diabetes. Association of the polymorphisms in the promoter region of the HL gene (LIPC) to the plasma HDL-C concentration has been investigated. In this study, we investigated whether the G-250A polymorphism of LIPC is associated with type 2 diabetes in Chinese Han population. SUBJECTS AND METHODS: A total of 130 patients with type 2 diabetes and 133 healthy subjects as control were randomly selected from January 2008 to January 2011 in endocrine wards of Zhengzhou People's Hospital. The G-250A polymorphisms were studied by polymerase chain reaction and restriction fragment length polymorphism. A logistic regression analysis was performed to determine the association between the rare allele and type 2 diabetes mellitus. RESULTS: The frequency of the -250A allele was 0.297 in the T2DM group and 0.388 in the control group (P<0.05), with the difference remaining significant. CONCLUSIONS: Patients who are carrying of the -250A allele in the promoter of the LIPC gene are susceptible to type 2 diabetes mellitus in Chinese Han population.

Intrathecal injection of anti-CX3CR1 neutralizing antibody delayed and attenuated pain facilitation in rat tibial bone cancer pain model.

This study was designed to investigate the effect of intrathecal injection of anti-CX3CR1 neutralizing antibody on pain behaviors in the rat tibial bone cancer pain model. Syngeneic Walker 256 mammary gland carcinoma cells were injected into the tibia medullary cavity to establish the rat model of bone cancer pain. Ambulatory pain, mechanical hindpaw withdrawal threshold, and latency of paw withdrawal to a thermal stimulus were observed. Haematoxylin/eosin staining was used to observe the bone damage on day 21. Intrathecal injection of anti-CX3CR1 neutralizing antibody both delayed the development of ambulatory pain and hyperalgesia and attenuated established pain facilitation, but had no effects on destruction of bone. Our results suggest that intrathecal injection of anti-CX3CR1 neutralizing antibody delayed and attenuated pain facilitation in the rat tibial bone cancer pain model.