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An altered microRNA (miRNA/miR)‑27a‑3p expression has been identified in cervical cancer, while the exact regulatory mechanisms responsible for the dysregulation of miR‑27a‑3p remain to be fully elucidated. In the present study, a NF‑κB/p65 binding site was identified upstream of the miR‑23a/27a/24‑2 cluster and p65 binding enhanced the transcription of pri‑miR‑23a/27a/24‑2, as well as the expression levels of mature miRNAs, including miR‑27a‑3p in HeLa cells. Mechanistically, using bioinformatics analyses and experimental validation, TGF‑β activated kinase 1 binding protein 3 (TAB3) was identified as a direct target of miR‑27a‑3p. By binding to the 3'UTR of TAB3, miR‑27a‑3p significantly enhanced TAB3 expression. Functionally, it was found that the overexpression of miR‑27a‑3p and TAB3 promoted the malignant potential of cervical cancer cells, as evaluated using cell growth, migration and invasion assays, and specific cell marker determinations in the epithelial mesenchymal transition progression, and vice versa. Further rescue experiments revealed that the enhanced malignant effects induced by miR‑27a‑3p were mediated via its upregulation of TAB3 expression. Moreover, miR‑27a‑3p and TAB3 also activated the NF‑κB signaling pathway and formed a positive feedback regulatory loop composing of p65/miR‑27a‑3p/TAB3/NF‑κB. On the whole, the findings presented herein may provide novel insight into the underlying cervical tumorigenesis and novel biomarker identification for clinical applications.

Cancer-causing human papillomavirus (HPV) E6 oncoproteins contain a well-characterized phosphoacceptor site within the PDZ (PSD-95/Dlg/ZO-1) binding motif (PBM) at the C terminus of the protein. Previous studies have shown that the threonine or serine residue in the E6 PBM is subject to phosphorylation by several stress-responsive cellular kinases upon the induction of DNA damage in cervical cancer-derived cells. However, there is little information about the regulation of E6 phosphorylation in the absence of DNA damage and whether there may be other pathways by which E6 is phosphorylated. In this study, we demonstrate that loss of E6AP results in a dramatic increase in the levels of phosphorylated E6 (pE6) despite the expected overall reduction in total E6 protein levels. Furthermore, phosphorylation of E6 requires transcriptionally active p53 and occurs in a manner that is dependent upon DNA-dependent protein kinase (DNA PK). These results identify a novel feedback loop, where loss of E6AP results in upregulation of p53, leading to increased levels of E6 phosphorylation, which in turn correlates with increased association with 14-3-3 and inhibition of p53 transcriptional activity. IMPORTANCE This study demonstrates that the knockdown of E6AP from cervical cancer-derived cells leads to an increase in phosphorylation of the E6 oncoprotein. We show that this phosphorylation of E6 requires p53 transcriptional activity and the enzyme DNA PK. This study therefore defines a feedback loop whereby activation of p53 can induce phosphorylation of E6 and which in turn can inhibit p53 transcriptional activity independently of E6's ability to target p53 for degradation.

Background: Cervical cancer (CC) is the 4th most prevalent cancer among females globally. In Ethiopia, around 7,095 new CC cases are diagnosed every year and it is the second common cause of cancer deaths in women. There is limited evidence on survival status as well as about predictors of time to death among CC patients in Ethiopia. Thus, this study investigated the five-year survival status and predictors of time to death among CC patients who had been admitted at Tikur Anbesa specialized Hospital (TASH) from 2014-2019., Methods: Facility-based, retrospective-cohort study was conducted at Tikur Anbesa specialized Hospital among 348 patients from June 2014 to June 2019. A systematic random sampling method was employed to select the study participants. Data were extracted from the patient card, and through phone calls. The data was collected using the android version CS-Entry tool. Data was analyzed by SPSS version 23. Kaplan and Meier's method was used to estimate survival functions and Cox-proportional hazard regression analysis was carried out in order to identify the independent predictors of time to death., Results: The overall incidence of death was 31 per 100 person-years of follow up. The median (IQR) follow-up time of the entire cohorts was 18.55 (8.96-49.65) months. The independent predictors for time to death included; age older than 50 years [AHR: 1.4; 95% CI: 1.1-1.9], late stage of CC at diagnosis [AHR: 2.2; 95% CI: 1.7-2.9], No CC treatment [AHR: 2.1; 95% CI: 1.5-3.1] and HIV positive [AHR: 2.3; 95% CI: 1.4-3.8]., Conclusion and Recommendation: The death rate of CC patients was high. The significant predictors associated with shorten time to death of CC patients were older age, advanced cancer stage at diagnosis, HIV infection and not receiving cancer treatment. Therefore, improving early detection and initiation of treatment for all CC patients is necessary in order to improve patient's survival status. The government needs to strengthen the routine CC screening programs to address high-risk women such as elderly and HIV positive women in Ethiopia., Competing Interests: The authors have declared that no competing interests exist.

A. membranaceus is a traditional Chinese medicine that regulates blood sugar levels, suppresses inflammation, protects the liver, and enhances immunity. In addition, A. membranaceus is also widely used in diet therapy and is a well-known health tonic. Formononetin is a natural product isolated from A. membranaceus that has multiple biological functions, including anti-cancer activity. However, the mechanism by which formononetin inhibits tumor growth is not fully understood. In this present study, we demonstrated that formononetin suppresses PD-L1 protein synthesis via reduction of MYC and STAT3 protein expression. Furthermore, formononetin markedly reduced the expression of MYC protein via the RAS/ERK signaling pathway and inhibited STAT3 activation through JAK1/STAT3 pathway. Co-immunoprecipitation experiments illustrated that formononetin suppresses protein expression of PD-L1 by interfering with the interaction between MYC and STAT3. Meanwhile, formononetin promoted PD-L1 protein degradation via TFEB and TFE3-mediated lysosome biogenesis. T cell killing assay revealed that formononetin could enhance the activity of cytotoxic T lymphocytes (CTLs) and restore ability to kill tumor cells in a co-culture system of T cells and tumor cells. In addition, formononetin inhibited cell proliferation, tube formation, cell migration, and promoted tumor cell apoptosis by suppressing PD-L1. Finally, the inhibitory effect of formononetin on tumor growth was confirmed in a murine xenograft model. The present study revealed the anti-tumor potential of formononetin, and the findings should support further research and development of anti-cancer drugs for cervical cancer., (Copyright © 2021. Published by Elsevier Inc.)

A key behavior observed during morphogenesis, wound healing, and cancer invasion is that of collective and coordinated cellular motion. Hence, understanding the different aspects of such coordinated migration is fundamental for describing and treating cancer and other pathological defects. In general, individual cells exert forces on their environment in order to move, and collective motion is coordinated by cell-cell adhesion-based forces. However, this notion ignores other mechanisms that encourage cellular movement, such as pressure differences. Here, using model tumors, it is found that increased pressure drove coordinated cellular motion independent of cell-cell adhesion by triggering cell swelling in a soft extracellular matrix (ECM). In the resulting phenotype, a rapid burst-like stream of cervical cancer cells emerged from 3D aggregates embedded in soft collagen matrices (0.5 mg mL -1 ). This fluid-like pushing mechanism, recorded within 8 h after embedding, shows high cell velocities and super-diffusive motion. Because the swelling in this model system critically depends on integrin-mediated cell-ECM adhesions and cellular contractility, the swelling is likely triggered by unsustained mechanotransduction, providing new evidence that pressure-driven effects must be considered to more completely understand the mechanical forces involved in cell and tissue movement as well as invasion., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Up to 26% of patients with early-stage cervical cancer experience relapse after primary surgery. However, little is known about which factors influence prognosis following disease recurrence. Therefore, our aims were to determine post-recurrence disease-specific survival (PR-DSS) and to identify respective prognostic factors for PR-DSS., Methods: Data from 528 patients with early-stage cervical cancer who relapsed after primary surgery performed between 2007 and 2016 were obtained from the SCANN study (Surveillance in Cervical CANcer). Factors related to the primary disease and recurrence were combined in a multivariable Cox proportional hazards model to predict PR-DSS., Results: The 5-year PR-DSS was 39.1% (95% confidence interval [CI] 22.7%-44.5%), median disease-free interval between primary surgery and recurrence (DFI1) was 1.5 years, and median survival after recurrence was 2.5 years. Six significant variables were identified in the multivariable analysis and were used to construct the prognostic model. Two were related to primary treatment (largest tumour size and lymphovascular space invasion) and four to recurrence (DFI1, age at recurrence, presence of symptoms, and recurrence type). The C-statistic after 10-fold cross-validation of prognostic model reached 0.701 (95% CI 0.675-0.727). Three risk-groups with significantly differing prognoses were identified, with 5-year PR-DSS rates of 81.8%, 44.6%, and 12.7%., Conclusions: We developed the robust model of PR-DSS to stratify patients with relapsed cervical cancer according to risk profiles using six routinely recorded prognostic markers. The model can be utilised in clinical practice to aid decision-making on the strategy of recurrence management, and to better inform the patients., Competing Interests: Declaration of Competing Interest Outside the submitted work, Dr. Abu-Rustum reports grants from Stryker/Novadaq and GRAIL (paid to the institution). The remaining authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: High-risk human papillomavirus (HR-HPV) infection is the main cause of cervical cancer, but additional alterations are necessary for its development. Abnormal DNA methylation has an important role in the origin and dissemination of cervical cancer and other human tumors. In this work, we analyzed the methylation of eight genes (AJAP1, CDH1, CDH13, MAGI2, MGMT, MYOD1, RASSF1A and SOX17) that participate in several biological processes for the maintenance of cell normality. We analyzed DNA methylation by methylation-specific PCR (MSP) and HPV infection using the INNO‑LiPA genotyping kit in 59 samples diagnostic of normal cervical tissue (non-SIL), 107 low-grade squamous intraepithelial lesions (LSILs), 29 high-grade squamous intraepithelial lesions (HSILs) and 51 cervical cancers (CCs)., Results: We found that all samples of LSIL, HSIL, and CC were HPV-positive, and the genotypes with higher frequencies were 16, 18, 51 and 56. In general, the genes analyzed displayed a significant tendency toward an increase in methylation levels according to increasing cervical lesion severity, except for the CDH13 gene. High CpG island methylator phenotype (CIMP) was associated with a 50.6-fold (95% CI 4.72-2267.3)-increased risk of HSIL and a 122-fold risk of CC (95% CI 10.04-5349.7)., Conclusions: We found that CIMP high was significantly associated with HSIL and CC risk. These results could indicate that CIMP together with HR-HPV infection and other factors participates in the development of HSIL and CC., (© 2022. The Author(s).)

The roles of gap junctions (GJs) and its components, connexins, in the autophagy of cervical cancer cells have been rarely investigated. Our previous study demonstrated that connexin 32 (Cx32) exerted an anti‑apoptotic effect on cervical cancer. However, as an important regulator of apoptosis, whether the autophagy is involved in the function of Cx32 on cervical cancer cells is not well defined. The present study aimed to investigate the role of Cx32 on autophagy and apoptosis inhibition in cervical cancer cells. The expression levels of Cx32 and the autophagy‑associated protein LC3‑Ⅱ in paracancerous cervical tissues (n=30) and cervical cancer (n=50) tissues were determined via western blotting. In total, 45 cervical cancer specimens were used to evaluate the clinical relevance of Cx32 and LC3‑Ⅱ. It was found that both Cx32 and LC3‑Ⅱ were upregulated in cervical cancer tissues compared with those in paracancerous cervical tissues. The effect of Cx32 on autophagy was examined by detecting the change of LC3‑Ⅱ using western blotting, transfection with enhanced green fluorescent protein‑LC3 plasmid and transmission electron microscopy analysis. Overexpression of Cx32 significantly enhanced autophagy in HeLa‑Cx32 cells, whereas knockdown of Cx32 suppressed autophagy in C‑33A cells. The flow cytometry results demonstrated that Cx32 inhibited the apoptosis of cervical cancer cells by promoting autophagy. Moreover, Cx32 triggered autophagy via the activation of the AMP‑activated protein kinase (AMPK) signalling, regardless of the presence or absence of GJs. Collectively, it was identified that Cx32 exerted its anti‑apoptotic effect by activating autophagy via the AMPK pathway in cervical cancer, which demonstrates a novel mechanism for Cx32 in human cervical cancer progression.

Wound healing requires static epithelial cells to gradually assume a mobile phenotype through a multi-step process termed epithelial-to-mesenchymal transition (EMT). Although it is inherently transient and reversible, EMT perdures and is abnormally activated when the epithelium is chronically exposed to pathogens: this event deeply alters the tissue and eventually contributes to the development of diseases. Among the many of them is uterine cervical squamous cell carcinoma (SCC), the most frequent malignancy of the female genital system. SCC, whose onset is associated with the persistent infection of the uterine cervix by high-risk human papillomaviruses (HR-HPVs), often relapses and/or metastasizes, being resistant to conventional chemo- or radiotherapy. Given that these fearsome clinical features may stem, at least in part, from the exacerbated and long-lasting EMT occurring in the HPV-infected cervix; here we have reviewed published studies concerning the impact that HPV oncoproteins, cellular tumor suppressors, regulators of gene expression, inflammatory cytokines or growth factors, and the interactions among these effectors have on EMT induction and cervical carcinogenesis. It is predictable and desirable that a broader comprehension of the role that EMT inducers play in SCC pathogenesis will provide indications to flourish new strategies directed against this aggressive tumor.

Introduction: Introduction: cervical cancer is the second most common cancer in women in the world. It is associated with a high body mass index. However, the phase angle has not been determined in women with cervical cancer. Electrical vector bioimpedance has been validated to assess body composition, nutritional status, and cell membrane integrity in cancer patients using phase angle. Objetive: to evaluate phase angle, body composition by electrical vector bioimpedance, and dietary intake in women with cervical diagnosis who are users of a second-level care hospital in San Luis Potosí, Mexico. Methods: an observational, cross-sectional, and analytical study. Seventy women with a diagnosis of cervical cancer were studied in the oncology service. Phase angle was measured, and the frequency of food from the Nutritional Habits Assessment System and a questionnaire to measure socioeconomic level were applied. Results: the data of the phase angle in a mean of 4.66 ° ± 0.87 ° with a range of 2.9 ° to 6.2 ° In a multiple linear regression model formed for phase angle as a dependent variable, and evolution of the cervical cancer, body mass index, skeletal muscle mass, extracellular water, fructose, saturated fatty acids, and trans fatty acids as independent variables, had an R2 value of 0.748 with a p-value of 0.001. Conclusion: women with cervical cancer have integrity damage of the cell membrane with a lower phase angle than the reference population.

Objective To investigate the epidemiological characteristics of high-risk human papillomavirus(HR-HPV) infection based on vaginal self-collected samples. Study Design and Setting The pooled data of 3045 self-collected samples used for the analysis derived from four previous studies on cervical cancer screening(The Chinese Multi-Center Screening Trial, CHIMUST; The Shenzhen Cervical Cancer Screening Trial-2, SHENCCAST-2; The Chinese Cervical Cancer Prevention Study, CHIPCAPS; Pingshan trial, PINGSHAN)conducted across China by our team since 2011. These cases were evaluated for HR-HPV type prevalence relative to lesion grade and age. The occurrence of cervical intraepithelial neoplasia(CIN) with specific HPV types and the influence of co-infection is explored. Results The top three most common genotypes among the HR-HPV positives were HPV-52(23.4%), HPV-16(18.0%), and HPV-58(15.50%). For women with CIN2+, the most frequent genotypes were HPV-16, 58, 52, and 18 in sequence. HPV-16 accounted for the majority of CIN2/CIN3/Ca with attribution rate of 23.86%, 44.78% and 50.00% respectively. HPV-58 accounted for 19.48%, 16.79% and 13.46% respectively. CIN2+ was found in the following types most frequently: HPV-16(31.23%), HPV-33(24.03%), HPV-58(18.41%), HPV-31(11.76%), HPV-18(7.75%), and HPV-52(7.30%). HPV-16 showed preference for co-infection with HPV-52 and HPV-58. Conclusion The prevalence of HR-HPV infection based on self-sampling among women in China exhibited some unique epidemiologic features., (Copyright © 2021. Published by Elsevier Inc.)

Human papillomavirus type 18 (HPV18) has high carcinogenic power in invasive cervical cancer (ICC) development. However, the underlying mechanism remains elusive. The carcinogenic properties of HPV18 require the PDZ-binding motif of its E6 oncoprotein (HPV18 E6) to degrade its target PSD95/Dlg/ZO-1 (PDZ) proteins. In this study, we demonstrated that the PDZ protein membrane-associated guanylate kinase, WW and PDZ domain containing 3 (MAGI3) inhibited the Wnt/β-catenin pathway, and subsequently cervical cancer (CC) cell migration and invasion, via decreasing β-catenin levels. By reducing MAGI3 protein levels, HPV18 E6 promoted CC cell migration and invasion through activation of Wnt/β-catenin signaling. Furthermore, HPV18 rather than HPV16 was preferentially associated with the downregulation of MAGI3 and activation of the Wnt/β-catenin pathway in CC. These findings shed light on the mechanism that gives HPV18 its high carcinogenic potential in CC progression., (© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Long noncoding RNAs (lncRNAs) have key functions in modulating cervical cancer (CC) genesis and progression. This work focused on exploring lncRNA HNRNPU-AS1's function in CC and the underlying mechanism. HNRNPU-AS1, AXIN2, and microRNA 205-5p (miR-205-5p) levels in CC cases were measured through reverse transcription-quantitative PCR. The relationship between miR-205-5p and AXIN2 or HNRNPU-AS1 was validated through a dual-luciferase assay. Cell proliferation was examined by CCK-8 and cell apoptosis by colony formation and flow cytometry analysis. HNRNPU-AS1 expression loss could be observed in CC patients and cell lines, which predicted the dismal prognosis of CC cases. Moreover, it was identified that the miR-205-5p level was upregulated, which acted as an inhibitory target of HNRNPU-AS1 and AXIN2. HNRNPU-AS1 inhibited cell proliferation and promoted apoptosis. As revealed by Kaplan-Meier curve, CC cases showing low HNRNPU-AS1, high miR-205-5p, and low AXIN2 levels had the poorest prognosis. AXIN2 reversed the CC cell proliferation-promoting, apoptosis-inhibiting, and Wnt/β-catenin signaling-activating behavior mediated by miR-205-5p or HNRNPU-AS1 knockout. In conclusion, the overexpression of lncRNA HNRNPU-AS1 suppressed CC progression by inhibiting the Wnt/β-catenin pathway through the miR-205-5p/AXIN2 axis.

Rationale: Primary signet ring cell carcinoma of the uterine cervix is extremely rare and the clinical characteristics and prognosis are not well known and there are no specific guidelines for treatment., Patient Concerns: A 43-year-old woman was referred to our hospital for abnormal uterine bleeding lasting 1 month., Diagnoses: Histological examination revealed a signet ring cell carcinoma of the uterine cervix. After evaluation of extragenital origin, the patient was diagnosed International Federation of Gynecology and Obstetrics stage IIIC1 primary signet ring cell carcinoma or the uterine cervix., Intervention: The patient was prescribed concomitant chemo-radiation followed by intracavitary brachytherapy., Outcomes: She showed no evidence of disease after treatment but, it recurred after 7 months of last treatment., Lessons: Different approaches to diagnosis and treatment of this rare disease are needed and molecular pathological studies related to the onset of the disease are required., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Technical advancements significantly improve earlier diagnosis of cervical cancer, but accurate diagnosis is still difficult due to various factors. We develop an artificial intelligence assistive diagnostic solution, AIATBS, to improve cervical liquid-based thin-layer cell smear diagnosis according to clinical TBS criteria. We train AIATBS with >81,000 retrospective samples. It integrates YOLOv3 for target detection, Xception and Patch-based models to boost target classification, and U-net for nucleus segmentation. We integrate XGBoost and a logical decision tree with these models to optimize the parameters given by the learning process, and we develop a complete cervical liquid-based cytology smear TBS diagnostic system which also includes a quality control solution. We validate the optimized system with >34,000 multicenter prospective samples and achieve better sensitivity compared to senior cytologists, yet retain high specificity while achieving a speed of <180s/slide. Our system is adaptive to sample preparation using different standards, staining protocols and scanners.

Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels-Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs.

Cell-cell communication is an essential mechanism for the maintenance and development of various organs, including the female reproductive system. Today, it is well-known that the function of the female reproductive system and successful pregnancy are related to appropriate follicular growth, oogenesis, implantation, embryo development, and proper fertilization, dependent on the main regulators of cellular crosstalk, exosomes. During exosome synthesis, selective packaging of different factors into these vesicles happens within the originating cells. Therefore, exosomes contain both genetic and proteomic data that could be applied as biomarkers or therapeutic targets in pregnancy-associated disorders or placental functions. In this context, the present review aims to compile information about the potential exosomes with key molecular cargos that are dysregulated in female reproductive diseases which lead to infertility, including polycystic ovary syndrome (PCOS), premature ovarian failure (POF), Asherman syndrome, endometriosis, endometrial cancer, cervical cancer, ovarian cancer, and preeclampsia, as well as signaling pathways related to the regulation of the reproductive system and pregnancy outcome during these pathological conditions. This review might help us realize the etiology of reproductive dysfunction and improve the early diagnosis and treatment of the related complications.

Since heat shock protein (HSP27) is a prognostic marker in cervical cancer, in the present study, the apoptotic mechanism of lambertianic acid (LA) was investigated in human cervical cancers in association with HSP27/STAT3/AKT signaling axis. LA exerted significant cytotoxicity, induced sub-G1 population, and increased the cleavage of Poly (ADP-ribose) polymerase (PARP) and cysteine aspartyl-specific protease 3 (caspase3) in HeLa and Caski cancer cells. Consistently, LA downregulated anti-apopotic genes such as B-cell lymphoma 2 (Bcl-2) and inhibitors of apoptosis proteins (c-IAP) in HeLa and Caski cells. Furthermore, LA-inhibited phosphorylation of HSP27, signal transducer, and activator of transcription 3 (STAT3) and Protein kinase B (AKT) through disturbing the binding of HSP27 with STAT3 or AKT in HeLa cells. Notably, LA upregulated the level of miR216b in HeLa and Caski cells. Consistently, miR216b mimic suppressed phosphorylation of HSP27 and reduced the expression of pro-PARP, while miR216b inhibitor reversed the ability of LA to attenuate phosphorylation of AKT, HSP27, and STAT3 and to reduce the expression of pro-PARP in HeLa cells. Overall, our findings suggest that miRNA216b mediated inhibition of HSP27/STAT3/ AKT signaling axis is critically involved in LA-induced apoptosis in cervical cancers., (© 2020 John Wiley & Sons Ltd.)

The pathogenesis of cervical cancer is related to oxidative damage caused by persistent infection by one of the oncogenic types of human papillomavirus (HPV). This damage comes from oxidative stress, which is the imbalance caused by the increase in reactive oxygen and nitrogen species and impaired antioxidant mechanisms, promoting tumor progression through metabolic processes. The incorporation of HPV into the cellular genome leads to the expression of oncoproteins, which are associated with chronic inflammation and increased production of reactive oxygen species, oxidizing proteins, lipids and DNA. The increase in these parameters is related, in general, to the reduction of circulating levels of enzymatic antioxidants-superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase; and non-enzymatic antioxidants-reduced glutathione, coenzyme Q10 and vitamins A, C and E, according to tumor staging. In contrast, some enzymatic antioxidants suffer upregulation in the tumor tissue as a way of adapting to the oxidative environment generated by themselves, such as glutathione-S-transferase, reduced glutathione, glutathione peroxidase, superoxide dismutase 2, induced nitric oxide synthase, peroxiredoxins 1, 3 and 6, and thioredoxin reductase 2. The decrease in the expression and activity of certain circulatory antioxidants and increasing the redox status of the tumor cells are thus key to cervical carcinoma prognosis. In addition, vitamin deficit is considered a possible modifiable risk factor by supplementation, since the cellular functions can have a protective effect on the development of cervical cancer. In this review, we will discuss the impact of oxidative damage on cervical cancer progression, as well as the main oxidative markers and therapeutic potentialities of antioxidants., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of the study was to determine the influence of beta-adrenoceptor (ADRB) antagonists on contractile activity of the nonpregnant human uterus in patients affected by gynecological malignancies., Design: This was a controlled and prospective ex vivo study., Setting: The work was conducted as a collaboration between 4 academic departments., Materials and Methods: Myometrial specimens were obtained from women undergoing hysterectomy for benign gynecological disorders (reference group; N = 15), and ovarian (N = 15), endometrial (N = 15), synchronous ovarian-endometrial (N = 3), and cervical cancer (N = 10). Contractions of myometrial strips in an organ bath before and after applications of ADRB antagonists (propranolol, bupranolol, SR 59230A, and butoxamine) were studied under isometric conditions., Results: Propranolol and bupranolol attenuated contractions in the endometrial and cervical cancer groups similar to that in the reference group (all p < 0.05), whereas opposite effects were observed in the ovarian and synchronous ovarian-endometrial cancer groups. SR 59230A and butoxamine significantly increased contractions in the ovarian cancer group (both p < 0.001)., Limitations: These results require now to be placed into a firm clinical context., Conclusions: Our study indicates that ovarian cancer considerably alters contractile activity of the nonpregnant human uterus in response to ADRB antagonists. This suggests a pathogenetic role of beta-adrenergic pathways in this malignancy. Furthermore, propranolol and bupranolol substantially influence spontaneous uterine contractility., (© 2021 S. Karger AG, Basel.)

Survivin is an inhibitor of apoptosis protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. It is selectively up-regulated in many human tumors and implicated in cellular radiation response through its role in apoptosis, cell division, and DNA damage response. This study aimed to investigate the effect and mechanisms of targeting survivin radiosensitivity in cervical cancer C33A cells. Here, the authors designed a small interfering RNA (siRNA) or plasmid-based small hairpin RNA (shRNA) targeting survivin and tested its effects on radiosensitivity to ionizing radiation (IR) treatment of C33A cells in vitro , as well as on the tumorigenicity of C33A cells in nude mice in vivo . Transient transfection of survivin siRNA into C33A cells suppressed survivin expression, induced cell apoptosis and G2/M arrest and reduced cell proliferation, clone formation ability after IR, followed by p53 upregulated modulator of apoptosis (PUMA) upregulation. But, transient transfection of survivin siRNA alone has no significant effect on cell growth and apoptosis. To confirm that PUMA upregulation is necessary for survivin silencing -induced radiosensitivity to IR treatment, the effect of targeting PUMA in survivin sliencing cells was observed. The results showed that targeting PUMA in survivin sliencing cells rescued C33A cells' radioresistance. Furthermore, knocking down survivin expression combined with IR treatment significantly slowed tumor growth and promoted tumor cell apoptosis in C33A xenografted tumors. It was concluded that survivin played a role in radiotherapy resistance. Targeting survivin increased the radiosensitivity of C33A cells through induction of PUMA expression.

Objective To investigate the effects of miR-23b-3p on proliferation, migration and invasion of human cervical carcinoma CasKi cells. Methods Human cervical carcinoma CasKi cells and normal epithelial HaCaT cells were cultured in vitro. Real-time quantitative RT-PCR was conducted to detect the expression of miR-23b-3p in CasKi and HaCaT cells. Synthetic miR-23b-3p mimic and its negative control were transfected into CasKi cells by liposome method. The effects of miR-23b-3p over-expression on cell proliferation were detected by CCK-8 assay. Wound scratch healing assay and Transwell TM assay were used to observe the migration and invasion abilities of CasKi cells, respectively. Western blot analysis was used to detect the protein expression of N-cadherin, vimentin, E-cadherin, Snail, PCNA and cyclin D1. Results The expression of miR-23b-3p in CasKi cells was lower than that of HaCaT cells. Compared with the negative control group, the expression of miR-23b-3p were significantly up-regulated in CasKi cells after transfected with miR-23b-3p mimic. CCK-8 and Western blot assays showed that the proliferation was inhibited and the expression of PCNA and cyclin D1 were down-regulated after the cells were treated with miR-23b-3p mimic. At the same time, after over-expression of miR-23b-3p, the migration and invasion abilities of the CasKi cells were significantly inhibited. In addition, the expression of E-cadherin was up-regulated, while vimentin, Snail and N-cadherin expression levels were significantly down-regulated. Conclusion Over-expression of miR-23b-3p may suppress the proliferation, migration, invasion and epithelial-mesenchymal transition process of human cervical cancer CasKi cells.

Background/Aim: There is an increasing demand for preserving the fertility of young women impacted with early-stage cervical cancer. The aim of this study is to evaluate the oncological and reproductive outcomes of abdominal radical trachelectomy ( ART ). Patients and Methods: We retrospectively reviewed patients with FIGO stageIA2-IB1 cervical cancer who underwent ART from 2007 to 2018. We also compared the oncological prognosis between the patients who underwent ART and radical hysterectomy ( RH ). Results: A total of 42 patients underwent ART. During median follow-up 62.5 months, there were 4 ( 9.5% ) recurrences and 1 ( 2.4% ) death. As for tumors ≤2 cm, the 5-year recurrence-free survival (RFS) rate and overall survival (OS) rate for patients who underwent ART was similar to those who underwent RH (89.8% vs. 92.7%, p =0.42 and 97.3% vs. 95.0%, p =0.44, respectively ). Nineteen patients attempted to conceive and seven of them were successful. There was one case of a first-trimester miscarriage, two cases of preterm delivery, three cases of full-term delivery and one ongoing pregnancy. Conclusion: ART could be a feasible alternative to RH for patients with tumors ≤2 cm with comparable oncological outcome., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The prognosis for cervical cancer (CCa) patients with lymph node metastasis (LNM) is dismal. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa patients with LNM. However, the precise mechanism of LNM in CCa remains unclear. Herein, we demonstrated that protein tyrosine phosphatase receptor type M (PTPRM), identified from TCGA dataset, was markedly upregulated in CCa with LNM and correlated with LNM. Moreover, PTPRM was an independent prognostic factor of CCa patients in multivariate Cox's proportional hazards model analysis and associated with poor prognosis. Furthermore, through gain-of-function and loss-of-function approaches, we found that PTPRM promoted CCa cells proliferation, migration, invasion, lymphangiogenesis, and LNM. Mechanistically, PTPRM promoted epithelial-mesenchymal transition (EMT) via Src-AKT signaling pathway and induced lymphangiogenesis in a VEGF-C dependent manner, resulting in LNM of CCa. Importantly, knockdown of PTPRM dramatically reduced LNM in vivo, suggesting that PTPRM plays an important role in the LNM of CCa. Taken together, our findings uncover a novel molecular mechanism in the LNM of CCa and identify PTPRM as a novel prognostic factor and potential therapeutic target for LNM in CCa.

Background: Treatments for cervical intraepithelial neoplasia remove precancerous cells from the cervix by excising or ablating the transformation zone. Most studies show no association between cervical intraepithelial neoplasia treatments and fertility outcomes. However, only 2 studies have examined time to pregnancy, both using retrospective study designs, with 1 study showing no association and the other showing a 2-fold increased risk of infertility (time to pregnancy >12 months) following excisional or ablative treatment., Objective: We examined the association between cervical intraepithelial neoplasia treatments and fecundability., Materials and Methods: We analyzed data from Pregnancy Study Online (PRESTO), a prospective cohort study of North American pregnancy planners enrolled during 2013-2019. At baseline, women reported whether they ever had an abnormal Papanicolaou test result, the number of abnormal Papanicolaou test results, and their age at first abnormal Papanicolaou test result. They also reported whether they underwent diagnostic (colposcopy) or treatment (excisional or ablative) procedures, and their age at each procedure. We restricted analyses to 8017 women with 6 or fewer cycles of attempt time at enrollment who reported receiving a Papanicolaou test in the previous 3 years. We estimated fecundability ratios and 95% confidence intervals using proportional probabilities models adjusted for sociodemographics, healthcare use, smoking, number of sexual partners, history of sexually transmitted infections, and human papillomavirus vaccination., Results: A history of abnormal Papanicolaou test results showed little association with fecundability (fecundability ratio, 1.00; 95% confidence interval, 0.95-1.06). Likewise, receipt of colposcopy or treatment procedures, and time since treatment were not materially associated with fecundability. Results were similar when stratified by age and smoking status., Conclusion: We observed no appreciable association of self-reported history of abnormal Papanicolaou test results, colposcopy, treatments for cervical intraepithelial neoplasia, or recency of treatment with fecundability. These results agree with the majority of previous studies in indicating little effect of cervical intraepithelial neoplasia treatments on future fertility., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Human immunodeficiency virus-infected (HIV + ) individuals are disproportionately at risk for human papillomavirus (HPV)-associated cancers, but the magnitude of risk estimates varies widely. We conducted a retrospective study using a large U.S.-based cohort to describe the relationship between HIV infection and incident cervical, oropharyngeal, and anal cancers., Methods: Using 2001-2012 U.S. Medicaid data from 14 states, we matched one HIV + to three HIV-uninfected (HIV - ) enrollees on sex, race, state, age, and year, and followed persons for up to 10 years. We developed Cox proportional hazards models comparing HIV + to HIV - for time to cancer diagnosis adjusted for demographic and comorbidity attributes., Results: Our cohorts included 443,592 women for the cervical cancer analysis, and 907,348 and 906,616 persons for the oropharyngeal and anal cancer analyses. The cervical cancer cohort had a mean age of 39 years and was 55% Black. The oropharyngeal and anal cancer cohorts were 50% male, had a mean age of 41 years, and were 51% Black. We estimated the following HRs: cervical cancer, 3.27 [95% confidence interval (CI), 2.82-3.80]; oropharyngeal cancer, 1.90 (95% CI, 1.62-2.23; both sexes), 1.69 (95% CI, 1.39-2.04; males), and 2.55 (95% CI, 1.86-3.50; females); and anal cancer, 18.42 (95% CI, 14.65-23.16; both sexes), 20.73 (95% CI, 15.60-27.56; males), and 12.88 (95% CI, 8.69-19.07; females)., Conclusions: HIV + persons were at an elevated risk for HPV-associated cancers, especially anal cancer., Impact: Medicaid claims data corroborate previous estimates based on registries and clinical cohorts., (©2020 American Association for Cancer Research.)

Genome regions that do not for code for proteins are generally transcribed into long non-coding RNAs. Growing evidence reveals that lncRNAs, defined as transcripts longer than 200 nucleotides, are commonly deregulated in cervical malignancies. New sequencing technologies have revealed a complete picture of the composition of the human transcriptome. LncRNAs perform diverse functions at transcriptional, translation, and post-translational levels through interactions with proteins, RNA and DNA. In the past decade, studies have shown that lncRNAs participate in the pathogenesis of many diseases, including cervical cancer. Hence, illuminating the roles of lncRNA will improve our understanding of cervical cancer. In this work, we summarize the current knowledge on lncRNAs in cervical cancer. We describe the emerging roles of lncRNAs in cervical cancer, particularly in cancer progression, metastasis, treatment resistance, HPV regulation, and metabolic reprogramming. The great promises of lncRNAs as potential biomarkers for cervical cancer diagnosis and prognosis are also discussed. We discuss current technologies used to target lncRNAs and thus control cancers, such as antisense oligonucleotides, CRISPR-Cas9, and exosomes. Overall, we show that lncRNAs hold great potentials as therapeutic agents and innovative biomarkers. Finally, further clinical research is necessary to advance our understanding of the therapeutic value of lncRNAs in cervical cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier Masson SAS.)

Importance: Accurate identification of lymph node metastasis preoperatively and noninvasively in patients with cervical cancer can avoid unnecessary surgical intervention and benefit treatment planning., Objective: To develop a deep learning model using preoperative magnetic resonance imaging for prediction of lymph node metastasis in cervical cancer., Design, Setting, and Participants: This diagnostic study developed an end-to-end deep learning model to identify lymph node metastasis in cervical cancer using magnetic resonance imaging (MRI). A total of 894 patients with stage IB to IIB cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy were reviewed. All patients underwent radical hysterectomy and pelvic lymphadenectomy, received pelvic MRI within 2 weeks before the operations, had no concurrent cancers, and received no preoperative treatment. To achieve the optimal model, the diagnostic value of 3 MRI sequences was compared, and the outcomes in the intratumoral and peritumoral regions were explored. To mine tumor information from both image and clinicopathologic levels, a hybrid model was built and its prognostic value was assessed by Kaplan-Meier analysis. The deep learning model and hybrid model were developed on a primary cohort consisting of 338 patients (218 patients from Sun Yat-sen University Cancer Center, Guangzhou, China, between January 2011 and December 2017 and 120 patients from Henan Provincial People's Hospital, Zhengzhou, China, between December 2016 and June 2018). The models then were evaluated on an independent validation cohort consisting of 141 patients from Yunnan Cancer Hospital, Kunming, China, between January 2011 and December 2017., Main Outcomes and Measures: The primary diagnostic outcome was lymph node metastasis status, with the pathologic characteristics diagnosed by lymphadenectomy. The secondary primary clinical outcome was survival. The primary diagnostic outcome was assessed by receiver operating characteristic (area under the curve [AUC]) analysis; the primary clinical outcome was assessed by Kaplan-Meier survival analysis., Results: A total of 479 patients (mean [SD] age, 49.1 [9.7] years) fulfilled the eligibility criteria and were enrolled in the primary (n = 338) and validation (n = 141) cohorts. A total of 71 patients (21.0%) in the primary cohort and 32 patients (22.7%) in the validation cohort had lymph node metastais confirmed by lymphadenectomy. Among the 3 image sequences, the deep learning model that used both intratumoral and peritumoral regions on contrast-enhanced T1-weighted imaging showed the best performance (AUC, 0.844; 95% CI, 0.780-0.907). These results were further improved in a hybrid model that combined tumor image information mined by deep learning model and MRI-reported lymph node status (AUC, 0.933; 95% CI, 0.887-0.979). Moreover, the hybrid model was significantly associated with disease-free survival from cervical cancer (hazard ratio, 4.59; 95% CI, 2.04-10.31; P < .001)., Conclusions and Relevance: The findings of this study suggest that deep learning can be used as a preoperative noninvasive tool to diagnose lymph node metastasis in cervical cancer.

Background: We examined the trend in prevalence of high-risk human papillomavirus (hrHPV) cervical infection among Rwandan women living with HIV (WLWH) over 12 years., Methods: Prevalence of cervical hrHPV DNA was measured in 3 studies at 3 different time periods in 3 different groups of WLWH using 3 different but comparable hrHPV tests: a MY09/MY11 PCR test in 2005 (RWISA; n = 497), careHPV in 2009-2010 (HPV Demonstration; n = 1242), and Xpert HPV test in 2016-2018 (U54; n = 4734). Prevalences were adjusted for age and CD4 cell count., Results: HrHPV prevalence decreased over time from 42.5% to 32.2% to 26.5% (P < .001). CD4 cell counts improved over time (Ptrend <.001) so that the percentage of WLWH with CD4 counts of ≥500 cells/μL increased from 7.7% in 2005 to 42.2% in 2009-2010 and 61.1% in 2016-2018. Thus, after adjustment for differences in CD4 counts and age, hrHPV prevalences were more similar over time: 32.6% for RWISA, 30.6% for HPV Demonstration, and 27.1% for U54 (P = .007)., Conclusions: Prevalence of hrHPV among WLWH has decreased over the past decade, most likely the result of improved immune reconstitution due to better HIV care and management in Rwanda., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background and Objectives: This article examines a cervical screening incident from the 1960s and draws lessons for screening policy., Study Design and Setting: Concern about harmful overtreatment of symptomless lesions prompted university gynecologist Herbert Green to study, between 1965 and 1970, a 'special series' of 33 women with carcinoma in situ (CIS) who were managed with only limited punch or wedge biopsy. These women were carefully followed up but not treated unless they showed evidence of progression to invasive cancer. This paper examines source documents and subsequent publications in order to ascertain lessons from this incident., Results: In keeping with the 1964 Helsinki Declaration, written consent was not sought. Green published the outcomes for his patients with CIS including the 'special series.' A Judicial inquiry (the Cartwright Inquiry) in 1987 concluded that some women had suffered harm and some had died, but numbers and evidence were not clearly stated. Medical case review for the Inquiry identified 25 women with only punch or wedge biopsy; in 21 of these, there were reasons why no further treatment was given; two had developed cervical cancer, and none were recorded as having died. The case review found eight patients, not necessarily in the 'special series,' who 'in retrospect and by 1987 standards' might have benefited from earlier conisation or hysterectomy., Conclusion: Subsequent claims relating to Green's practice have wrongly stated that as many as one hundred women or more had treatment withheld and over 30 died as a result. These claims are inaccurate., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Objectives : Telomeric zinc finger-associated protein (TZAP) is a telomere-associated factor that was previously called ZBTB48. This protein binds preferentially to long telomeres, competing with telomeric repeat factors 1 and 2. Genetic changes in TZAP may be associated with cancer pathogenesis; however, this relationship has not yet been elucidated for any type of cancer. In this study, we aimed to examine the clinicopathologic and prognostic value of TZAP expression in cervical cancer (CC). Materials and Methods: The data were extracted from The Cancer Genome Atlas cohorts by OncoLnc (21 cancer types, 7700 cancers). The prognostic value of TZAP for different stages of 264 CCs was examined using survival analysis. Results : The TZAP expression did not differ significantly between CC and normal matched tissues. Age, cancer stage, and viral infection were not associated with TZAP expression. Survival analysis revealed a shorter overall survival in CC patients with a lower TZAP expression (χ 2 = 3.62, p = 0.057). The prognostic value of TZAP expression was greater in patients with N1 stage CC (χ 2 = 5.64, p = 0.018). Conclusion: TZAP expression is a possible prognostic marker for CC, especially stage N1 CC., Competing Interests: The authors declare no conflicts of interest.

Protein phosphorylation is a posttranslational modification that is essential for normal cellular processes; however, abnormal phosphorylation is one of the prime causes for alteration of many structural, functional, and regulatory proteins in disease conditions. In cancer, changes in the states of protein phosphorylation in tyrosine residues have been more studied than phosphorylation in threonine or serine residues, which also undergo alterations with greater predominance. In general, serine phosphorylation leads to the formation of multimolecular signaling complexes that regulate diverse biological processes, but in pathological conditions such as tumorigenesis, anomalous phosphorylation may result in the deregulation of some signaling pathways. Cervical cancer (CC), the main neoplasm associated with human papillomavirus (HPV) infection, is the fourth most frequent cancer worldwide. Persistent infection of the cervix with high-risk human papillomaviruses produces precancerous lesions starting with low-grade squamous intraepithelial lesions (LSIL), progressing to high-grade squamous intraepithelial lesions (HSIL) until CC is generated. Here, we compared the proteomic profile of phosphorylated proteins in serine residues from healthy, LSIL, HSIL, and CC samples. Our data show an increase in the number of phosphorylated proteins in serine residues as the grade of injury rises. These results provide a support for future studies focused on phosphorylated proteins and their possible correlation with the progression of cervical lesions., Competing Interests: The authors have declared no conflict of interest., (Copyright © 2020 Juan Ramón Padilla-Mendoza et al.)

This review sought to evaluate the current literature on reproductive and oncologic outcomes after fertility-sparing surgery for early stage cervical cancer (stage IA1-IB1) including cold-knife conization/simple trachelectomy, vaginal radical trachelectomy, abdominal radical trachelectomy, and laparoscopic radical trachelectomy with or without robotic assistance. A systematic review using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist to evaluate the current literature on fertility-sparing surgery for early stage cervical cancer and its subsequent clinical pregnancy rate, reproductive outcomes, and cancer recurrence was performed. Sixty-five studies were included encompassing 3,044 patients who underwent fertility-sparing surgery, including 1,047 pregnancies with reported reproductive outcomes. The mean clinical pregnancy rate of patients trying to conceive was 55.4%, with the highest clinical pregnancy rate after vaginal radical trachelectomy (67.5%). The mean live-birth rate was 67.9% in our study. Twenty percent of pregnancies after fertility-sparing surgery required assisted reproductive technology. The mean cancer recurrence rate was 3.2%, and the cancer death rate was 0.6% after a median follow-up period of 39.7 months with no statistically significant difference across surgical approaches. Fertility-sparing surgery is a reasonable alternative to traditional radical hysterectomy for early-stage cervical cancer in women desiring fertility preservation. Vaginal radical trachelectomy had the highest clinical pregnancy rate, and minimally invasive approaches to fertility-sparing surgery had equivalent oncologic outcomes compared with an abdominal approach. The results of our study allow for appropriate patient counseling preoperatively and highlight the importance of a multidisciplinary approach to achieve the best outcomes for each patient., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Menopausal symptoms may adversely affect quality of life and health in women diagnosed with a gynecologic malignancy. The aim of this study was to determine the incidence of adverse outcomes, including cancer recurrence, venous thromboembolism, and secondary malignancies, among patients with a history of endometrial, ovarian, or cervical cancer prescribed vaginal estrogen for genitourinary syndrome of menopause., Methods: A retrospective cohort study was performed including women who were diagnosed with endometrial, ovarian, or cervical cancer from January 1, 1991 to December 31, 2017 and subsequently treated with vaginal estrogen for genitourinary syndrome of menopause. Patients were included if not undergoing active cancer treatment and were disease-free based on most recent cancer surveillance visit with physical exam and/or imaging. Demographics, oncologic variables, estrogen use, and adverse outcomes were recorded. Descriptive statistics and univariate analysis were performed., Results: Of 244 women who received vaginal estrogen, 52% (n=127) had a history of endometrial, 25.4% (n=62) cervical, 18.9% (n=46) ovarian cancer, and 3.7% (n=9) low malignant potential tumors. The mean age and body mass index were 55.5±12.5 years and 29.2±8.6 mg/kg 2 , respectively. With a median follow-up of 80.2 months, the incidence of recurrence for endometrial, ovarian, and cervical cancer was 7.1% (n=9), 18.2% (n=10), and 9.7% (n=6), respectively. In patients with endometrial cancer who recurred, the incidence was 2.4% (n=3) for stage I/II and 4.7% (n=6) for stage III/IV disease. Similarly, recurrence rates for ovarian cancer were 4.3% (n=2) for stage I/II and 17.4% (n=8) for stage III/IV disease. All cervical cancer recurrences were in patients with stage I/II disease. Adverse outcomes including breast cancer (1.6%, n=4), secondary malignancy (2.5%, n=6), and venous thromboembolism (2.5%, n=6) were rare., Conclusion: In women with a history of endometrial, ovarian, or cervical cancer prescribed vaginal estrogen use for genitourinary syndrome of menopause, adverse outcomes, including recurrence and thromboembolic events, are infrequent. Vaginal estrogen may be considered safe in gynecologic cancer survivors., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The prevalence of smoking among cervical cancer survivors typically exceeds what is found among women in the general population and other cancer survivors. Yet, there is a dearth of literature on risk and protective factors related to smoking among cervical cancer survivors, especially when it comes to identification of variables that are amendable to intervention. To help fill this gap in the literature, this qualitative study examines the nature of smoking-related causal attributions and risk perceptions in cervical cancer survivors who smoked at cancer diagnosis., Methods: Participants are 21 female cervical cancer survivors (M=45.7, SD=8.4 years old), all diagnosed in the past five years. Nearly three-quarters of participants reported smoking in the past month., Results: Smoking was not uniformly recognized as a cause of cervical cancer (whether in general or participants' own cancer); the link between smoking and lung, head-neck, and other cancers was more readily accepted. Despite generally weak endorsements of causal attributions, many participants reported smoking significantly increases risk for poor clinical (e.g., recurrence) and quality of life (e.g., pain) outcomes after cervical cancer diagnosis., Conclusions: Findings suggest cervical cancer survivors may not fully understand or appreciate the role of smoking in cervical cancer risk whereas their beliefs about the role of smoking in cervical cancer prognosis are more well-formed. This study highlights the potential role of causal attributions and risk perceptions in understanding and addressing the smoking-related experience of cervical cancer survivors., (© 2019 John Wiley & Sons, Ltd.)

Every year, more than 500,000 new cases of cervical cancer are reported, making it the fourth leading cause of cancer globally. Although human papillomavirus (HPV) vaccines show promise as a protective measure, HPV-related cancers remain a public health problem since the vaccines, which are only specific to certain viral types, are unavailable for mass distribution. Furthermore, the effects of toxicity following ionizing radiation therapy have reoriented views toward the search for radiosensitizers that can reduce toxicity as a consequence of decreased radiation doses. Here, we isolated ergosterol peroxide (EP) from Pleurotus ostreatus and purified it to test its potential effects in vitro. We thus observed that a gradual increase in EP dose correlates with a loss of viability in HeLa and CaSki cervical cell lines. Dose/response curves were constructed using cervical cancer cell lines, as well as normal human peripheral blood mononuclear cells. The selectivity of EP in human lymphocytes and cervical cancer cell lines was tested, and no toxicity was found in normal cells. A combination of treatments revealed a radiosensitizer effect in HeLa cells, when measuring the exposure to EP followed by irradiation with 137Cs. Our findings suggest that EP may be effective as a radiosensitizer in treating cervical cancer.

Background: Nowadays, the potential therapeutic role of various bioflavonoids including Curcumin, Luteolin and Resveratrol has currently been well-documented in a vast range of fatal complications including synaptic failure and cancers. These bioflavonoids are widely being implemented for the treatment of various cancers as they possess anti-cancerous, anti-oxidant and anti-inflammatory properties. Moreover, they are also used as a better alternative to conventional therapies since; these are non-toxic to cells and having no or least side effects. Notably, the pertinent therapeutic role of Rutin in cervical cancer is still unsettled however, its anti-cancerous role has already been reported in other cancers including prostate and colon cancer. Rutin (Vitamin P or Rutoside) is a polyphenolics flavonoid exhibiting multi-beneficial roles against several carcinomas., Objective: Despite the evidence for its several biological activities, the anticancer effects of Rutin on human cervical cancer (C33A) cells remain to be explored. In this study, the anticancer potential of Rutin was investigated by employing the key biomarkers such as nuclear condensation reactive oxygen species (ROS), apoptosis, and changes in mitochondrial membrane potential (MMP)., Results: Our findings showed that Rutin treatment reduced the cell viability, induced significant increase in ROS production and nuclear condensation in dose-dependent manner. Moreover, Rutin provoked apoptosis by inducing decrease in MMP and activation of caspase-3. Cell cycle analysis further confirmed the efficacy of Rutin by showing cell cycle arrest at G0/G1 phase., Conclusion: Thus, our study is envisaged to open up interests for elucidating Rutin as an anticancerous agent against cervical cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To uncover the role of FOXD2-AS1 in aggravating the progression of cervical cancer (CC) by negatively regulating caudal-related homeobox 1 (CDX1)., Materials and Methods: FOXD2-AS1 levels in CC tissues with different tumor sizes and tumor staging were detected. Meanwhile, FOXD2-AS1 levels in CC patients either with vascular invasion, lymphatic metastasis or not were detected. Survival analysis on CC patients expressing high level or low level of FOXD2-AS1 was conducted by introducing the Kaplan-Meier method. After the silence of FOXD2-AS1, proliferative changes in SiHa and HeLa cells were assessed through cell counting kit-8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU) assay. Subcellular distribution of FOXD2-AS1 in CC cells was analyzed. Next, CDX1 level in CC tissues and para-tumor tissues was determined. The potential correlation between CDX1 level and FOXD2-AS1 level was evaluated by the linear regression analysis. At last, the regulatory effects of FOXD2-AS1/CDX1 on the proliferative ability of CC were examined., Results: FOXD2-AS1 was upregulated in CC tissues relative to those of para-tumor tissues, especially in those with larger tumor size and advanced tumor staging. Its level was not correlated to vascular invasion and lymphatic metastasis of CC. CC patients expressing a high level of FOXD2-AS1 suffered worse prognosis than those with low level. The silence of FOXD2-AS1 attenuated SiHa and HeLa cells to proliferate. FOXD2-AS1 was found to be mainly enriched in the nucleus. CDX1 was downregulated in CC tissues and its level was negatively regulated by FOXD2-AS1. The silence of CDX1 could reverse the regulatory effect of FOXD2-AS1 on the proliferative ability of CC cells., Conclusions: FOXD2-AS1 is upregulated in CC and its high level predicts a poor prognosis of CC patients. It accelerates the malignant progression of CC via negatively regulating CDX1 level.

Introduction: There is currently no standard of care for women with cervical cancer stage IB2 (FIGO 2018, ≥2 cm and <4 cm in greatest dimension) who wish to preserve their fertility. Generally, two approaches are offered. Option 1: neoadjuvant platinum-based chemotherapy (NACT) to reduce the tumor size to ≤ 2 cm, followed by Vaginal Radical Trachelectomy (VRT) with Pelvic Lymph Node Dissection (PLND) either before chemotherapy or at the time of VRT. Option 2: Abdominal Radical Trachelectomy (ART) with PLND., Objective: To compare rates of fertility, pregnancy, life births as well as recurrence for women with cervical cancer stage IB2 treated with either NACT followed by VRT, or ART., Methods: A systematic review was performed using the PubMed database. Articles reporting the search term 'trachelectomy' as text word or as Medical Subject Headings (MeSH) were identified., Results: Ten studies were identified with a total of 338 patients. After NACT followed by VRT 39% of the women tried to conceive, 70% of these women got pregnant, of which 63% resulted in a life birth. The overall recurrence and death rate were 10% and 2.9% respectively. After ART 40% of the women tried to conceive, 21% of these women got pregnant, which resulted in a life birth rate of 42%. Recurrence and death rate after ART were 6.9%, and 3.4% respectively., Conclusion: Women with cervical cancer stage IB2 and a wish to preserve fertility treated with NACT followed by VRT have a significantly higher chance of pregnancy than women treated with ART, with comparative oncological results., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Voltage-gated potassium channel subfamily A member 1 (KCNA1/Kv1.1) is an important component of type A potassium channels, which has been found to be involved in various tumors. This study aimed to identify the role of KCNA1 in cervical cancer and explore the related mechanism. The levels of KCNA1 in cervical cancer tissues and cell lines were examined by Western blot and qPCR. Cell proliferation and invasion were assessed by CCK-8 and transwell assays, respectively. Protein levels of Hedgehog (Hhg), Wnt and Notch were detected by Western blot. The mitochondrial capacity was examined by immunostaining with MitoTracker Red CMXRos. KCNA1 was highly expressed in cervical cancer tissues and cell lines, and correlated with poor prognosis. In addition, depletion of KCNA1 suppressed growth, proliferation, migration and invasion of HeLa cells. Moreover, KCNA1 could regulate the Hhg, Wnt and Notch signaling pathways and cause mitochondrial dysfunction. The present study has demonstrated that KCNA1 is an oncogene excessively expressed in cervical cancer, and promotes tumor progression by regulating the Hhg, Wnt and Notch signaling pathways and the mitochondrial capacity. Therefore, our results provide a theoretical basis for the discovery of novel clinical treatment against cervical cancer.

Background: Emergency departments (EDs) have the potential to promote critical public and preventive health interventions. Cervical cancer (CC) screening has been a cornerstone of preventive health efforts for decades. Approximately 20% of U.S. women are not adherent with CC screening guidelines-considerably below the U.S. Federal Government's target. ED patients are disproportionately nonadherent with CC screening guidelines. The ED, therefore, is an optimal setting to target women with an intervention that promotes CC screening., Objectives: To assess the feasibility and potential efficacy of an intervention, grounded in behavioral change theory, to promote uptake of CC screening among ED patients., Methods: Design: Randomized clinical trial pilot study; Patients: Women aged 21-65 years that were identified in the ED to be nonadherent with CC screening recommendations; Setting: Single center urban academic ED., Results: Among enrolled participants, 355 (79%) were determined to be adherent with screening recommendations and 95 (21%) were determined to be either nonadherent or have uncertain adherence. Among the nonadherent/uncertain group, 47 were randomized to the control condition (referral only) and 48 were randomized to the intervention condition. Thirty-six percent of participants in the control condition received or scheduled screening during the follow-up period. In the intervention condition, 43% received or scheduled screening during the follow-up period-a 19% relative improvement over the control condition., Conclusion: This pilot study demonstrates feasibility and preliminary efficacy of a behavioral intervention to increase uptake of CC screening among ED patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Cervical cancer is the second-leading cause of cancer-related mortality in females. Coix lacryma-jobi L. var. ma-yuen (Rom.Caill.) Stapf ex Hook. f. is the most widely recognized medicinal herb for its remedial effects against inflammation, endocrine system dysfunctions, warts, chapped skin, rheumatism, and neuralgia and is also a nourishing food., Methods: To investigate the activity of Coix lacryma-jobi sprout extract (CLSE) on cell proliferation in human cervical cancer HeLa cells, we conducted a Cell Counting Kit-8 (CCK-8) assay. Flow-cytometric analysis and western blot analysis were performed to verify the effect of CLSE on the regulation of the cell cycle and apoptosis in HeLa cells., Results: We observed that CLSE significantly inhibited cell proliferation. Furthermore, CLSE dose-dependently promoted cell cycle arrest at the sub-G1/ S phase in HeLa cells, as detected by bromodeoxyuridine (BrdU) staining. The cell-cycle-arrest effects of CLSE in HeLa cells were associated with downregulation of cyclin D1 and cyclin-dependent kinases (CDKs) 2, 4, and 6. Moreover, CLSE induced apoptosis, as determined by flow-cytometric analysis and nuclear DNA fragmentation with Annexin V/propidium iodide (PI) and 4'6'-diamidino-2-phenylindole (DAPI) staining. Induction of apoptosis by CLSE was involved in inhibition of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) and upregulation of the apoptotic proteins p53, cleaved poly (ADP-ribose) polymerase (PARP), cleaved caspase-3, and cleaved caspase-8. Finally, we observed that CLSE inactivated the phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) pathways., Conclusions: CLSE causes cell cycle arrest and apoptotic cell death through inactivation of the PI3K/AKT pathway in HeLa cells, suggesting it is a viable therapeutic agent for cervical cancer owing to its anticancer effects.

Objective: Long non-coding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressor genes in the development of various cancers. However, the function of lncRNA SNHG7 in cervical cancer remains unclear. Therefore, the aim of this study was to investigate the potential role of lncRNA SNHG7 in cervical cancer and to explore the possible underlying mechanism., Patients and Methods: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of lncRNA SNHG7 in 60 cervical cancer tissues and adjacent normal tissues. Cell Counting Kit-8 (CCK-8) and transwell assays were used to study the effects of lncRNA SNHG7 on the proliferation and invasion of cervical cancer cells, respectively. Furthermore, Western blot was used to detect the expression levels of proteins in the epithelial-mesenchymal transition (EMT) process., Results: LncRNA SNHG7 expression increased significantly in cervical cancer tissues. The inhibition of lncRNA SNHG7 expression markedly inhibited cervical cell proliferation and invasion. Meanwhile, the inhibition of lncRNA SNHG7 resulted in the increased protein expression level of E-cadherin, and decreased protein expressions of N-cadherin and Vimentin. In addition, the survival time of patients with high expression of lncRNA SNHG7 was remarkably shortened., Conclusions: LncRNA SNHG7 contributes to cell proliferation and invasion of cervical cancer. Moreover, SNHG7 has emerged as an independent and significant factor associated with poor survival of cervical cancer patients.

Background and Objectives : In 2004, Lithuania started the Nationwide Cervical Cancer Screening Programme. However, screening is more opportunistic than population-wide and the programme's coverage is insufficient. The aim of this study was to assess the effect of systematic personal invitation on coverage of cervical cancer (CC) screening in urban and rural regions of Lithuania. Materials and Methods : The study was conducted in an urban primary healthcare centre (PHCC) and in a rural PHCC, where prevailing CC screening practice was highly opportunistic. Over the first year, all women aged 25-60 who had not received a Pap smear test within the last three years in urban ( n = 1591) and rural ( n = 1843) PHCCs received a personal invitation letter to participate in the screening. Over the second year, the reminder letter was sent to the non-attendees ( n = 1042 in urban and n = 929 in rural PHCCs). A random sample of women ( n = 93), who did not attend for screening after two letters, was contacted by phone in order to identify the barriers of non-attendance. Results : Before the study, only 9.6% of the target population in urban and 14.7% in rural PHCCs participated in CC screening. After the first invitation letter, the participation in CC screening increased up to 24.6% in urban and 30.8% in rural areas ( p < 0.001). After the reminder letter, the attendance was 16.4% in urban and 22.2% in rural PHCCs ( p < 0.001). The most common barriers for the non-attendance were lack of time, long waiting time for family doctor's appointment, worries that a Pap test might be unpleasant and preventive gynaecological examination outside of the screening program. Conclusions : A systematic personal invitation with one reminder letter significantly increased the coverage of CC screening and was more effective in rural regions than in urban regions. The assessed barriers for non-attendance can be used to improve the coverage of screening.

Wide tumour excision is currently the standard approach to surgical treatment of solid cancers including carcinomas of the lower genital tract. This strategy is based on the premise that tumours exhibit isotropic growth potential. We reviewed and analysed local tumour spreading patterns in 518 patients with cancer of the uterine cervix who underwent surgical tumour resection. Based on data obtained from pathological examination of the surgical specimen, we applied computational modelling techniques to simulate local tumour spread in order to identify parameters influencing preferred infiltration patterns and used area-proportional Euler diagrams to detect and confirm ordered patterns of tumour spread. Some anatomical structures, e.g. tissues of the urinary bladder, were significantly more likely to be infiltrated than other structures, e.g. the ureter and the rectum. Computational models assuming isotropic growth could not explain these infiltration patterns. Introducing ontogenetic distance of a tissue relative to the uterine cervix as a parameter led to accurate predictions of the clinically observed infiltration likelihoods. The clinical data indicates that successive infiltration likelihoods of ontogenetically distant tissues are nearly perfect subsets of ontogenetically closer tissues. The prevailing assumption of isotropic tumour extension has significant shortcomings in the case of cervical cancer. Rather, cervical cancer spread seems to follow ontogenetically defined trajectories.

Objective: To evaluate the health-related quality of life (HRQOL) in locally advanced cervical cancer (LACC) patients treated with neoadjuvant concurrent chemoradiation (CCRT) or radiation (RT) alone followed by radical surgery (RS)., Methods: In a single-center retrospective study from a prospective database, 275 FIGO Stage IB2-IIIB patients who underwent CCRT/RT + RS were included. HRQOL was prospectively assessed by EORTC QLQ-C30 and EORTC QLQ-CX24 prior to any treatment (baseline) and 6 months after surgery, respectively., Results: A statistically significant and clinically relevant improvement in physical functioning (P < 0.001) and role functioning (P = 0.002, P = 0.031) was observed in patients receiving either CCRT+RS or RT + RS at follow-up. In addition, quality of life (QoL), physical functioning, and social functioning were better in the RT + RS group than the CCRT+RS group after treatment (P = 0.028, P = 0.010, P = 0.014). Symptom scores of fatigue decreased in both groups over time (P < 0.001, P = 0.004) while insomnia decreased only in the RT + RS group (P = 0.042). Worsened menopausal symptoms were documented in both groups at follow-up (P = 0.001, P = 0.047), while lymphedema was deteriorated only in patients receiving CCRT + RS (P < 0.001). Sexuality scores did not differ between groups or over time with the exception of sexual worry, which was deteriorated in patients receiving RT + RS (P = 0.042)., Conclusions: QLQ-C30 functioning and tumor-related symptoms scores improved while lymphedema and menopausal symptoms worsened 6 months after neoadjuvant CCRT or RT alone followed by RS in LACC patients. Patients treated with RT + RS had a generally better HRQOL compared with those receiving CCRT+RS, though further validation with prospective randomized clinical trials is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Previous findings from our centre suggest that carcinoma of the cervix propagates within ontogenetic cancer fields, tissue compartments defined by staged morphogenesis. We aimed to determine whether surgical treatment that accounts for stage-associated, ontogenetic cancer fields and their associated lymphoid tissues results in locoregional tumour control without the need for adjuvant radiotherapy., Methods: We did the final clinical and histopathological evaluation of data from, the single-centre, observational, cohort study, the Leipzig School Mesometrial Resection Study. Patients of any age with stage IB1, IB2, IIA1, IIA2, or IIB cervical cancer (according to 2009 International Federation of Gynecology and Obstetrics [FIGO]) had total mesometrial resection or extended mesometrial resection and therapeutic lymph node dissection, done on the basis of ontogenetic cancer fields. We defined sentinel node, first-line, second-line, and third-line lymph node regions as progressive regional cancer fields. Primary outcomes were disease-specific survival and recurrence-free survival, and treatment-related morbidity (assessed with the Franco-Italian glossary). Applying Cox proportional hazard models, ontogenetic local (T) and regional (N) tumour staging was compared with pathological T and N staging. This trial is registered with the German Clinical Trials Register, number DRKS00015171., Findings: Between Oct 16, 1999, and June 27, 2017, 523 patients were treated per protocol and followed up for a median of 61·8 months (IQR 49·3-94·8). In 495 patients with cervical cancer treated with cancer field surgery, 5-year disease-specific survival was 89·4% (95% CI 86·5-92·4) and recurrence-free survival was 83·1% (79·7-86·6). In the per-protocol population of 523 patients, treatment-related morbidity comprised 112 (21%) grade 2 and 15 (3%) grade 3 complications. The most common moderate and severe treatment-related complications and sequelae were wound dehiscence (17 [3%]), hydronephrosis (17 [3%]), bowel obstruction (26 [5%]), and lymph oedema (33 [6%]). One patient (<1%), who received total mesometrial resection, died from postoperative brain infarction., Interpretation: Total or extended mesometrial resection with therapeutic lymph node dissection based on ontogenetic cancer fields results in good survival outcomes of patients with cervical cancer in our institution, but needs to be investigated further in multicentre trials., Funding: Leipzig School of Radical Pelvic Surgery, University of Leipzig Medical School, and the Gynecologic Oncology Research Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: To evaluate and identify the risk factors for abnormal menstruation after radical trachelectomy., Methods: This study included 58 patients who underwent radical trachelectomy at our hospital between April 2005 and January 2018. Patients were divided into groups of those with no change in postoperative menstruation (regular [R] group; n = 46) and those with abnormal menstruation such as amenorrhea or hypomenorrhea (irregular [I] group; n = 12). The perioperative characteristics and fertility of the groups were compared retrospectively. The data were statistically analyzed using Student's t-test, Fisher's exact test and Mann-Whitney U test for univariate analysis and logistic regression analysis for multivariate analysis, with the level of statistical significance set at P < 0.05., Results: Based on Federation of Gynecology and Obstetrics staging, 54 patients had stage IB1, 2 had stage IB2 and 2 had stage IIA1 cervical cancer. Eight patients received neoadjuvant chemotherapy. Pretreatment tumor size, residual uterine cavity length and neoadjuvant and postoperative chemotherapy use were not significantly different between the groups. Abnormal menstruation was significantly more common in patients with postoperative pelvic infection (R group, 13.0%; I group, 58.3%) and cervical stenosis (R group, 15.2%; I group, 58.3%)., Conclusion: To maintain healthy menstruation even after radical trachelectomy, it is important to prevent postoperative pelvic infection and cervical stenosis., (© 2019 Japan Society of Obstetrics and Gynecology.)

Background: In Mexico, 80% women with cervical cancer are diagnosed at locally advanced stages and are treated with concomitant chemoradiotherapy. The treatment modality and catabolic state confer a nutritional risk. The present study aimed to thoroughly evaluate the nutritional status and change in body composition of locally advanced cervical cancer (LACC) patients throughout treatment., Methods: An observational prospective study, carried out at the Mexican National Cancer Institute, included 55 LACC patients. Nutritional status was evaluated before, during and after treatment, using anthropometric, dietary and biochemical measurements. Body composition was analysed using computed tomography images obtained at the time of diagnosis and approximately 4 months after treatment completion. Clinical outcomes were associated with changes in body composition., Results: At the time of diagnosis, no patients were clinically malnourished, although 33.3% presented sarcopenia and most were overweight; by the end of treatment, 69% became clinically malnourished and 58% were sarcopenic. Average weight loss was 7.4 kg (P = 0.001). Adequacy of energy intake was reduced to 54%, obtained predominantly from carbohydrates. By the week 9, 62.8% patients became anemic and 34.5% had low albumin levels. Body composition analysis revealed that patients lost both, muscle and adipose tissues, although 27% patients were muscle depleted by the end of treatment. Patients who lost ≥10% skeletal muscle presented a higher tumour recurrence (hazard ratio = 2.957, P = 0.006) and a tendency towards diminished overall survival (hazard ratio = 2.572, not significant)., Conclusions: The nutritional status of cervical cancer patients deteriorates during treatment with concomitant chemoradiotherapy and, most importantly, muscle loss impacts the clinical outcome of patients., (© 2019 The British Dietetic Association Ltd.)