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Abstract Background Cisplatin (DDP) is an efficacious and widely applied chemotherapeutic drug for cervical cancer patients who are diagnosed as metastatic and inoperable, or desiring fertility preservation. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) selectively triggers cancer cells apoptosis by binding to cognate death receptors (DR4 and DR5). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been regarded as ideal drug carriers on account of their nanoscale, low toxicity, low immunogenicity, high stability, biodegradability, and abundant sources. Methods Human chorion-derived mesenchymal stem cells (hCD-MSCs) were isolated by adherent culture method. TRAIL-engineered hCD-MSCs (hCD-MSCsTRAIL) were constructed by lentivirus transfection, and its secreted Exo (hCD-MSCs-ExoTRAIL) were acquired by differential centrifugation and confirmed to overexpress TRAIL by western blotting. Next, nanoscale drug delivery systems (DDP & hCD-MSCs-ExoTRAIL) were fabricated by loading DDP into hCD-MSCs-ExoTRAIL via electroporation. The CCK-8 assay and flow cytometry were conducted to explore the proliferation and apoptosis of cervical cancer cells (SiHa and HeLa), respectively. Cervical cancer-bearing nude mice were constructed to examine the antitumor activity and biosafety of DDP & hCD-MSCs-ExoTRAIL in vivo. Results Compared with hCD-MSCs-Exo, hCD-MSCs-ExoTRAIL weakened proliferation and enhanced apoptosis of cervical cancer cells. DDP & hCD-MSCs-ExoTRAIL were proved to retard cervical cancer cell proliferation and propel cell apoptosis more effectively than DDP or hCD-MSCs-ExoTRAIL alone in vitro. In cervical cancer-bearing mice, DDP & hCD-MSCs-ExoTRAIL evidently hampered tumor growth, and its role in inducing apoptosis was mechanistically associated with JNK/p-c-Jun activation and survivin suppression. Moreover, DDP & hCD-MSCs-ExoTRAIL showed favorable biosafety in vivo. Conclusions DDP & hCD-MSCs-ExoTRAIL nanoparticles exhibited great promise for cervical cancer treatment as an Exo-based chemo-gene combinational therapy in clinical practice. Graphical abstract

Resistance to cisplatin presents a major obstacle in managing advanced-stage cervical cancer. Cuproptosis, a newly identified form of cell death induced by copper ions, has potential in overcoming chemoresistance. But the application of cuproptosis in cervical cancer resistant to cisplatin has not yet been reported. In this study, treatment with Elsm-Cu in cervical cancer cells induced cuproptosis, affecting cell proliferation and apoptosis was found. Moreover, cuproptosis in cervical cancer cells was significantly induced by baicalein. The combination of baicalein and cisplatin exhibited a synergistic effect on cervical cancer cells by promoting apoptosis and inhibiting cell viability via the induction of cuproptosis. Animal experiments demonstrated that this combination significantly suppressed tumor growth. Upon treating cells with SC79 (Akt agonist), a significant inhibition of the expression of cuproptosis-related proteins SDHB and FDX1 were observed, indicating that baicalein induced cuproptosis through the Akt pathway. These results indicated that baicalein, mediated through the Akt pathway to induce cuproptosis, had the potential to improve the sensitivity of cervical cancer cells to cisplatin.

Abstract Cervical cancer poses a serious threat to women’s health globally. Our previous studies found that upregulation of TM7SF2, which works as an enzyme involved in the process of cholesterol biosynthesis expression, was highly correlated with cervical cancer. However, the mechanistic basis of TM7SF2 promoting cervical cancer progression via lipid metabolism remains poorly understood. Therefore, quantification of fatty acids and lipid droplets were performed in vitro and in vivo. The protein-protein interaction was verified by Co-IP technique. The mechanism and underlying signaling pathway of TM7SF2 via CPT1A associated lipid metabolism in cervical cancer development were explored using Western blotting, IHC, colony formation, transwell assay, and wound healing assay. This study reported that overexpression of TM7SF2 increased fatty acids content and lipid droplets both in vivo and in vitro experiments. While knockout of TM7SF2 obviously attenuated this process. Moreover, TM7SF2 directly bonded with CPT1A, a key enzyme in fatty acid oxidation, and regulated CPT1A protein expression in cervical cancer cells. Notably, the proliferation and metastasis of cervical cancer cells were elevated when their CPT1A expression was upregulated. Then, rescue assay identified that CPT1A overexpressed could enhance the cell viability and migration in TM7SF2-knockout cells. Furthermore, depletion of TM7SF2 significantly inhibited WNT and β-catenin proteins expression, which was enhanced by CPT1A-overexpressed. The proliferation and migration of cervical cancer cells were reversed in CPT1A-overexpressed cells with the treatment of MSAB, an inhibitor of Wnt/β-Catenin pathway. This study put forward an idea that TM7SF2-induced lipid reprogramming promotes proliferation and migration via CPT1A/Wnt/β-Catenin axis in cervical cancer, underlying the progression of cervical cancer.

Abstract Background The effect of DOCK1 gene on the biological behavior of endometrial carcinoma cells and its related pathway has not been reported. Methods The immunohistochemical method and western blot were utilized to analyze DOCK1 protein expression in endometrial tissues and cells, respectively. CCK-8, BrdU, transwell and flow cytometry were performed to analyze the effect of DOCK1 expression changes on the viability, proliferation, invasion, migration and apoptosis of endometrial cancer cells, respectively. The effects of DOCK1 gene on Bcl-2, MMP9, Ezrin, E-cadherin and c-RAF/ERK1/2 signaling pathway were evaluated by western blot. The xenograft models were constructed to analyze the effect of DOCK1 in vivo. Results DOCK1 expression was increased in endometrial cancer tissues and cells compared with those in normal adjacent tissues and cells. DOCK1 knockout could inhibit the malignant biological behavior of endometrial cancer cells, while DOCK1 overexpression played the opposite effect. The expression of E-cadherin was upregulated and those of MMP9, Ezrin, Bcl-2, p-c-RAF (S338) and p-ERK1/2 (T202/Y204) were downregulated after DOCK1 knockout, while DOCK1 overexpression played the opposite effect. Additionally, Raf inhibitor LY3009120 reversed the function of DOCK1 on malignant biological behavior. In vivo experiment results showed that the growth and weight of transplanted tumors in nude mice were inhibited after DOCK1 knockout. The changes of E-cadherin, MMP9, Ezrin and Bcl-2 expressions in the transplanted tumors were consistent with those in vitro. Conclusion DOCK1 could enhance the malignant biological behavior of endometrial cancer cells, which might be through c-RAF/ERK1/2 signaling pathways in vitro and in vivo.

Summary: Ovarian cancer is a highly lethal gynecological malignancy, emphasizing the need for effective treatment strategies. This study investigated the synergistic effects of quercetin and paclitaxel on ovarian cancer. Using SKOV3 and A2780 cell lines, we found that the combined treatment significantly enhanced cell apoptosis and inhibited invasion and migration compared to individual treatments. Then, we identified 32 common targets between quercetin/paclitaxel and ovarian cancer, with 29 genes showing differential expression between normal ovarian tissue and ovarian tumor tissue. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that quercetin and paclitaxel modulated cancer-related pathways in ovarian cancer treatment. Mechanistic analysis further discovered that the synergistic effect was mediated by downregulating ERBB2 and BIRC5 and upregulating CASP3 expression. This study provides strong evidence that quercetin enhances the effectiveness of paclitaxel in treating ovarian cancer.

Abstract Cervical cancer (CC) is a common gynecological malignancy. Despite the current screening methods have been proved effectively and significantly decreased CC morbidity and mortality, deficiencies still exist. Single-cell RNA sequencing (scRNA-seq) approach can identify the complex and rare cell populations at single-cell resolution. By scRNA-seq, the heterogeneity of tumor microenvironment across cervical carcinogenesis has been mapped and described. Whether these alterations could be detected and applied to CC screening is unclear. Herein, we performed scRNA-seq of 56,173 cervical exfoliated cells from 15 samples, including normal cervix, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and malignancy. The present study delineated the alteration of immune and epithelial cells derived during the cervical lesion progression. A subset of lipid-associated macrophage was identified as a tumor-promoting element and could serve as a biomarker for predicting the progression of LSIL into HSIL, which was then verified by immunofluorescence. Furthermore, cell–cell communication analysis indicated the SPP1-CD44 axis might exhibit a protumor interaction between epithelial cell and macrophage. In this study, we investigated the cervical multicellular ecosystem in cervical carcinogenesis and identified potential biomarkers for early detection.

Abstract Background Ovarian cancer is one of the most common gynecological malignancies due to the lack of early symptoms, early diagnosis and limited screening. Therefore, it is necessary to understand the molecular mechanism underlying the occurrence and progression of ovarian cancer and to identify a basic biomarker for the early diagnosis and clinical treatment of ovarian cancer. Methods The association between FBXO28 and ovarian cancer prognosis was analyzed using Kaplan‒Meier survival analysis. The difference in FBXO28 mRNA expression between normal ovarian tissues and ovarian tumor tissues was obtained from The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) cohorts. The expression levels of the FBXO28 protein in ovarian cancer tissues and normal ovarian tissues were measured via immunohistochemical staining. Western blotting was used to determine the level of FBXO28 expression in ovarian cancer cells. The CCK-8, the colony formation, Transwell migration and invasion assays were performed to evaluate cell proliferation and motility. Results We found that a higher expression level of FBXO28 was associated with poor prognosis in ovarian cancer patients. Analysis of the TCGA and GTEx cohorts showed that the FBXO28 mRNA level was lower in normal ovarian tissue samples than in ovarian cancer tissue samples. Compared with that in normal ovarian tissues or cell lines, the expression of FBXO28 was greater in ovarian tumor tissues or tumor cells. The upregulation of FBXO28 promoted the viability, proliferation, migration and invasion of ovarian cancer cells. Finally, we demonstrated that FBXO28 activated the TGF-beta1/Smad2/3 signaling pathway in ovarian cancer. Conclusions In conclusion, FBXO28 enhanced oncogenic function via upregulation of the TGF-beta1/Smad2/3 signaling pathway in ovarian cancer.

Abstract Mesenchymal stromal cells (MSCs) show considerable promise in regenerative medicine with superior anti-fibrotic, immunomodulatory, and angiogenic functions. More recently, discovered with the tumor tropism, MSCs have been exploited as the basis of targeted cancer therapy. In this scenario, MSCs can directly home to tumor tissues and play anti-tumor properties. In addition, MSCs, MSC-derived exosomes and MSC-derived membranes are often developed as carriers for precisely delivering cytotoxic agents to cancer sites, including chemotherapeutic drugs, therapeutic genes, or oncolytic viruses. However, it has revealed the tumorigenic risk of MSCs as an important component within the tumor microenvironment, hampering the translation of MSC-based cancer therapies into clinical settings. Therefore, in this review, we introduce the specific tumor-tropic ability of MSCs and underlying mechanisms. We also summarize the current application of MSC-based therapeutic approaches in treating gynecologic cancers, mainly including cervical, ovarian, and endometrial cancers. Moreover, we discuss the main challenges that the current MSC-based cancer therapies are facing.

Lightweight cryptography algorithms are a class of ciphers designed to protect data generated and transmitted by the Internet of Things. They typically have low requirements in terms of storage space and power consumption, and are well-suited for resource-limited application scenarios such as embedded systems, actuators, and sensors. The NIST-approved competition for lightweight cryptography aims to identify lightweight cryptographic algorithms that can serve as standards. Its objective is to enhance data security in various scenarios. Among the chosen standards for lightweight cryptography, ASCON has been selected. ASCON-HASH is a hash function within the ASCON family. This paper presents a detailed analysis of the differential characteristics of ASCON-HASH, utilizing the quadratic S-box. Additionally, we employ message modification techniques and ultimately demonstrate a non-practical collision attack on the 2-round ASCON-HASH, requiring a time complexity of 298 hash function calls.

Abstract Bromodomain-containing protein 4 (BRD4), the major component of bromodomain and extra-terminal domain (BET) protein family, has important functions in early embryonic development and cancer development. However, the posttranslational modification of BRD4 is not well understood. Multiple approaches were used to explore the mechanism of PRMT1-mediated BRD4 methylation and to determine the biological functions of BRD4 and PRMT1 in ovarian cancer. Here we report that BRD4 is asymmetrically methylated at R179/181/183 by PRMT1, which is antagonized by the Jumonji-family demethylase, JMJD6. PRMT1 is overexpressed in ovarian cancer tissue and is a potential marker for poor prognosis in ovarian cancer patients. Silencing of PRMT1 inhibited ovarian cancer proliferation, migration, and invasion in vivo and in vitro. PRMT1-mediated BRD4 methylation was found to promote BRD4 phosphorylation. Compared to BRD4 wild-type (WT) cells, BRD4 R179/181/183K mutant-expressing cells showed reduced ovarian cancer metastasis. BRD4 arginine methylation is also associated with TGF-β signaling. Our results indicate that arginine methylation of BRD4 by PRMT1 is involved in ovarian cancer tumorigenesis. Targeting PRMT1-mediated arginine methylation may provide a novel diagnostic target and an effective therapeutic strategy for ovarian cancer treatment.

Abstract Background Cervical cancer is emerging as a potential target of increased susceptibility to coronavirus disease-2019 (COVID-19), leading to compromised survival rates. Despite this critical link, efficacious anti-cervical cancer/COVID-19 interventions remain limited. Quercetin, known for its efficacy against both cancer and viral infections, holds promise as a therapeutic agent. This study aims to elucidate quercetin’s anti-cervical cancer/COVID-19 mechanisms and potential targets. Methods We initiated our investigation with differential gene expression analysis using cervical cancer transcriptome data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx), focusing on intersections with COVID-19-related genes. Network pharmacology was employed to identify the shared targets between cervical cancer/COVID-19 DEGs and quercetin’s targets. Subsequently, Cox proportional hazards analyses were employed to establish a risk score based on these genes. Molecular docking techniques were applied to predict quercetin’s therapeutic targets and mechanisms for mitigating cervical cancer and COVID-19. Results Our findings unveiled 45 potential quercetin targets with anti-cervical cancer/COVID-19 actions. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses highlighted significant enrichment in immune pathways and COVID-19-related pathways. A refined risk score model, comprising PLA2G7, TNF, TYK2, F2, and NRP1, effectively stratified cervical cancer patients into distinct risk groups. Importantly, molecular docking analyses illuminated quercetin’s remarkable binding affinity to the primary protease of the coronavirus. Conclusions In summation, our study suggests that quercetin holds promise as a potential therapeutic agent for mitigating coronavirus function, specifically through its interaction with the primary protease. This research offers novel insights into exploring COVID-19 susceptibility and enhancing survival in cervical cancer patients.

Abstract Purpose DYNLT3 is identified as an age‐related gene. Nevertheless, the specific mechanism of its carcinogenesis in breast tumor has not been clarified. This research aims to elucidate the role and the underlying molecular pathways of DYNLT3 on breast cancer tumorigenesis. Methods The differential expression of DYNLT3 among breast cancer, breast fibroids, and normal tissues, as well as in various breast cancer cell lines were detected by immunohistochemical staining, real‐time quantitative reverse transcription‐PCR and Western blotting, respectively. Additionally, the role of DYNLT3 on cell viability and proliferation were observed through cell counting kit‐8, bromodeoxyuridine, and colony formation experiments. Migratory and invasive abilities was envaulted by wound healing and Transwell methods. Apoptotic cells rate was examined by flow cytometry. Furthermore, nude mice xenograft models were established to confirm the role of DYNLT3 in tumor formation in vivo. Results DYNLT3 expression was highly rising in both breast cancer tissues and cells. DYNLT3 knockdown obviously suppressed cell growth, migration and invasion, and induced cell apoptosis in MDA‐MB‐231 and MCF‐7 breast cancer cells. The overexpression of DYNLT3 exerted the opposite effect in MDA‐MB‐231 cells. Moreover, DYNLT3 knockdown inhibited tumor formation in vivo. Mechanistically, an elevation of N‐cadherin and vimentin levels and a decline of E‐cadherin were observed when DYNLT3 was upregulated, which was reversed when DYNLT3 knockdown was performed. Conclusion DYNLT3 may function as a tumor‐promotor of age‐associated breast cancer, which is expected to provide experimental basis for new treatment options.

Abstract Background Propofol is a drug with potential anticancer effect. This study aimed to explore the effect of propofol on chemosensitivity of cervical cancer cells to paclitaxel. Methods HeLa and CaSki cells were selected for drug experiments. Cell viability was evaluated via CCK‐8 assay, and the combination index (CI) was calculated by CompuSyn software. A clinically relevant concentration and IC30 of propofol were selected in combination with 5 nM paclitaxel. BrdU incorporation, transwell, and flow cytometry assays were utilized to evaluate cell proliferation, migration, invasion, and apoptosis. The expression of β‐tubulin, stathmin 1, and GAPDH proteins was evaluated by Western blot. The stathmin 1 cDNA plasmid was used to establish stathmin 1‐overexpressing CaSki cells. Results At clinically relevant concentrations (0–80 μM), propofol did not affect cancer cell viability, but high concentrations (100–800 μM) reduced cell viability. The CI values of propofol with IC30 (200 μM in HeLa; 400 μM in CaSki) combined with 5 nM paclitaxel were

AbstractThis retrospective, monocentric study quantified hidden blood loss (HBL) and investigated its influencing factors in benign ovarian tumour patients undergoing laparoscopic ovarian cystectomy. Data from 153 patients who underwent laparoscopic ovarian cystectomy were retrospectively reviewed. HBL was calculated using the formula derived from ‘Nadler’ and ‘Cross’. Pearson correlation was carried out to measure the association between HBL and potential risk factors. The average HBL was 280.22 ± 168.42 mL, accounting for 84.13 ± 19.20% of total blood loss (TBL) (347.48 ± 179.05 mL), which was a change of almost fourteen-fold relative to median visible blood loss [20.00 mL (10.00 mL, 57.5 mL)]. Surgical time, number of excisional tumours and preoperative albumin values were risk factors for HBL. HBL represents a large proportion more than 80% of TBL in patients undergoing laparoscopic ovarian cystectomy. Collectively, HBL is helpful for estimating intraoperative blood loss and better guidance of haemostatic agents, which reduces postoperative complications and expedites postoperative recovery. Additionally, the estimation of HBL also contributes to the summary, reflection and improvement of surgical technique.IMPACT STATEMENTWhat is already known on this subject? There has been a growing number of surgical patients with perioperative anaemia, which appears to be inconsistent with measured levels of visible intraoperative blood loss and postoperative drainage. This substantial but easily underestimated blood loss is known as hidden blood loss. To date, no published articles have evaluated HBL and its related risk factors in benign ovarian tumour patients undergoing laparoscopic ovarian cystectomy.What the results of this study add? HBL accounts for a large amount of TBL in laparoscopy for benign ovarian tumours. Surgical time, number of excisional tumours and preoperative albumin values are risk factors for HBL.What the implications are of these findings for clinical practice and/or further research? The management of HBL is important for the administration of perioperative blooding loss. In this context, HBL can be applied to estimate intraoperative blood loss and be better guidance of haemostatic agents to reduce postoperative complications and hasten postoperative rehabilitation. Additionally, the estimation of HBL also contributes to the summary, reflection and improvement of surgical technique.

Abstract F-box only protein 22 (FBXO22) is a key subunit of the Skp1-Cullin 1-F-box protein (SCF) E3 ubiquitin ligase complex. Little is known regarding its biological function and underlying molecular mechanisms in regulating cervical cancer (CC) progression. In this study, we aim to explore the role and mechanism of FBXO22 in CC progression. The correlation between FBXO22 and clinicopathological characteristics of CC was analyzed by tissue microarray. MTT, colony formation, flow cytometry, Western blotting, qRT-PCR, protein half-life, co-immunoprecipitation, ubiquitination, and xenograft experiments were performed to assess the functions of FBXO22 and potential molecular mechanisms of FBXO22-mediated malignant progression in CC. The expression of FBXO22 protein in CC tissues was higher than that in adjacent non-tumor cervical tissues. Notably, high expression of FBXO22 was significantly associated with high histology grades, positive lymph node metastasis, and poor outcomes in CC patients. Functionally, ectopic expression of FBXO22 promoted cell viability in vitro and induced tumor growth in vivo, while knockdown of FBXO22 exhibited opposite effects. In addition, overexpression of FBXO22 promoted G1/S phase progression and inhibited apoptosis in CC cells. Mechanistically, FBXO22 physically interacted with the cyclin-dependent kinase inhibitor p57Kip2 and subsequently mediated its ubiquitination and proteasomal degradation leading to tumor progression. FBXO22 protein level was found negatively associated with p57Kip2 protein levels in patient CC samples. FBXO22 promotes CC progression partly through regulating the ubiquitination and proteasomal degradation of p57Kip2. Our study indicates that FBXO22 might be a novel prognostic biomarker and therapeutic target for CC.

Abstract Purpose Patient-derived xenograft (PDX) models were established to reproduce the clinical situation of original cancers and have increasingly been applied to preclinical cancer research. Our study was designed to establish and genetically characterize cervical cancer PDX models. Methods A total of 91 fresh fragments obtained from 22 surgically resected cervical cancer tissues were subcutaneously engrafted into female NOD-SCID mice. Hematoxylin and eosin (H&E) staining was performed to assess whether the established PDX models conserved the histological features of original patient cervical cancer tissues. Moreover, a Venn diagram was applied to display the overlap of all mutations detected in whole-genome sequencing (WGS) data from patient original cervical cancer (F0) and F2-, F3-PDX models. The whole exome sequencing (WES) and the “maftools” package were applied to determine the somatic mutations among primary cervical cancers and the established PDX models. Results Our study successfully developed a panel of cervical cancer PDX models and the latency time of cervical cancer PDX model establishment was variable with a progressive decrease as the passage number increased, with a mean time to initial growth of 94.71 days in F1 engraftment to 40.65 days in F3 engraftment. Moreover, the cervical cancer PDX models preserved the histological features of their original cervical cancer. WGS revealed that the genome of original cervical cancer was preserved with high fidelity in cervical cancer PDX models throughout the xenografting and passaging process. Furthermore, WES demonstrated that the cervical cancer PDX models maintained the majority somatic mutations of original cervical cancer, of which the KMT2D, LRP1B, NAV3, TP53, FAT1, MKI67 and PKHD1L1 genes were identified as the most frequently mutated genes. Conclusions The cervical cancer PDX models preserved the histologic and genetic characteristics of their original cervical cancer, which helped to gain a deeper insight into the genetic alterations and lay a foundation for further investigation of the molecular targeted therapy of cervical cancer.

Abstract Background Cancer cell membrane-camouflaged nanotechnology for metal complex can enhance its biocompatibility and extend the effective circulation time in body. The ruthenium polypyridyl complex (RuPOP) has extensive antitumor activity, but it still has disadvantages such as poor biocompatibility, lack of targeting, and being easily metabolized by the organism. Cancer cell membranes retain a large number of surface antigens and tumor adhesion molecules CD47, which can be used to camouflage the metal complex and give it tumor homing ability and high biocompatibility. Results Therefore, this study provides an electrostatic adsorption method, which uses the electrostatic interaction of positive and negative charges between RuPOP and cell membranes to construct a cancer cell membrane-camouflaged nano-platform (RuPOP@CM). Interestingly, RuPOP@CM maintains the expression of surface antigens and tumor adhesion molecules, which can inhibit the phagocytosis of macrophage, reduce the clearance rate of RuPOP, and increase effective circulation time, thus enhancing the accumulation in tumor sites. Besides, RuPOP@CM can enhance the activity of cellular immune response and promote the production of inflammatory cytokines including TNF-α, IL-12 and IL-6, which is of great significance in treatment of tumor. On the other hand, RuPOP@MCM can produce intracellular ROS overproduction, thereby accelerating the apoptosis and cell cycle arrest of tumor cells to play an excellent antitumor effect in vitro and in vivo. Conclusion In brief, engineering cancer cell membrane-camouflaged metal complex is a potential strategy to improve its biocompatibility, biological safety and antitumor effects.

PurposeAimed to identify the anti-uterine corpus endometrial carcinoma (UCEC) function and characterize the mechanism of quercetin in the treatment of patients infected with COVID-19 via integrated in silico analysis.MethodsThe Cancer Genome Atlas and Genotype Tissue Expression databases were applied to obtain differentially expressed genes of UCEC and non-tumor tissue. Several in silico methods such as network pharmacology, functional enrichment analysis, Cox regression analyses, somatic mutation analysis, immune infiltration and molecular docking were used to investigate and analysis the biological targets, functions and mechanisms of anti-UCEC/COVID-19 of quercetin. Multiple methods such as CCK8 assay, Transwell assay and western blotting were performed to test proliferation, migration, and protein level of UCEC (HEC-1 and Ishikawa) cells.ResultsFunctional analysis disclosed that quercetin against UCEC/COVID-19 mainly by ‘biological regulation’, ‘response to stimulus’, and ‘regulation of cellular process’. Then, regression analyses indicated that 9 prognostic genes (including ANPEP, OAS1, SCGB1A1, HLA‐A, NPPB, FGB, CCL2, TLR4, and SERPINE1) might play important roles in quercetin for treating UCEC/COVID-19. Molecular docking analysis revealed that the protein products of 9 prognostic genes were the important anti-UCEC/COVID-19 biological targets of quercetin. Meanwhile, the proliferation and migration of UCEC cells were inhibited by quercetin. Moreover, after treatment with quercetin, the protein level of ubiquitination-related gene ISG15 was decreased in UCEC cells in vitro.ConclusionsTaken together, this study provides new treatment option for UCEC patients infected with COVID-19. Quercetin may work by reducing the expression of ISG15 and participating in ubiquitination-related pathways.

Abstract The underlying mechanisms of methionine adenosyltransferase 2 A (MAT2A)-mediated cervical cancer progression under nutrient stress are largely elusive. Therefore, our study aims to investigate molecular mechanism by which MAT2A-indcued cervical oncogenesis. The interaction between MAT2A and programmed cell death protein 6 (PDCD6) in cervical cancer cell lines was detected by immunoprecipitation, immunoblotting and mass spectrometric analysis. A panel of inhibitors that are linked to stress responsive kinases were utilized to detect related pathways by immunoblotting. Cell proliferation and apoptosis were investigated by CCK-8 and flow cytometry. Apoptosis related protein level of Bcl-2, Bax and Caspase-3 was also analyzed in cells with PDCD6 K90 methylation mutation. The association between MAT2A and PDCD6 was detected by immunohistochemistry and clinicopathological characteristics were further analyzed. We found that the interaction between MAT2A and PDCD6 is mediated by AMPK activation and facilitates PDCD6 K90 methylation and further promotes protein stability of PDCD6. Physiologically, expression of PDCD6 K90R leads to increased apoptosis and thus suppresses growth of cervical cancer cells under glucose deprivation. Furthermore, the clinical analysis indicates that the MAT2A protein level is positively associated with the PDCD6 level, and the high level of PDCD6 significantly correlates with poor prognosis and advanced stages of cervical cancer patients. We conclude that MAT2A facilitates PDCD6 methylation to promote cervical cancer growth under glucose deprivation, suggesting the regulatory role of MAT2A in cellular response to nutrient stress and cervical cancer progression.

Exosomes are extracellular vesicles with a diameter of 30–150 nm that function in mediating intercellular communication and intercellular material exchange. The liposomal membrane of exosomes protects the cargo carried by exosomes from degradation and assists in transporting cargo to recipient cells to regulate a variety of physiological and pathological processes. The incidence of gynecologic cancers is increasing annually, which is extremely harmful to the lives and health of women because such cancers are challenging to detect at the early stage. Recently, exosomes have emerged as novel biomarkers for diagnosing and predicting the development of gynecologic cancers. In particular, non-coding RNAs (microRNAs [miRNAs], long non-coding RNAs [lncRNAs], and circular RNAs [circRNAs]) carried by exosomes have been extensively investigated in gynecologic cancers. Therefore, the purpose of this review is to focus on the potential roles of exosomes of different origins in ovarian cancer, cervical cancer, and endometrial cancer, which will help to determine the molecular mechanism of carcinogenesis.

Abstract Transmembrane 7 superfamily member 2 (TM7SF2) coding an enzyme involved in cholesterol metabolism has been found to be differentially expressed in kinds of tissues. Nevertheless, the role of TM7SF2 in the regulation of growth and progression among various cancers is unclear. In this study, the immunohistochemistry (IHC) assay, real-time RT-PCR and western blotting analysis were used to determine the TM7SF2 expression in cervical cancer tissues. Next, we used multiple methods to determine the ability of cell proliferation, migration, invasion, apoptosis, and cell cycle in cervical cancer cells after TM7SF2 modulation, such as CCK8 assay, colony formation assay, Transwell assay, wound healing assay, and flow cytometry. Our results revealed that upregulation of TM7SF2 facilitated cell proliferation and metastasis, suppressed cell apoptosis and prevented G0/G1 phase arrests in C33A and SiHa cells. Consistently, the opposite effects were observed after TM7SF2 knockout in cervical cancer cells. Further, we found that TM7SF2 participated in promoting tumorigenesis and progression via activation of C-Raf/ERK pathway in cervical cancer, which can be partly reversed by Raf inhibitor LY3009120. Moreover, TM7SF2 overexpression contributed to enhancement of xenograft tumor growth in vivo. Our findings indicated that TM7SF2 plays a vital role in tumor promotion by involving in C-Raf/ERK activation. Therefore, TM7SF2 could serve as a therapeutic target in future cervical cancer treatment.

Abstract Cancer immunotherapy has recently shown promising antitumor effects in various types of tumors. Among all immune checkpoints, the PD-1/PD-L1 pathway plays an important role in the immune evasion of tumor cells, making it a potent target in antitumor immunity. Accordingly, antibodies targeting the PD-1/PD-L1 pathway have been developed to attack tumor cells; however, resistance to immune therapy remains to be solved. Hence, identification of the underlying modulators of the PD-1/PD-L1 pathway is of significant importance to understand the mechanisms of antitumor immunotherapy. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been identified to regulate the PD-1/PD-L1 pathway, leading to participation in the immune response and immunotherapy. Therefore, this review focuses on the functions of lncRNAs and circRNAs in regulation of the PD-1/PD-L1 axis in tumorigenesis and tumor progression. We hope this review will stimulate research to supply more precise and effective cancer immune checkpoint therapies for a large number of tumors.

Cervical cancer is the most common gynecologic malignancy worldwide. Methyltransferase-like 3 (METTL3) is involved in tumorigenesis; however, it is unclear whether METTL3 plays a potential role in regulating cisplatin (DDP) resistance. Therefore, the role of METTL3 in the regulation of cisplatin sensitivity in cervical cancer cells was determined. Our immunohistochemistry (IHC) data showed that METTL3 was highly expressed in para-cancerous compared with cervical cancer tissues. Furthermore, METTL3 overexpression inhibited viability and increased cisplatin sensitivity of cervical cancer cells in vitro. Overexpression of METTL3 inhibited tumor growth in vivo. IHC results showed that the receptor for advanced glycation and products (RAGE) had higher expression levels in cervical cancer tissues. RAGE downregulation increased cell sensitivity to cisplatin treatment. Moreover, the combination of FPS-ZM1 with cisplatin was more effective in inhibiting cell viability as compared with FPS-ZM1 or cisplatin only. Additionally, METTL3 reduced RAGE expression in cervical cancer cells. Overexpression of METTL3 downregulated RAGE expression and caused more sensitivity to cisplatin treatment in the SiHa-DDP cell line. METTL3 inhibited cell viability and increased apoptosis as well as enhanced the sensitivity of cisplatin via downregulating RAGE expression in cervical cancer cells.

E26 transformation-specific (ETS) variant 4 (ETV4) is an important transcription factor that belongs to the ETS transcription factor family and is essential for much cellular physiology. Recent evidence has revealed that ETV4 is aberrantly expressed in many types of tumors, and its overexpression is related to poor prognosis of cancer patients. Additionally, increasing studies have identified that ETV4 promotes cancer growth, invasion, metastasis, and drug resistance. Mechanistically, the level of ETV4 is regulated by some post-translation modulations in a broad spectrum of cancers. However, little progress has been made to comprehensively summarize the critical roles of ETV4 in different human cancers. Hence, this review mainly focuses on the physiological functions of ETV4 in various human tumors. In addition, the molecular mechanisms of ETV4-mediated cancer progression were elucidated, including how ETV4 modulates its downstream signaling pathways and how ETV4 is regulated by some factors. On this basis, the present review may provide a valuable therapeutics strategy for future cancer treatment by targeting ETV4-related pathways.

Cervical cancer is a common female malignancy that is mainly caused by human papillomavirus (HPV) infection. However, the incidence of HPV-negative cervical cancer has shown an increasing trend in recent years. Because the mechanism of HPV-negative cervical cancer development is unclear, this study aims to find the pattern of differential gene expression in HPV-negative cervical cancer and verify the underlying potential mechanism. Differentially expressed genes were compared among HPV-positive cervical cancer, HPV-negative cervical cancer, and normal cervical tissues retrieved from TCGA. Subsequently, dysregulated differentially expressed genes specifically existed in HPV-negative cervical cancer tissues and HPV-negative cell lines were validated by qRT-PCR, western blotting, and immunohistochemical staining. We found seventeen highly expressed genes that were particularly associated with HPV-negative cervical cancer from analysis of TCGA database. Among the 17 novel genes, 7 genes (preferentially expressed antigen in melanoma [PRAME], HMGA2, ETS variant 4 [ETV4], MEX3A, TM7SF2, SLC19A1, and tweety-homologs 3 [TTYH3]) displayed significantly elevated expression in HPV-negative cervical cancer cells and HPV-negative cervical cancer tissues. Additionally, higher expression of MEX3A and TTYH3 was associated with a shorter overall survival of patients with HPV-negative cervical cancer. Our study implies that these seven genes are more likely to provide novel insights into the occurrence and progression of HPV-negative cervical cancer.

Understanding the role of N6-adenosine methylation (m6A) in the tumor microenvironment (TME) is important since it can contribute to tumor development. However, the research investigating the association between m6A and TME and cervical cancer is still in its early stages. The aim of this study was to discover the possible relationship between m6A RNA methylation regulators, TME, PD-L1 expression levels, and immune infiltration in cervical cancer. We gathered RNA-seq transcriptome data and clinical information from cervical cancer patients using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. To begin, researchers assessed the differences in m6A regulatory factor expression levels between cervical cancer and normal tissues. Clustering analysis was adapted to assess PD-L1 expression, immunological score, immune cell infiltration, TME, and probable pathways in cervical cancer samples. The majority of m6A regulators were found to be considerably overexpressed in cervical cancer tissues. Using consensus clustering of 21 m6A regulators, we identified two subtypes (clusters 1/2) of cervical cancer, and we found that WHO stage and grade were associated with the subtypes. PD-L1 expression increased dramatically in cervical cancer tissues and was significantly linked to ALKBH5, FTO, METTL3, RBM15B, YTHDF1, YTHDF3, and ZC3H13 expression levels. Plasma cells and regulatory T cells (Tregs) were considerably elevated in cluster 2. Cluster 1 is involved in numerous signature pathways, including basal transcription factors, cell cycle, RNA degradation, and the spliceosome. The prognostic signature-based riskscore (METTL16, YTHDF1, and ZC3H13) was found to be an independent prognostic indicator of cervical cancer. The tumor immune microenvironment (TIME) was linked to m6A methylation regulators, and changes in their copy number will affect the quantity of tumor-infiltrating immune cells dynamically. Overall, our research discovered a powerful predictive signature based on m6A RNA methylation regulators. This signature correctly predicted the prognosis of cervical cancer patients. The m6A methylation regulator could be a critical mediator of PD-L1 expression and immune cell infiltration, and it could have a significant impact on the TIME of cervical cancer.

The role of the dynein light chain Tctex-type 3 (DYNLT3) protein in the biological behavior of cervical cancer and its relative molecular mechanisms were investigated. Immunohistochemical staining was used to detect DYNLT3 protein expression in cervical cancer tissues. Cell proliferation and apoptosis rates and invasiveness and migratory capacities were determined by CCK-8 assays, BrdU staining assays and colony formation assays, fluorescence activated cell sorting (FACS), wound healing assays, and Transwell invasion assays of cervical cancer cells after DYNLT3 modulation. The expression levels of Wnt signaling pathway- and EMT-related proteins were examined by Western blotting. Furthermore, the effects of DYNLT3 on the tumorigenicity and metastasis of cervical cancer in nude mice were analyzed by performing immunohistochemistry, and we found that the expression level of the DYNLT3 protein was higher in human normal cervical tissues than in cervical cancer tissues. Overexpression of DYNLT3 obviously attenuated the proliferation, migration and invasion of CaSki and SiHa cells, and promoted cell apoptosis. Upregulation of DYNLT3 expression markedly decreased the expression of Wnt signaling pathway-related proteins (Dvl2, Dvl3, p-LRP6, Wnt3a, Wnt5a/b, Naked1, Naked2, β-catenin and C-Myc) and EMT-related proteins (N-cadherin, SOX2, OCT4, vimentin and Snail), and increased the expression of E-cadherin and Axin1. However, the opposite results were observed after down-regulation of DYNLT3 expression. Up-regulation of DYNLT3 expression significantly inhibited tumor growth in a nude mouse model, while downregulation of DYNLT3 showed the opposite results. In addition, the major metastatic site of cervical cancer cells in mice was the lung, and downregulation of DYNLT3 expression increased cancer metastasis in vivo. DYNLT3 exerted inhibitory effects on cervical cancer by inhibiting cell proliferation, migration and invasion, promoting cell apoptosis in vitro, and inhibiting tumor growth and metastasis in vivo, possibly by suppressing the Wnt signaling pathway and the EMT.

Background: Uterine leiomyomas (ULs) is the most common gynecological benign tumor in women. Our previous study showed that the phenomenon of vitamin D deficiency existed in patients with ULs. However, the association of vitamin D anabolism-related gene polymorphisms and susceptibility to ULs was unclear.Methods: Vitamin D anabolism-related gene polymorphisms in 110 patients with ULs and 110 healthy controls were detected by sequencing and the differences of the 92 SNPs were analyzed in the two groups via chi-square test. To verify the association between the significantly different SNPs and the risk of ULs, the SNPs were genotyped in another 340 patients and 340 healthy controls. Additionally, an unconditional logistic regression model was conducted to calculate the odds ratio (OR) of ULs occurrence and the 95% confidence interval (CI), adjusting for age and BMI.Findings: In sequencing samples, there were differences in DHCR7 rs1044482 C > T (p = 0.008) and NADSYN1 rs2276360 G > C (p = 0.025) between patients with ULs and healthy controls. DHCR7 rs1044482 was related to the susceptibility to ULs in validation samples (heterogeneous: adjusted OR = 1.967, p = 0.002; homogenous: adjusted OR = 2.494, p = 0.002; additive: adjusted OR = 1.485, p < 0.041; and dominant: adjusted OR = 2.084, p < 0.001). Stratified analysis further showed that the DHCR7 rs1044482 polymorphisms were associated with ULs risks in women over 40 and with 18.5–25.0 BMI. In contrast to the wild-type CG haplotype vectors, individuals with TC haplotypes had a higher risk of developing ULs.Interpretation: The vitamin D anabolism-related gene DHCR7 rs1044482 C > T polymorphism was a risk factor of ULs, especially in patients over 40 with 18.5–25.0 BMI, while the relationship between NADSYN1 rs2276360 and ULs risk was not clear.

Abstract Background As LEEP (loop electrosurgical excision procedure) is being increasingly used for the diagnosis and treatment of uterine cervical intraepithelial neoplasia, surgical smoke during LEEP has become an inevitable health issue. Therefore, in this study, exposure to the chemical substances in surgical smoke produced during LEEP was assessed. Methods Smoke samples from patients with high-grade cervical intraepithelial neoplasia undergoing LEEP were collected by smoke-absorbing devices situated 1 m away from the operating table and near the nose of the operator during LEEP. Each plume sample was collected after 5 patients underwent LEEP, requiring 5 min for smoke collection for each patient. The chemicals of exposure to surgical smoke were assessed, and the hazard classes of these chemical components were evaluated by the International Agency for Research on Cancer. Results Qualitative analysis of the smoke produced during LEEP revealed a variety of potentially toxic chemicals under standard detection, such as benzene, toluene, xylene, ethylbenzene, styrene, butyl acetate, acrylonitrile, 1,2-dichloroethane, phenol, chlorine, cyanide, hydrogen cyanide and carbon monoxide. Additionally, the average concentration of carbon dioxide was 0.098 ± 0.015% during surgery and was higher than that before surgery (0.072 ± 0.007%, P < 0.001), and the concentration of formaldehyde was significantly higher during surgery (0.023 ± 0.009 mg/m3, P < 0.05) than before surgery (0.012 ± 0.001 mg/m3, P < 0.05). Conclusions Most of the detected chemical concentrations in smoke generated during LEEP were below the exposure limits when local exhaust ventilation procedures were efficiently used. However, the concentrations of carbon dioxide and formaldehyde found in smoke were significantly higher after surgery. Wearing a high-filtration mask and using evacuation devices routinely and consistently when performing LEEP are recommended to protect perioperative personnel.

In order to improve transmission performance of Wireless Power Transfer (WPT) system, this paper proposes the concept of optimal receiver radius. The planar square transmitter coil WPT system is studied to explore the variation rule of optimal receiver radius with the parameters of WPT system. The key parameters that affect optimal radius are transmitter coil turns, turn spacing, side length and transmission distance. On this basis, by introducing BP neural network to learn the variation rule, the accurate prediction of optimal receiver radius under different parameters is realized. Finally, the finite element simulation proves the existence of optimal receiver radius and the accuracy of the prediction value.

Abstract The nuclear speckle-type pox virus and zinc finger (POZ) protein (SPOP), a representative substrate-recognition subunit of the cullin-RING E3 ligase, has been characterized to play a dual role in tumorigenesis and cancer progression. Numerous studies have determined that SPOP suppresses tumorigenesis in a variety of human malignancies such as prostate, lung, colon, gastric, and liver cancers. However, several studies revealed that SPOP exhibited oncogenic function in kidney cancer, suggesting that SPOP could exert its biological function in a cancer type-specific manner. The role of SPOP in thyroid, cervical, ovarian, bone and neurologic cancers has yet to be determined. In this review article, we describe the structure and regulation of SPOP in human cancer. Moreover, we highlight the critical role of SPOP in tumorigenesis based on three major categories: physiological evidence (animal models), pathological evidence (human cancer specimens) and biochemical evidence (downstream ubiquitin substrates). Furthermore, we note that SPOP could be a promising therapeutic target for cancer treatment.

Background: Endometriosis affects endometrial receptivity, a key factor for successful embryo implantation. Metformin treatment is associated with alleviating the symptoms of endometriosis; however the mechanism of metformin action is unclear. Neoangiogenesis plays an important role in the development and recurrence of endometriosis. In addition, the leukemia inhibitor factor (LIF) and HOXA10 genes are also distinguishing markers of endometriosis (decrease) and endometrial receptivity (increase). This study investigated the therapeutic potentials of metformin and the underlying mechanism using an in vivo rat endometriosis model.Methods: Female Wistar albino mature rats with experimentally induced endometriosis were used in this study. Metformin was administered at doses of 100 mg/kg/d and 200 mg/kg/d. The volume of endometriotic implants was assessed. The protein and mRNA expression of the vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), the endometrial receptivity markers, LIF and HOXA10, were measured in the endometrium of rats with endometriosis.Results: Metformin treatment significantly suppressed the growth of endometriotic implants. Further, the expression of VEGF and MMP-9 protein and mRNA in endometriotic implants were significantly reduced. Metformin also significantly upregulated LIF and HOXA10 expression in endometrium from rats with endometriosis. The inhibitory effect of metformin on the growth of endometriotic implants, VEGF and MMP-9, and upregulating effect on LIF and HOXA10, was optimal at a dose of 100 mg/kg/d.Conclusion: Our in vivo data demonstrates that metformin treatment alleviates endometriosis and potentiates endometrial receptivity. The underlying mechanisms are associated with decreased expression of VEGF and MMP-9 genes and upregulation of the LIF and HOXA10 genes. The effect of metformin was optimal at 100 mg/kg/d. These findings provide a potential alternative for women with endometriosis with the potential to increase fertility. Metformin is an approved drug by FDA for diabetes and this study may add another potential clinical use for metformin.

Yimucao has been used as an herbal medicine to treat gynecological diseases. Common genes of Yimucao active compounds were investigated using network pharmacology. The components and targets of Yimucao were retrieved from the TCMSP database. Cervical cancer targets were collected from GeneCards, TTD, DisGeNET, and KEGG. Cisplatin-related genes were downloaded from GeneWeaver. The protein-protein interaction (PPI) network was created using the STRING database. A drug-bioactive compound-disease-target network was constructed using Cytoscape. GO and KEGG analyses were performed to investigate common targets of quercetin and cisplatin in cervical cancer. We found that quercetin was the highly bioactive compound in Yimucao. The drug-bioactive compound-disease-target network contained 93 nodes and 261 edges. Drug-related key targets were identified, including EGFR, IL6, CASP3, VEGFA, MYC, CCND1, ERBB2, FOS, PPARG, and CASP8. Core targets were primarily related to the response to metal ions, cellular response to xenobiotic stimulus, and transcription factor complex. The KEGG pathway analysis revealed that quercetin and cisplatin may affect cervical cancer through platinum drug resistance and the p53 and HIF-1 pathways. Furthermore, quercetin combined with cisplatin downregulated the expression of EGFR, MYC, CCND1, and ERBB2 proteins and upregulated CASP8 expression in HeLa and SiHa cells. Functionally, quercetin enhanced cisplatin-induced anticancer activity in cervical cancer cells. Our results indicate that quercetin can be used to overcome cisplatin resistance in cervical cancer cells.

The abnormally methylated tumor suppressor genes (TSGs) associated with cervical cancer are unclear. DNA methylation data, RNA-seq expression profiles, and overall survival data were downloaded from TCGA CESC database. DMGs and DEGs were obtained through CHAMP and DESeq packages, respectively. TSGs were downloaded from TSGene 2.0. Candidate hypermethylated/down-regulated TSGs were further evaluated and pyrosequencing was used to confirm their difference in methylation levels of selected TSGs in cervical cancer patients. A total of 25946 differentially methylated CpGs corresponding to 2686 hypermethylated genes and 4898 hypomethylated genes between cervical cancer and adjacent normal cervical tissues were found in this study. Besides, 693 DEGs (109 up-regulated and 584 down-regulated) were discovered in cervical cancer tissues. Then, 192 hypermethylated/down-regulated genes were obtained in cervical cancer compared to adjacent tissues. Interestingly, 26 TSGs were found in hypermethylated/down-regulated genes. Among these genes, low expression of MRVI1 and NTRK3 was associated with poor overall survival in cervical cancer. Moreover, GEO data showed that MRVI1 and NTRK3 were significantly decreased in cervical cancer tissues. The expression levels of MRVI1 and NTRK3 were negatively correlated with the methylation levels of their promoter CpG sites. Additionally, elevated methylation levels of MRVI1 and NTRK3 promoter were further verified in cervical cancer tissues by pyrosequencing experiments. Finally, the ROC results showed that the promoter methylation levels of MRVI1 and NTRK3 had the ability to discriminate cervical cancer from healthy samples. The study contributes to our understanding of the roles of MRVI1 and NTRK3 in cervical cancer.

Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) is an E3 ubiquitin ligase that has been reported to participate in multiple cellular procedures by regulating of substrate ubiquitination and subsequent protein degradation. A great amount of evidence has demonstrated that NEDD4L mainly functions as a tumor suppressor in most cancer types, while it also acts as an oncogene in a few cancers. In this review, we summarize the potential role of NEDD4L in carcinogenesis and the related underlying molecular mechanism to improve our understanding of its functions in the tumorigenesis of human malignancies. Developing clinical drugs targeting NEDD4L could be a potential therapeutic strategy for cancer therapy in the future.

Purpose To explore clinicopathological characteristics and their prognostic value among young patients with cervical cancer (who are aged ≤25 years old). Methods The Surveillance, Epidemiology, and End Results Program (SEER) database was used to extract data on cervical cancer patients. They were then stratified by age as young women (≤25 years old) and old women (26–35 years old) and analyzed for clinicopathology characteristics and treatment modalities. Prognosis was analyzed using Kaplan–Meier survival curve, as well as hazard ratios using Cox regression modeling. The nomogram was developed based on Cox hazards regression model. Results Compared to 26–35 years old women, patients aged ≤25 years tended to be white ethnicity, unmarried, had earlier stage of disease. There was also a better prognosis among younger cohort. Grade, FIGO stage, histologic subtypes, and surgical modalities influenced the survival outcomes of young patients. Among young cohorts, surgery prolonged the survival time of IA-IIA stage patients while surgical and non-surgical management presented no statistically prognostic difference among patients at IIB-IVB stage. Besides, the nomogram which constructed according to Cox hazards regression model which contained independent prognosis factors including FIGO stage, surgery type, and histologic type of tumor can robustly predict survival of young patients. Conclusion Cervical cancer patients ≤25 years old were uncommon and lived longer than the older patients. Among these young patients at IA-IIA stage, surgical treatment could be more effective at preventing death than non-surgery. The nomogram could perfectly predict the prognosis of young adults and adolescents with cervical cancer.

Ovarian cancer ranks as the fifth most common cause of cancer-related death in females. The molecular mechanisms of ovarian carcinogenesis need to be explored in order to identify effective clinical therapies for ovarian cancer. Recently, multi-omics approaches have been applied to determine the mechanisms of ovarian oncogenesis at genomics (DNA), transcriptomics (RNA), proteomics (proteins), and metabolomics (metabolites) levels. Multi-omics approaches can identify some diagnostic and prognostic biomarkers and therapeutic targets for ovarian cancer, and these molecular signatures are beneficial for clarifying the development and progression of ovarian cancer. Moreover, the discovery of molecular signatures and targeted therapy strategies could noticeably improve the prognosis of ovarian cancer patients.

E-cadherin plays a pivotal role in cancer progression, including the epithelial-mesenchymal transition (EMT) process and tumor metastasis. Loss of E-cadherin contributes to enhanced invasion and metastasis in human cancers. Therefore, restoring E-cadherin could be a potential approach for cancer therapy. Multiple natural compounds have been shown to possess anti-tumor activities through the regulation of key molecules in signaling pathways, including E-cadherin. In this review, we describe the numerous compounds that restore the expression of E-cadherin in genital and urinary malignancies. We further discuss the potential anti-tumor molecular mechanisms of these agents as the activators of E-cadherin in genital and urinary cancers. Although these compounds exhibit their potential to inhibit the development and progression of cancers, there are several challenges to developing them as therapeutic drugs for cancer patients. Poor bioavailability in vivo is the main disadvantage of these compounds. Modification of compound structures has produced actual improvements in bioavailability. Nanoparticle-based delivery systems could be useful to deliver the agents to targeted organs. These compounds could be new promising therapeutic agents for the treatment of human genital and urinary cancers. Further investigations are required to determine the safety and side effects of natural compounds using animal models prior to clinical trials. Keywords: E-cadherin, EMT, invasion, cancer, natural agents, therapy

Abstract Background This study aims to investigate the expression of thioredoxin 1, peroxiredoxin 1 and peroxiredoxin 2 in bulky cervical squamous carcinoma and its predictive role in cisplatin-based neoadjuvant chemotherapy. Methods Initially, the expression of thioredoxin 1, peroxiredoxin 1 and peroxiredoxin 2 protein was analyzed in 13 human cervical squamous cancer tissues and their paired adjacent non-cancerous tissues by western-blotting and immunohistochemistry. Then, correlation between the expression of thioredoxin 1, peroxiredoxin 1, peroxiredoxin 2 and responses to cisplatin-based neoadjuvant chemotherapy was analyzed in 35 paired tumor samples (pre- and post-chemotherapy) from bulky cervical squamous cancer patients by immunohistochemistry. Results A clinical response occurred in 48.6% (17/35) of patients, including 14.3% (5/35) with a complete response and 34.3% (12/35) with a partial response. The expression of thioredoxin 1, peroxiredoxin 1 and peroxiredoxin 2 was much higher in cervical squamous cancer tissues compared with paired adjacent non-cancerous tissues by western-blotting and immunohistochemistry. Additionally, the expression of thioredoxin 1, peroxiredoxin 1 and peroxiredoxin 2 was significantly up-regulated in post-chemotherapy tissues compared to pre-chemotherapy cervical cancer tissues. High levels of thioredoxin 1, peroxiredoxin 1 and peroxiredoxin 2 were associated with a poor chemotherapy response in cervical squamous cancer patients. Conclusions Thioredoxin 1, peroxiredoxin 1 and peroxiredoxin 2 are frequently over-expressed in cervical squamous cancer. High expression levels of these proteins were related to a poor response to cisplatin-based neoadjuvant chemotherapy. The present study is the first report that thioredoxin peroxidase system may serve as a prediction of the responses to neoadjuvant chemotherapy in cervical squamous cancer.

Abstract Emerging evidence shows that epithelial-mesenchymal transition (EMT) plays a crucial role in tumor invasion, metastasis, cancer stem cells, and drug resistance. Data obtained thus far have revealed that F-box proteins are critically involved in the regulation of the EMT process and stem cell differentiation in human cancers. In this review, we will briefly describe the role of EMT and stem cells in cell metastasis and drug resistance. We will also highlight how numerous F-box proteins govern the EMT process and stem cell survival by controlling their downstream targets. Additionally, we will discuss whether F-box proteins involved in drug resistance are associated with EMT and cancer stem cells. Targeting these F-box proteins might be a potential therapeutic strategy to reverse EMT and inhibit cancer stem cells and thus overcome drug resistance in human cancers.

Abstract Accumulated evidence has demonstrated that WNT1 inducible signaling pathway protein (WISP) genes, which belong to members of the CCN growth factor family, play a pivotal role in tumorigenesis and progression of a broad spectrum of human cancers. Mounting studies have identified that WISP proteins (WISP1-3) exert different biological functions in various human malignancies. Emerging evidence indicates that WISP proteins are critically involved in cell proliferation, apoptosis, invasion and metastasis in cancers. Because the understanding of a direct function of WISP proteins in cancer development and progression has begun to emerge, in this review article, we describe the physiological function of WISP proteins in a variety of human cancers. Moreover, we highlight the current understanding of how the WISP protein is involved in tumorigenesis and cancer progression. Furthermore, we discuss that targeting WISP proteins could be a promising strategy for the treatment of human cancers. Hence, the regulation of WISP proteins could improve treatments for cancer patients.

Cervical cancer is one of the common malignancies in women worldwide. Exploration of pathogenesis and molecular mechanism of cervical cancer is pivotal for development of effective treatment for this disease. Recently, systems biology approaches based on high-throughput technologies have been carried out to investigate the expression of some genes and proteins in genomics, transcriptomics, proteomics, and metabonomics of cervical cancer. Compared with traditional methods，systems biology technology has been shown to provide large of information regarding prognostic biomarkers and therapeutic targets for cervical cancer. These molecular signatures from system biology technology could be useful to understand the molecular mechanisms of cervical cancer development and progression, and help physicians to design targeted therapeutic strategies for patients with cervical cancer. Keywords: Cervical cancer, Systems biology, Genomics, Transcriptomics, Proteomics

Topological metamaterial has been a research hotpot in both physics and engineering due to its unique ability of wave manipulation. The topological interface state, which can efficiently and robustly centralize the elastic wave energy, is promising to attain high-performance energy harvesting. Since most of environmental vibration energy is in low frequency range, the interface state is required to be designed at subwavelength range. To this end, this paper developed a topological metamaterial beam with local resonators and studied its energy-harvesting performance. First, the unit cell of this topological metamaterial beam consists of a host beam with two pairs of parasitic beams with tip mass. Then, the band structure and topological features are determined. It is revealed that by tuning the distance between these two pairs of parasitic beams, band inversion where topological features inverse can be obtained. Then, two sub-chains, their design based on two topologically distinct unit cells, are assembled together with a piezoelectric transducer placed at the conjunction, yielding the locally resonant, topological, metamaterial, beam-based piezoelectric energy harvester. After that, its transmittance property and output power were obtained by using the frequency domain analysis of COMSOL Multiphysics. It is clear that the subwavelength interface state is obtained at the band-folding bandgap. Meanwhile, in the interface state, elastic wave energy is successfully centralized at the conjunction. From the response distribution, it is found that the maximum response takes place on the parasitic beam rather than the host beam. Therefore, the piezoelectric transducer is recommended to be placed on the parasitic beam rather than host beam. Finally, the robustness of the topological interface state and its potential advantages on energy harvesting were studied by introducing a local defect. It is clear that in the interface state, the maximum response is always located at the conjunction regardless of the defect degree and location. In other words, the piezoelectric transducer placed at the conjunction can maintain a stable and high-efficiency output power in the interface state, which makes the whole system very reliable in practical implementation.

Introduction Uterine fibroids are the most common pelvic benign tumour with no satisfactory long-term medical treatment. Recent studies have demonstrated that vitamin D significantly inhibited the growth of fibroids in vitro, vivo and a small-sample clinical trial. Therefore, the aim of this randomised clinical trial (RCT) is to evaluate whether supplementation with vitamin D could reduce the risk and inhibit the growth of uterine fibroids in reproductive stage women.Methods and analysis The open-label, RCT comprises two parts, including parts I and II. In part I, 2230 vitamin D deficiency or vitamin D insufficiency patients without uterine fibroids will be randomly assigned to two groups: intervention group (according to the level of serum 25-hydroxyvitamin D3, receive 1600 or 800 IU/day of vitamin D3 for 2 years) and control group (followed up at the same time points). By using gynaecological ultrasound examinations, the incidence of uterine fibroids will be employed to measure the outcome in different groups. In part II, 360 uterine fibroids patients with vitamin D deficiency or vitamin D insufficiency will be randomly assigned to intervention group or control group. According to the level of serum 25-hydroxyvitamin D3, 180 patients will receive 1600 or 800 IU/day of vitamin D3 for 2 years. Control group will receive regular follow-up. The outcome measure will be conducted using gynaecological ultrasound examinations to detect the growth of uterine fibroids in each group.Ethics and dissemination This study has been approved by the institutional review board of the Second Affiliated Hospital of Wenzhou Medical University (No. LCKY2018-35).Trial registration numbers NCT03586947 and NCT03584529.

Objective This study was performed to quantify hidden blood loss (HBL) and explore its influential factors in myomectomy. Methods Two hundred nine patients who underwent myomectomy by laparotomy or laparoscopy from 1 January 2017 to 31 December 2018 were analyzed. Each patient’s estimated blood volume and total blood loss (TBL) were calculated by the Nadler formula and Gross formula, respectively. The HBL was calculated by subtracting the visible blood loss (VBL) from the TBL. A multivariate linear stepwise analysis was applied to identify the influential factors of HBL in myomectomy. Results The mean perioperative VBL and estimated TBL during myomectomy were 137.81 ±104.43 and 492.24 ± 225.00 mL, respectively. The mean HBL was 354.39 ± 177.69 mL, which accounted for 71.52% ± 15.75% of the TBL and was two to three times higher than the VBL. The duration of surgery, number of removed leiomyomas, and location of removed leiomyomas were independent risk factors for HBL in myomectomy. Conclusions HBL accounted for a significant percentage of TBL in myomectomy. A full understanding of the HBL in perioperative blood management may improve patients’ postoperative rehabilitation.

Objective To investigate the associations between serum vitamin D, calcium and uterine fibroids in a Chinese female population. Methods In this case-control study, adult female patients with fibroids (cases) were compared with females without fibroids (controls) in terms of serum 25-hydroxyvitamin D (25OHD) and calcium levels. Results Out of 546 total participants (mean age, 41.68 ± 5.99 years; 279 with fibroids and 267 without fibroids), only 232 had serum 25OHD levels above the sufficient threshold (>20 ng/ml). In addition, females with fibroids had lower serum 25OHD levels versus those without fibroids. The prevalence of fibroids in females with deficient (20 ng/ml) 25OHD levels. Serum calcium levels were within normal range in both groups. Conclusion Hypovitaminosis D was highly prevalent among a population of Chinese females of reproductive-age, and serum 25OHD levels were lower in female patients with fibroids.

Aims. This study is aimed at identifying a prognostic signature for cervical cancer. Main Methods. The gene expression data and clinical information of cervical cancer and normal cervical tissues were acquired from The Cancer Genome Atlas and from three datasets of the Gene Expression Omnibus database. DESeq2 and Limma were employed to screen differentially expressed genes (DEGs). The overlapping DEGs among all datasets were considered the final DEGs. Then, the functional enrichment analysis was performed. Moreover, the Cox proportional hazards regression was performed to establish a prognostic signature of the DEGs. The Kaplan-Meier analysis was applied to test the model. Relationships between gene expression and clinicopathological parameters in cervical cancer, including age, HPV status, histology, stage, and lymph node metastasis, were analysed by the chi-square test. The somatic mutations of these prognostic genes were assessed through cBioPortal. The robustness of the model was verified in another two independent validation cohorts. Key Findings. In total, 169 overlapping upregulated genes and 29 overlapping downregulated genes were identified in cervical cancer compared with normal cervical tissues. Functional enrichment analysis indicated that the DEGs were mainly enriched in DNA replication, the cell cycle, and the p53 signalling pathway. Finally, a 5-gene- (ITM2A, DSG2, SPP1, EFNA1, and MMP1) based prognostic signature was built. According to this model, each patient was given a prognostic-related risk value. The Kaplan-Meier analysis showed that a higher risk was related to worse overall survival in cervical cancer, with an area under the receiver operating characteristic curve of 0.811 for 15 years. The validity of this model in the prediction of cervical cancer outcome was verified in another two independent datasets. In addition, our study also found that the low expression of ITM2A was associated with cervical adenocarcinoma. Interestingly, DSG2 was associated with the HPV status of cervical cancer. Significance. Our study constructed a prognostic model in cervical cancer and discovered two novel genes, ITM2A and DSG2, associated with cervical carcinogenesis and survival.

Abstract Background Several epidemiological researches have indicated that microvessel density (MVD), reflecting angiogenesis, was a negatively prognostic factor of cervical cancer. However, the results were inconsistent. Therefore, we performed a meta-analysis to evaluate the association between microvessel density and the survival probability of patients with cervical cancer. Method There was a comprehensive search of the PubMed, EMBASE and Cochrane databases up to August 31, 2017. Based on a fixed-effects or random-effects model, the hazard ratio (HR) and 95% confidence intervals (CIs) were calculated from researches on overall survival (OS) and disease-free survival (DFS). Result Totally, we included 13 observational researches, involving 1097 patients with cervical cancer. The results showed that high level of microvessel density was negatively correlated with OS (HR = 1.79, 95% CIs 1.31–2.44, I 2 = 60.7%, P = 0.003) and DFS (HR = 1.47, 95% CIs 1.13–1.80, I 2 = 0%, P = 0.423) of cervical cancer patients. In subgroup analysis, high counts of MVD were significantly associated with a poor survival (including OS and DFS) of the patients detected by anti-factor VIII antibodies or in European origin. Conclusion The present meta-analysis indicated that survival with high level of MVD was significant poorer than with low MVD in cervical cancer patient. Standardization of MVD assessment is needed.

Abstract Background Medical therapeutic options remain quite limited for uterine fibroids treatment. Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have anti-tumoral effects on multiple cancer types, however, little is known about their effects on uterine fibroids. Methods Initially, we conducted a retrospective study of 120 patients with uterine fibroids and hyperlipidemia from the Second Affiliated Hospital of Wenzhou Medical University. Then, we evaluated the effect of atorvastatin on proliferation and apoptosis both in immortalized uterine fibroids cells and primary uterine fibroids cells. Furthermore, the molecular mechanism by which atorvastatin suppressed uterine fibroids cell growth was explored. Results Our results showed that atorvastatin use for 1 or 2 years significantly suppressed growth of uterine fibroids. Atorvastatin inhibited the proliferation of immortalized and primary uterine fibroids cells in a dose and time-dependent manner and stimulated apoptosis of uterine fibroids cells by inducing caspase-3 activation, up-regulating Bim and down-regulating Bcl-2. Additionally, atorvastatin treatment suppressed phosphorylation of ERK1/2 and JNK. Furthermore, GGPP, a downstream lipid isoprenoid intermediate, significantly rescued the effect of atorvastatin. Conclusions These results suggest that atorvastatin exerts anti-tumoral effects on uterine fibroids through inhibition of cell proliferation and induction of apoptosis in HMG-CoA-dependent pathway. Our results provide the first clinical and preclinical data on the use of atorvastatin as a promising nonsurgical treatment option for uterine fibroids.

The prognostic role of human epidermal growth factor receptor 2 (HER2) in ovarian cancer has been investigated in previous studies, but the results remain controversial. Here we present a meta-analysis to systematically review the association between HER2 expression and ovarian cancer prognosis.Observational studies published until July 2017 were searched in Pubmed, Embase, and Cochrane library databases. Hazard ratios (HRs) for survival with 95% confidence intervals (CIs), subgroup analyses, publication bias and sensitivity analyses were implemented under a standard manner. Estimates of overall survival (OS), progress-free survival (PFS) and disease-free survival (DFS) were weighted and pooled using Der Simonian-Laird random-effect model.Thirty-four studies that include 5180 ovarian cancer patients were collected for analysis. Expression of HER2 was negatively correlated with clinical prognosis of overall survival (HR = 1.57, 95% CI: 1.31 to 1.89, P < 0.001) and disease-free survival / progress-free survival (HR = 1.26, 95% CI = 1.06 to 1.49) in ovarian cancers. The association between HER2 expression and poor ovarian cancer prognosis in overall survival was also statistically significant in subgroups of unclassified ovarian cancer, Caucasian population and Asian population, while irrespective of detection method.HER2 expression was related with poor prognosis in ovarian cancer patients and can be used as a predicting cancer prognostic biomarker in ovarian cancer patients.