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AIM: Endometrial cancer (EC) is heterogeneous with respect to epidemiology, clinical course, histopathology and tumor biology. Recently, The Cancer Genome Atlas (TCGA) network has identified four molecular subtypes with distinct clinical courses by an integrated multi-omics approach. These subtypes are of critical importance in the clinical management of EC. However, determination of TCGA molecular subtypes requires a complex methodological approach that is resource intensive and difficult to implement in diagnostic routine procedures. In this context, Talhouk et al. reported the precise determination of modified subtypes based on molecular surrogates obtained by a two-method approach comprising immunohistochemistry and DNA-sequence analysis (Proactive Molecular Risk Classifier for Endometrial Cancer; ProMisE). In this study, we aimed to identify EC molecular subtypes in analogy to TCGA and ProMisE applying an innovative whole exome-sequencing (WES) based single-method approach. METHODS: WES was performed in a cohort comprising N = 114 EC patients. WES data were analyzed using the oncology treatment decision support software MH Guide (Molecular Health, Heidelberg, Germany) and EC molecular subtypes in analogy to TCGA and ProMisE were determined. Results from both classifications were compared regarding their prognostic values using overall survival and progression-free survival analyses. RESULTS: Applying a single-method WES-approach, EC molecular subtypes analogue to TCGA and ProMisE were identified in the study cohort. The surrogate marker-analogue classification precisely identified high-risk and low-risk EC, whereas the TCGA-analogue classification failed to obtain significant prognostic values in this regard. CONCLUSION: Our data demonstrate that determination of EC molecular subtypes analogue to TCGA and ProMisE is feasible by using a single-method WES approach. Within our EC cohort, prognostic implications were only reliably provided by applying the surrogate marker-analogue approach. Designation of molecular subtypes in EC will be increasingly important in routine clinical practice. Thus, the single-method WES approach provides an important simple tool to tailor therapeutic decisions in EC.
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Neoplasias do Endométrio , Sequenciamento do Exoma , Humanos , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/classificação , Feminino , Sequenciamento do Exoma/métodos , Idoso , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Prognóstico , Idoso de 80 Anos ou mais , AdultoRESUMO
Tumour immunotherapy is an effective and essential treatment for cancer. However, the heterogeneity of tumours and the complex and changeable tumour immune microenvironment (TME) creates many uncertainties in the clinical application of immunotherapy, such as different responses to tumour immunotherapy and significant differences in individual efficacy. It makes anti-tumour immunotherapy face many challenges. Immunometabolism is a critical determinant of immune cell response to specific immune effector molecules, significantly affecting the effects of tumour immunotherapy. It is attributed mainly to the fact that metabolites can regulate the function of immune cells and immune-related molecules through the protein post-translational modifications (PTMs) pathway. This study systematically summarizes a variety of novel protein PTMs including acetylation, propionylation, butyrylation, succinylation, crotonylation, malonylation, glutarylation, 2-hydroxyisobutyrylation, ß-hydroxybutyrylation, benzoylation, lactylation and isonicotinylation in the field of tumour immune regulation and immunotherapy. In particular, we elaborate on how different PTMs in the TME can affect the function of immune cells and lead to immune evasion in cancer. Lastly, we highlight the potential treatment with the combined application of target-inhibited protein modification and immune checkpoint inhibitors (ICIs) for improved immunotherapeutic outcomes.
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The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1low/CAMSAP3low cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1low/CAMSAP3low cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients.
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Biomarcadores Tumorais , Neoplasias do Endométrio , Regulação Neoplásica da Expressão Gênica , Estadiamento de Neoplasias , Proteômica , Humanos , Feminino , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/mortalidade , Prognóstico , Biomarcadores Tumorais/genética , Proteômica/métodos , Microambiente Tumoral/genética , Perfilação da Expressão Gênica , Pessoa de Meia-Idade , Transcriptoma , Multiômica , Proteínas de Choque Térmico HSP90RESUMO
During acute respiratory infections, women may concurrently receive human papillomavirus (HPV) and respiratory vaccines, as observed during the coronavirus disease 2019 (COVID-19) pandemic in China. However, few studies have assessed the safety of such concurrent administration, which could impact HPV vaccination schedules. This study analyzes the safety and optimal sequence of concurrent HPV and COVID-19 vaccinations. For this purpose, we surveyed women with both vaccines from January to October 2023 in Fujian Province, China. During this process, we collected vaccination history and adverse event (AE) data via telephone or interviews. Participants were grouped as Before, Concurrent, or After based on their vaccination sequence. A Chi-squared test, exact Fisher tests, and logistic regression were used to analyze the incidence of AEs and factors influencing vaccine safety. Overall, 1416 eligible participants were included. Although overall AE risk with the HPV vaccine was unaffected by vaccination sequence, individual AEs varied statistically between groups, including pain at the vaccination site (p < 0.001) and prolonged menstruation duration (p = 0.003). Based on the results, the optimal sequence would be to receive the HPV vaccine after the COVID-19 vaccine (After group). This insight may guide future emergency vaccination sequences for HPV and other respiratory infectious diseases.
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Analysis of exosomes provides important information for rapid and non-invasive screening of tumors. However, sensitive and convenient detection of exosomes remains technically challenging to date. Herein, a colorimetric aptasensor based on the light-stimulated oxidase-mimicking activity of FITC was constructed for detecting ovarian cancer (OC) exosomes. The aptasensor contained an EpCAM aptamer to capture OC exosomes. Cholesterol and fluorescein (FITC) were used to modify either end of the DNA (DNA anchor). The DNA anchor could combine with exosomes through a hydrophobic reaction between cholesterol and the lipid membrane. FITC oxidized 3,3',5,5'-tetramethylbenzidine (TMB) under a 365 nm LED light source in a temporally controllable manner under mild conditions, causing the solution to change from colorless to blue, and the corresponding UV-vis absorbance increased. Based on this principle, the exosomes were qualitatively analyzed by observing the color change with the naked eye. In parallel, the exosome concentration was also detected using UV-vis spectrophotometry. The linear range was from 2 × 105 to 100 × 105 particles per mL with a limit of detection of 1.77 × 105 particles per mL. The developed aptasensor also exhibited favorable selectivity and could discriminate the exosomes from OC cells and normal cells. Besides, the receiver operating characteristic (ROC) curve demonstrates that it is possible to distinguish between patients with OC and healthy donors (HDs) using exosomes as the biomarker. Our technology may expand the applications of DNA-based detection method-enabled OC diagnostic tools.
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Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Colorimetria , Exossomos , Exossomos/química , Exossomos/metabolismo , Humanos , Colorimetria/métodos , Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/métodos , Feminino , Neoplasias Ovarianas , Oxirredutases/química , Oxirredutases/metabolismo , Luz , Limite de Detecção , Fluoresceína/química , Benzidinas/química , Linhagem Celular TumoralRESUMO
Oridonin is the primary active component in the traditional Chinese medicine Rabdosia rubescens, displaying anti-inflammatory, anti-tumor, and antibacterial effects. It is widely employed in clinical therapy for acute and chronic pharyngitis, tonsillitis, as well as bronchitis. Nevertheless, the clinical application of oridonin is significantly restricted due to its reproductive toxicity, with the exact mechanism remaining unclear. The aim of this study was to investigate the mechanism of oridonin-induced damage to HTR-8/SVneo cells. Through the integration of epigenetics, proteomics, and metabolomics methodologies, the mechanisms of oridonin-induced reproductive toxicity were discovered and confirmed through fluorescence imaging, RT-qPCR, and Western blotting. Experimental findings indicated that oridonin altered m6A levels, gene and protein expression levels, along with metabolite levels within the cells. Additionally, oridonin triggered oxidative stress and mitochondrial damage, leading to a notable decrease in WNT6, ß-catenin, CLDN1, CCND1, and ZO-1 protein levels. This implied that the inhibition of the Wnt/ß-catenin signaling pathway and disruption of tight junction might be attributed to the cytotoxicity induced by oridonin and mitochondrial dysfunction, ultimately resulting in damage to HTR-8/SVneo cells.
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Objective: This study introduced a novel subtype classification method for endometrial cancer (EC) with mismatch repair deficiency (MMRd) by employing immune status and prognosis as the foundational criteria. The goal was to enhance treatment guidance through precise subtype delineation. Methods: Study Cohort: This study encompassed a cohort of 119 patients diagnosed with MMRd-EC between 2015 and 2022. Analyses using t-tests and Mann-Whitney U-tests were performed to assess prognostic markers and peripheral blood immune cell profiles in patients with MutS deficiency (MutS-d) versus those with MutL deficiency (MutL-d). Logistic regression analysis was used to identify independent risk factors. Bioinformatics Analysis: An online database was used to assess the prognostic implications, immune cell infiltration, and immune checkpoint involvement associated with the deficiency of MutS versus MutL in EC. Results: Patients with MutL-d exhibited heightened risk factors, including elevated cancer grade and increased myometrial invasion, leading to poorer prognosis and shorter overall survival and progression-free survival. Regarding systemic immune status, patients with MutL-d demonstrated decreased peripheral blood lymphocyte percentage, lymphocyte count, and CD8+ T cell percentage. For local immunity, the infiltration of natural killer cells, CD8+ T cells, and cytotoxic T lymphocytes in the tumor tissue was reduced in patients with MutL-d. Additionally, patients with MutL-d exhibited lower expression of immune checkpoint markers. The composition of immune subtypes and survival outcomes also indicate that patients with MutL-d have a poorer immune status and prognosis than the patients with MutS-d. Conclusion: Patients with MMRd-EC can be subclassified according to MutS or MutL deficiency. Patients with MutS-d exhibited better immune status, prognosis, and immunotherapy benefits than those with MutL-d. These results can help guide patients to a more precise treatment.
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Objective: This study aimed to evaluate the role of plasma cytokine detection in endometrial cancer screening and tumor progression assessment in patients with abnormal uterine bleeding. Methods: In this multicenter retrospective cohort study of 287 patients with abnormal uterine bleeding, comprehensive clinical information and laboratory assessments, including cytokines, routine blood tests, and tumor markers, were performed. Associations between the clinical indicators and endometrial carcinogenesis/progression were evaluated. The independent risk factors for endometrial cancer and endometrial cancer with deep myometrial invasion were analyzed using multivariate binary logistic regression. Additionally, a diagnostic model was used to evaluate the predictive efficacy of these identified risk factors. Results: In patients with abnormal uterine bleeding, low IL-4 and high IL-8 levels were independent risk factors for endometrial cancer (p < 0.05). Combining IL-4, IL-8, CA125, and menopausal status improved the accuracy of assessing endometrial cancer risk. The area under curve of the model is 0.816. High IL-6 and IL-8 levels were independent risk factors for deep myometrial invasion in patients with endometrial cancer (p < 0.05). Similarly, combining IL-6, IL-8, and Monocyte counts enhanced the accuracy of assessing endometrial cancer risk with deep myometrial invasion. The area under curve of the model is 0.753. Conclusions: Cytokines such as IL-4, IL-8, and IL-6 can serve as markers for monitoring endometrial cancer and its progression in women with abnormal uterine bleeding.
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Citocinas , Neoplasias do Endométrio , Humanos , Feminino , Estudos Retrospectivos , Interleucina-8 , Interleucina-4 , Interleucina-6 , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/diagnóstico , Hemorragia Uterina/etiologia , CarcinogêneseRESUMO
PURPOSE: Few studies have focused on the impact of human papillomavirus (HPV) positivity in male partners on female HPV infection and cervical lesions. The purpose of this study was to evaluate the impact of the HPV infection status of husbands on wives' cervical HPV infection and lesions. METHODS: We surveyed 251 monogamous couples who attended the outpatient department of Fujian Maternity and Child Health Hospital from 2013 to 2021. HPV type analysis was performed on exfoliated cells of the females' cervix and males' urethra by the PCR-reverse dot blot method. We analyzed the prevalence and consistency of HPV types in 251 couples. Subsequently, the risk of HPV infection in females with HPV-positive male partners was analyzed. SPSS version 26 (IBM, Chicago, USA) was used for statistical analysis. RESULTS: In 251 couples, the most commonly detected high-risk HPV (HR-HPV) genotypes were 52, 51, 16, and 58 for males and 16, 52, 18, and 58 for females. Wives with HPV-positive husbands had higher infection rates for most HR-HPV genotypes. HR-HPV positivity in husbands was a risk factor for the development of cervical lesions in wives (OR = 2.250, P = 0.014). Both single-type (OR = 2.085, P = 0.040) and multiple-type (OR = 2.751, P = 0.036) infection in husbands will contributed to an increased risk of non-HR-HPV infection and cervical lesions in wives. CONCLUSION: Husbands' HPV positivity increases the burden of non-HR-HPV infection and increases the risk of cervical lesions developing in wives. It is hoped to provide a reference value for cervical cancer prevention in females and HPV vaccination in males.
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Infecções por Papillomavirus , Neoplasias do Colo do Útero , Gravidez , Criança , Humanos , Masculino , Feminino , Heterossexualidade , Infecções por Papillomavirus/epidemiologia , Papillomaviridae/genética , Colo do Útero , Genótipo , Prevalência , Neoplasias do Colo do Útero/epidemiologiaRESUMO
BACKGROUND: Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. METHODS: The interaction between ERRα and HIF-1α was verified using co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERRα on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database. RESULTS: Triggered by a hypoxic microenvironment, highly expressed ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERRα activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in EC progression. CONCLUSIONS: ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.
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Neoplasias do Endométrio , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Camundongos , Animais , Feminino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Caspase 1/genética , Caspase 1/metabolismo , Caspase 1/farmacologia , Camundongos Nus , Piroptose , Cisplatino/farmacologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Glicólise , Microambiente Tumoral , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/farmacologia , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
PURPOSE: The aim of this study was to evaluate the pre- and postoperative changes in the recently urodynamic and quality of life (QoL) in nonmenopausal women diagnosed with cervical cancer and treated with radical hysterectomy (RH). PATIENTS AND METHODS: Twenty-eight nonmenopausal women (28-49 years) with cervical carcinoma (FIGO stage Ia2-IIa) underwent a radical hysterectomy. Urodynamic studies were performed 1 week before (U0) and 3-6 months (U1) after surgery. A self-administered condition-specific QoL questionnaire (PFDI-20, PFIQ-7) was applied at U0 and U1. RESULTS: Data from the urodynamics analysis performed at U1 showed that the average first sensation volume (119.39 ± 12.28 ml vs 150.43 ± 31.45 ml, P < 0.001), the residual urine volume (6.39 ± 10.44 ml vs. 42.32 ± 33.72 ml, P < 0.001), and the time of urination (46.10 ± 16.65 s vs. 74.31 ± 23.94 s, P < 0.001) were increased, while the bladder volume at a strong desire to void (448.89 ± 86.62 ml vs. 322.82 ± 50.89 ml, P < 0.001), the bladder compliance (82.63 ± 58.06 ml/cmH2O vs. 37.45 ± 28.66 ml/cmH2O, P < 0.001), the average flow rate (Qave) (23.86 ± 4.25 ml/s vs. 12.57 ± 2.37 ml/s, P < 0.001), the maximum natural flow rate (Qmax) (25.42 ± 6.46 ml/s vs. 14.43 ± 5.32 ml/s, P < 0.001), and the pressure at a peak flow rate (PdetQmax) (36.53 ± 11.20 cmH2O vs. 31.43 ± 10.56 cmH2O, P < 0.05) were decreased. At the same time, functional pelvic problems derived from prolapse (PFDI-20 scores) and their impact on the patients' Qol (PFIQ-7 score) were significantly improved at 3-6 months postoperation. CONCLUSION: Radical hysterectomy results in urodynamic changes, and 3-6 months postoperation may be an important period for changes in bladder dysfunction after RH. Urodynamic and QoL analyses may provide methods for assessing symptoms.
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Bexiga Urinária , Neoplasias do Colo do Útero , Humanos , Feminino , Bexiga Urinária/patologia , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Urodinâmica , Qualidade de Vida , Histerectomia/métodosRESUMO
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are capable of effectively repressing immune responses against tumors and orchestrating the tumor microenvironment, which can promote tumor angiogenesis and metastasis. The pathway networks used to modulate tumor-expanded MDSC accumulation and function remain unclear. This study identified microRNA-211 (miR-211), whose expression was significantly decreased by factors derived from tumors. METHODS: miR-211 was assumed to be critical in modulating the accumulation and activity of MDSCs isolated from ovarian cancer (OC)-bearing mice by targeting C/EBP homologous protein (CHOP). RESULTS: The upregulation of miR-211 repressed MDSC proliferation, inhibited MDSC immunosuppressive functions, and increased the number of co-incubated CD4+ and CD8+ cells. Furthermore, overexpression of miR-211 led to decreased activities of the NF-κB, PI3K/Akt, and STAT3 pathways and the subsequent downregulation of matrix metalloproteinases to promote tumor cell invasion and metastasis. CHOP overexpression counteracted the effects of miR-211 elevation on these phenotypic changes. Upregulation of miR-211 also dramatically impaired the activity of MDSCs and suppressed OC tumor growth in vivo. CONCLUSION: These results indicated that the miR-211-CHOP axis in MDSCs plays an essential role in the metastasis and proliferation of tumor-expanded MDSCs and might represent a promising cancer treatment target.
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MicroRNAs , Células Supressoras Mieloides , Neoplasias , Animais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Células Mieloides , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias/patologia , Proliferação de Células , Microambiente Tumoral/genéticaRESUMO
Purpose: The platelet-to-lymphocyte ratio (PLR) is considered correlated with cancer prognosis including cervical cancer, in addition to high-risk papillomavirus (HR-HPV) infection, of which the predictive value in prognosis of high-grade squamous intraepithelial lesions (HSILs) remains unknown. Here, the prognostic predictive value of PLR in HSIL after loop electrosurgical excision procedure (LEEP) was evaluated. Patients and Methods: This study included 335 nonpregnant participants with histopathologically confirmed HSIL and 3- and 5-year follow-ups from the Fujian Cervical Lesions Screening Cohorts (FCLSCs) between September 2016 and September 2018. PLR and other variables were evaluated to identify the factors related to the recurrence/residual cervical intraepithelial neoplasia (CIN)-free survival (RFS), namely, the time from LEEP at baseline to first detection of recurrence/residual CIN or end of follow-up, by logistic and Cox regression. Results: In the KaplanâMeier analysis, HR-HPV infection (p=0.049/0.012), higher PLR (p=0.031/0.038), and gland invasion (p=0.047) had a higher risk for recurrence/residual CIN at the 3-/5-year follow-up. The univariate logistic and Cox regression analyses showed significant differences and a higher cumulative risk in patients with HR-HPV infection (OR=3.917, p=0.026; HR=3.996, p=0.020) and higher PLR (OR=2.295, p=0.041; HR=2.161, p=0.030) at the 5-year follow-up. The findings by multivariate Cox regression analysis were similar, indicating a poor prognosis for patients with HR-HPV infection (HR=3.901, p=0.023) and higher PLR (HR=2.082, p=0.038) at the 5-year follow-up. The calibration plot showed a better model fit for RFS at the 3-year follow-up. Conclusion: Preoperative PLR level and HR-HPV infection could be available markers for predicting recurrence/residual disease of HSIL after LEEP. Clinically, combining PLR with HR-HPV tests may provide novel evaluation method and reference for management in post-treatment patients with cervical precancerous lesions.
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BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant health issue closely associated with multiple extrahepatic cancers. The association between MAFLD and clinical outcomes of endometrial cancer (EC) remains unknown. METHODS: We retrospectively included 725 EC patients between January 2012 and December 2020. The odds ratios (ORs) were calculated using logistic regression analyses. Kaplan-Meier survival curves were used for survival analysis. RESULTS: Among EC patients, the prevalence of MAFLD was 27.7% (201/725, 95% confidence interval (Cl) = 0.245-0.311). MAFLD was significantly associated with cervical stromal involvement (CSI) (OR = 1.974, 95% confidence interval (Cl) = 1.065-3.659, p = 0.031). There was a significant correlation between overall survival (OS) and CSI (HR = 0.31; 95%CI: 0.12-0.83; p = 0.020), while patients with MAFLD had a similar OS to those without MAFLD (p = 0.952). Moreover, MAFLD was significantly associated with CSI in the type I EC subgroup (OR = 2.092, 95% confidence interval (Cl) = 1.060-4.129, p = 0.033), but not in the type II EC subgroup (p = 0.838). Further logistic regression analysis suggested that the hepatic steatosis index (HSI) was significantly associated with CSI among type I EC patients without type 2 diabetes mellitus (T2DM) (OR = 1.079, 95% confidence interval (Cl) = 1.020-1.139, p = 0.012). CONCLUSIONS: About one-quarter of our cohort had MAFLD. MAFLD was associated with the risk of CSI in EC patients, and this association existed in type I EC patients but not in type II EC patients. Furthermore, the HSI can help predict CSI in type I EC patients without T2DM.
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Diabetes Mellitus Tipo 2 , Neoplasias do Endométrio , Hepatopatias , Humanos , Feminino , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Estudos Retrospectivos , Neoplasias do Endométrio/complicações , China/epidemiologiaRESUMO
BACKGROUND: There is a close correlation between HPV infection and systemic immune status. The purpose of this study was to determine which lymphocytes in peripheral blood influence human papillomavirus (HPV) infection and to identify whether peripheral blood lymphocyte (PBL) subsets could be used as biomarkers to predict HPV clearance in the short term. METHODS: This study involved 716 women undergoing colposcopy from 2019 to 2021. Logistic and Cox regression were used to analyze the association of PBLs with HPV infection and clearance. Using Cox regression, bidirectional stepwise regression and the Akaike information criterion (AIC), lymphocyte prediction models were developed, with the C-index assessing performance. ROC analysis determined optimal cutoff values, and their accuracy for HPV clearance risk stratification was evaluated via KaplanâMeier and time-dependent ROC. Bootstrap resampling validated the model and cutoff values. RESULTS: Lower CD4 + T cells were associated with a higher risk of HPV, high-risk HPV, HPV18 and HPV52 infections, with corresponding ORs (95% CI) of 1.58 (1.16-2.15), 1.71 (1.23-2.36), 2.37 (1.12-5.02), and 3.67 (1.78-7.54), respectively. PBL subsets mainly affect the natural clearance of HPV, but their impact on postoperative HPV outcomes is not significant (P > 0.05). Lower T-cell and CD8 + T-cell counts, as well as a higher NK cell count, are unfavorable factors for natural HPV clearance (P < 0.05). The optimal cutoff values determined by the PBL prognostic model (T-cell percentage: 67.39%, NK cell percentage: 22.65%, CD8 + T-cell model risk score: 0.95) can effectively divide the population into high-risk and low-risk groups, accurately predicting the natural clearance of HPV. After internal validation with bootstrap resampling, the above conclusions still hold. CONCLUSIONS: CD4 + T cells were important determinants of HPV infection. T cells, NK cells, and CD8 + T cells can serve as potential biomarkers for predicting natural HPV clearance, which can aid in patient risk stratification, individualized treatment, and follow-up management.
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Infecções por Papillomavirus , Humanos , Feminino , Papillomavirus Humano , Estudos Retrospectivos , Linfócitos T CD4-Positivos , BiomarcadoresRESUMO
In this work, a simple and sensitive electrochemiluminescence (ECL) biosensor has been devised based on target-induced steric hindrance of an antibody-modified electrode surface. Estrogen-related receptor alpha (ERRα) is closely related to estrogen-dependent tumors, which had been chosen as a model target. The ERRα antigen can bind to the antibody modified on the electrode surface with high specificity and results in the increase of steric hindrance, which prevented the ECL indicators (tris(2,2'-bipyridine) dichlororuthenium(II) hexahydrate) from approaching the electrode surface, and the ECL intensity of the system decreased. The ECL response of the system has a good linear relationship with ERRα concentration in the range of 1.0-60 ng/L, and the limit of detection is 0.5 ng/L. Different from the traditional sandwiched immune ECL detection system, which need the modification of ECL indicators on the secondary antibody, only one antibody had been used in this system. The system is easy to operate and has good sensitivity. The designed biosensor has been applied to detect ERRα in the serum and different cell line samples with satisfied results.
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Técnicas Biossensoriais , Medições Luminescentes , Medições Luminescentes/métodos , Anticorpos , Eletrodos , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Limite de Detecção , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological malignancies globally, and the development of innovative, effective drugs against EC remains a key issue. Phytoestrogen kaempferol exhibits anti-cancer effects, but the action mechanisms are still unclear. METHOD: MTT assays, colony-forming assays, flow cytometry, scratch healing, and transwell assays were used to evaluate the proliferation, apoptosis, cell cycle, migration, and invasion of both ER-subtype EC cells. Xenograft experiments were used to assess the effects of kaempferol inhibition on tumor growth. Next-generation RNA sequencing was used to compare the gene expression levels in vehicle-treated versus kaempferol-treated Ishikawa and HEC-1-A cells. A network pharmacology and molecular docking technique were applied to identify the anti-cancer mechanism of kaempferol, including the building of target-pathway network. GO analysis and KEGG pathway enrichment analysis were used to identify cancer-related targets. Finally, the study validated the mRNA and protein expression using real-time quantitative PCR, western blotting, and immunohistochemical analysis. RESULTS: Kaempferol was found to suppress the proliferation, promote apoptosis, and limit the tumor-forming, scratch healing, invasion, and migration capacities of EC cells. Kaempferol inhibited tumor growth and promotes apoptosis in a human endometrial cancer xenograft mouse model. No significant toxicity of kaempferol was found in human monocytes and normal cell lines at non-cytotoxic concentrations. No adverse effects or significant changes in body weight or organ coefficients were observed in 3-7 weeks' kaempferol-treated animals. The RNA sequencing, network pharmacology, and molecular docking approaches identified the overall survival-related differentially expressed gene HSD17B1. Interestingly, kaempferol upregulated HSD17B1 expression and sensitivity in ER-negative EC cells. Kaempferol differentially regulated PPARG expression in EC cells of different ER subtypes, independent of its effect on ESR1. HSD17B1 and HSD17B1-associated genes, such as ESR1, ESRRA, PPARG, AKT1, and AKR1C1\2\3, were involved in several estrogen metabolism pathways, such as steroid binding, 17-beta-hydroxysteroid dehydrogenase (NADP+) activity, steroid hormone biosynthesis, and regulation of hormone levels. The molecular basis of the effects of kaempferol treatment was evaluated. CONCLUSIONS: Kaempferol is a novel therapeutic candidate for EC via HSD17B1-related estrogen metabolism pathways. These results provide new insights into the efficiency of the medical translation of phytoestrogens.
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Neoplasias do Endométrio , Estradiol Desidrogenases , Quempferóis , Farmacologia em Rede , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Estrogênios/metabolismo , Quempferóis/farmacologia , Simulação de Acoplamento Molecular , PPAR gama/metabolismo , Esteroides/metabolismo , Estradiol Desidrogenases/metabolismoRESUMO
The effect of cervical cancer immunotherapy is limited. Combination therapy will be a new direction for cervical cancer. Thus, it is essential to discover a novel and available predictive biomarker to stratify patients who may benefit from immunotherapy for cervical cancer. In this study, 563 participants were enrolled. Adenylate cyclase 7 (ADCY7) mRNA was detected by real-time quantitative PCR (qPCR) with cervical cytology specimens. The relationship between ADCY7 and cervical intraepithelial neoplasia in grade 2 and higher (CIN2+) was analyzed, and the optimal cut-off values of the relative expression of ADCY7 mRNA to predict CIN2+ were calculated. In addition, the clinical significance of ADCY7 in cervical cancer was determined by the Kaplan-Meier Cox regression based on the TCGA database. The mean ADCY7 mRNA expression increased significantly with cervical lesion development, especially compared with CIN2+ (p < 0.05). Moreover, the expression of ADCY7 increased significantly in high-risk human papillomavirus (HR-HPV) infection but not in HPV-A5/6 species. The area under the receiver operating characteristic curve (AUC) of ADCY7 was 0.897, and an optimal cut-off was 0.435. Furthermore, ADCY7 had the highest OR (OR= 8.589; 95% CI (2.281-22.339)) for detecting CIN 2+, followed by HPV genotyping, TCT, and age (OR = 4.487, OR = 2.071, and OR = 1.345; 95% CI (1.156-10.518), (0.370-8.137), and (0.171-4.694), respectively). Moreover, this study indicated that higher ADCY7 levels could be a suitable predictor for poor prognosis in cervical cancer due to immune cell infiltration. A new auxiliary predictor of CIN2+ in cervical cytology specimens is ADCY7 ≥ 0.435. Furthermore, it may be a promising prognosis predictor and potential immunotherapy target for the combined treatment of cervical cancer and possibly further block HR-HPV persistent infection.
RESUMO
Estrogen-related receptor alpha (ERRα) plays an important role in endometrial cancer (EC) progression. However, the biological roles of ERRα in EC invasion and metastasis are not clear. This study aimed to investigate the role of ERRα and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating intracellular cholesterol metabolism to promote EC progression. ERRα and HMGCS1 interactions were detected by co-immunoprecipitation, and the effects of ERRα/HMGCS1 on the metastasis of EC were investigated by wound-healing and transwell chamber invasion assays. Cellular cholesterol content was measured to verify the relationship between ERRα and cellular cholesterol metabolism. Additionally, immunohistochemistry was performed to confirm that ERRα and HMGCS1 were related to EC progression. Furthermore, the mechanism was investigated using loss-of-function and gain-of-function assays or treatment with simvastatin. High expression levels of ERRα and HMGCS1 promoted intracellular cholesterol metabolism for invadopodia formation. Moreover, inhibiting ERRα and HMGCS1 expression significantly weakened the malignant progression of EC in vitro and in vivo. Our functional analysis showed that ERRα promoted EC invasion and metastasis through the HMGCS1-mediated intracellular cholesterol metabolism pathway, which was dependent on the epithelial-mesenchymal transition pathway. Our findings suggest that ERRα and HMGCS1 are potential targets to suppress EC progression.
Assuntos
Neoplasias do Endométrio , Podossomos , Feminino , Humanos , Linhagem Celular Tumoral , Neoplasias do Endométrio/patologia , Hidroximetilglutaril-CoA Sintase , Podossomos/fisiologia , Receptores de Estrogênio/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
INTRODUCTION: Myometrial invasion is a prognostic factor for lymph node metastases and decreased survival in non-endometrioid endometrial carcinoma patients. Herein, we explored the mode of myometrial invasion diagnosis in FIGO stage I non-endometrioid carcinoma and evaluated the differences in diagnostic efficiency among intraoperative frozen section (IFS), intraoperative gross examination (IGE), magnetic resonance imaging (MRI), and computed tomography (CT) in clinical practice. Finally, we suggested which test should be routinely performed. METHOD: This was a historical cohort study nationwide with 30 centers in China between January 2000 and December 2019. Clinical data, including age, histology, method of myometrial invasion evaluation (MRI, CT, IGE, and IFS), and final diagnosis of postoperative paraffin sections, were collected from 490 non-endometrioid endometrial carcinoma (serous, clear cell, undifferentiated, mixed carcinoma, and carcinosarcoma) women in FIGO stage I. RESULTS: Among the 490 patients, 89.59% presented myometrial invasion. The methods reported for myometrial invasion assessment were IFS in 23.47%, IGE in 69.59%, MRI in 37.96%, and CT in 10.20% of cases. The highest concordance was detected between IFS and postoperative paraffin sections (Kappa = 0.631, accuracy = 93.04%), followed by IGE (Kappa = 0.303, accuracy = 82.40%), MRI (Kappa = 0.131, accuracy = 69.35%), and CT (Kappa = 0.118, accuracy = 50.00%). A stable diagnostic agreement between IFS and the final results was also found through the years (2000-2012: Kappa = 0.776; 2013-2014: Kappa = 0.625; 2015-2016: Kappa = 0.545; 2017-2019: Kappa = 0.652). CONCLUSION: In China, the assessment of myometrial invasion in non-endometrioid endometrial carcinoma is often performed via IGE, but the reliability is relatively low in contrast to IFS. In clinical practice, IFS is a reliable method that can help accurately assess myometrial invasion and intraoperative decision-making (lymph node dissection or not). Hence, it should be routinely performed in non-endometrioid endometrial carcinoma patients.