Prognostic significance of lymphovascular space invasion in early-stage low-grade endometrioid endometrial cancer: a fifteen-year retrospective Chinese cohort study.

OBJECTIVE: In 2016, the ESMO-ESGO-ESTRO consensus included LVSI (Lymph-vascular space invasion, LVSI) status as a risk stratification factor for stage I endometrioid endometrial cancer (EEC) patients and as one of the indications for adjuvant therapy. Furthermore, LVSI is included in the new FIGO staging of endometrial cancer (EC) in 2023. However, the data contribution of the Chinese population in this regard is limited. The present study aimed to further comfirm the influence of LVSI on the prognosis of early-stage low-grade EEC in a fifteen-year retrospective Chinese cohort study. METHODS: This retrospective analysis cohort included 702 EEC patients who underwent TAH/BSO surgery, total abdominal hysterectomy, bilateral salpingooophorectomy in Peking University People's Hospital from 2006 to 2020. Patients were stratified based on LVSI expression status as: LVSI negative group and LVSI positive group. Clinical outcome measures related to LVSI, assessed with a univariate and multivariate Cox proportional hazards regression model. RESULTS: 702 EEC patients with stage I and grade 1-2 were analyzed. 58 patients (8.3%) were LVSI-positive and 14 patients (2.0%) was relapse. Recurrence rates in LVSI-negative and LVSI-positive were 1.6% and 6.9%, respectively. 5-year disease-free survival (DFS) rate in LVSI-negative and LVSI-positive were 98.4% and 93.1%, respectively. These rates for 5-year overall (OS) survival in LVSI-negative were 98.9% while it was 94.8% in LVSI-positive. Multivariate analysis showed that LVSI is an independent risk factor for 5-year DFS (HR = 4.60, p = 0.010). LVSI has a similar result for 5-year OS(HR = 4.39, p = 0.028). CONCLUSIONS: LVSI is an independent predictor of relapse and poor prognosis in early-stage low-grade endometrioid endometrial cancer in the Chinese cohort.

The comparison of pure uterine serous carcinoma and mixed tumor with serous component: a single-institution review of 91 cases.

BACKGROUND: Pure uterine serous carcinoma (p-USC) and mixed tumors with serous component (m-USC) are aggressive subtypes of endometrial cancer associated with high mortality rates. This retrospective study aimed to compare clinicopathologic features and outcomes of p-USC and m-USC in a single center. METHODS: This study retrospectively reviewed patients diagnosed with USC at Peking University People's Hospital between 2008 and 2022. T-tests and chi-square tests were used to compare clinicopathological characteristics between p-USC and m-USC. Kaplan-Meier survival curve and Cox regression analysis were used to analyze the impact of clinical and pathological variables on OS and PFS. RESULTS: Among the 91 patients who underwent surgery, 65.9% (n = 60) were p-USC, and 34.1% (n = 31) were m-USC. Patients with p-USC had earlier menopause (P = 0.0217), a lower rate of progesterone receptor(PR) expression (P < 0.001), and were more likely to have positive peritoneal cytology (P = 0.0464). After a median follow-up time of 40 months, 28 (46.7%) p-USC and 9 (29%) m-USC patients had progression disease, 18 (30%) and 8 (25.8%) patients died of their disease. 5-year PFSR were 51.2% and 75.3%, respectively, and 5-year OS rates were 66% and 67.4%. Kaplan-Meier survival analysis showed that p-USC was more likely to relapse than m-USC (P = 0.034), but there was no significant difference in OS. Cox regression analysis showed that lymph node metastasis and surgical approach were risk factors for OS, and myoinvasion depth ≥ 1/2 was an independent risk factor for PFS. CONCLUSIONS: p-USC was more likely to relapse than m-USC, but there was no significant difference in OS between the two subtypes.

Development and validation of a prognostic model based on metabolic risk score to predict overall survival of endometrial cancer in Chinese patients.

OBJECTIVE: Metabolic syndrome (MetS) is closely related to the increased risk and poor prognosis of endometrial cancer (EC). The purpose of this study was to analyze the relationship between metabolic risk score (MRS) and EC, and establish a predictive model to predict the prognosis of EC. METHODS: A retrospective study was designed of 834 patients admitted between January 2004 to December 2019. Univariate and multivariate Cox analysis were performed to screen independent prognostic factors for overall survival (OS). A predictive nomogram is built based on independent risk factors for OS. Consistency index (C-index), calibration plots and receiver operating characteristic curve were used to evaluate the predictive accuracy of the nomogram. RESULTS: The patients were randomly divided into training cohort (n=556) and validation cohort (n=278). The MRS of EC patients, ranging from -8 to 15, was calculated. Univariate and multivariate Cox analysis indicated that age, MRS, FIGO stage, and tumor grade were independent risk factors for OS (p<0.05). The Kaplan-Meier analysis demonstrated that EC patients with low score showed a better prognosis in OS. Then, a nomogram was established and validated based on the above four variables. The C-index of nomogram were 0.819 and 0.829 in the training and validation cohorts, respectively. Patients with high-risk score had a worse OS according to the nomogram. CONCLUSION: We constructed and validated a prognostic model based on MRS and clinical prognostic factors to predict the OS of EC patients accurately, which may help clinicians personalize prognostic assessments and effective clinical decisions.

Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells.

Ginsenoside Rh3 (GRh3) is a seminatural product obtained by chemical processing after isolation from Chinese herbal medicine that has strong antitumor activity against human tumors. However, its antitumor role remains to be elucidated. The aim of this study is to explore the mechanisms underlying the tumor suppressive activity of GRh3 from the perspective of pyroptosis and ferroptosis. GRh3 eliminates colorectal cancer (CRC) cells by activating gasdermin D (GSDMD)-dependent pyroptosis and suppressing solute carrier family 7 member 11 (SLC7A11), resulting in ferroptosis activation through the Stat3/p53/NRF2 axis. GRh3 suppresses nuclear factor erythroid 2-related factor 2 (NRF2) entry into the nucleus, leading to the decrease of heme oxygenase 1 (HO-1) expression, which in turn promotes NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and caspase-1 expression. Finally, caspase-1 activates GSDMD-dependent pyroptosis. Furthermore, GRh3 prevents NRF2 from entering the nucleus, which suppresses SLC7A11, causing the depletion of glutathione (GSH) and accumulation of iron, lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and eventually leading to ferroptosis in CRC cells. In addition, GRh3 effectively inhibits the proliferation of CRC cells in vitro and in nude mouse models. Collectively, GRh3 triggers pyroptotic cell death and ferroptotic cell death in CRC cells via the Stat3/p53/NRF2 axis with minimal harm to normal cells, showing great anticancer potential.

Deciphering the Molecular Mechanism of Yifei-Sanjie Pill in Cancer-Related Fatigue.

Background: The incidence of cancer-related fatigue (CRF) is increasing, but its lack of clear pathogenesis makes its prevention and treatment difficult. Therefore, it is of great significance to clarify the pathogenesis of CRF and find effective methods to treat it. Methods: The CRF model was established by intraperitoneal injection of LLC cells in ICR mice to explore the pathogenesis of CRF and verify the therapeutic effect of the Yifei-Sanjie pill (YFSJ). The active components of YFSJ were found by LC/MS, the in vitro inflammatory infiltration model of skeletal muscle was constructed by TNF-α and C2C12 myoblasts, and the results of in vivo experiments were verified by this model. Results: Behavioral analysis results showed that YFSJ alleviated CRF; histological examination results showed that YFSJ could reverse the tumor microenvironment leading to skeletal muscle injury; ELISA and RNA-seq results showed that the occurrence of CRF and the therapeutic effect of YFSJ were closely related to the tumor inflammatory microenvironment; IHC and WB results showed that the occurrence of CRF and the therapeutic effect of YFSJ were closely related to the Stat3-related signaling pathway and autophagy. Conclusions: YFSJ can reduce the level of inflammation in the tumor microenvironment in vivo, inhibit the abnormal activation of the Stat3/HIF-1α/BNIP3 signaling pathway induced by tumor-related inflammation, thereby inhibiting the overactivation of mitophagy in skeletal muscle, and finally alleviate CRF. Quercetin, one of the components of YFSJ, plays an important role in inhibiting the phosphorylation activation of Stat3.

Desolvation Synergy of Multiple H/Li-Bonds on an Iron-Dextran-Based Catalyst Stimulates Lithium-Sulfur Cascade Catalysis.

Traditional lithium-sulfur battery catalysts are still facing substantial challenges in solving sulfur redox reactions, which involve multistep electron transfer and multiphase transformations. Here, inspired by the combination of iron dextran (INFeD) and ascorbic acid (VC) as a blood tonic for the treatment of anemia, a highly efficient VC@INFeD catalyst is developed in the sulfur cathode, accomplishing the desolvation and enrichment of high-concentration solvated lithium polysulfides at the cathode/electrolyte interface with the assistance of multiple H/Li-bonds and resolving subsequent sulfur transformations through gradient catalysis sites where the INFeD promotes long-chain lithium polysulfide conversions and VC accelerates short-chain lithium polysulfide conversions. Comprehensive characterizations reveal that the VC@INFeD can substantially reduce the energy barrier of each sulfur redox step, inhibit shuttle effects, and endow the lithium-sulfur battery with high sulfur utilization and superior cycling stability even under a high sulfur loading (5.2 mg cm-2 ) and lean electrolyte (electrolyte/sulfur ratio, ≈7 µL mg-1 ) condition.

A detailed analysis of lymph node recurrence in endometrial carcinoma.

Background: The lymph node (LN) is one of the main sites of recurrence in patients with endometrial carcinoma (EC). Literature specifically analyzing LN recurrence (LNR) in EC remains limited in number. Methods: Patients with EC undergoing surgery between 2006 and 2021 in Peking University People's Hospital was included, clinicopathological data of whom were collected and analyzed retrospectively by R 4.0.3. Results: A total of 792 patients were included, with 73 patients having recurrence, among whom 21 patients had LNR. Median recurrence-free survival (RFS) in patients with LNR was 16 [4-39] months. LNR was extensive, with pelvic LNs most commonly involved (9/21). There are various patterns of LNR, with 33.3% (7/21) LN-only recurrence. Multivariable analysis suggested advanced stage, larger tumor diameter and poor histology were independent risk factors for LNR. Patients with LN metastasis (LNM) diagnosed at initial treatment accounted for 47.6% (10/21) of cases with LNR, 60.0% (6/10) of whom had recurrent LNs beyond the region of LNM, 90.0% (9/10) of whom had recurrence nodes overlapping with the range of lymphadenectomy. Uni- and multi-variable analysis suggested lymphadenectomy was not a protective factor for LNR, with both the range and number of LNs harvested considered. Conclusions: LNR is common in patients with EC, with an extensive range and various patterns of recurrence. The International Federation of Gynecology and Obstetrics (FIGO) stage, tumor diameter and histology were independent risk factors for LNR, but lymphadenectomy seemed not a protective factor for LNR.

Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes.

Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patientEC+/dia+ ). To explore new therapeutic targets, Ishikawa is cultured with high glucose (IshikawaHG ) mimicking hyperglycemia in patientEC+/dia+ . Subsequently, it is discovered that IshikawaHG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of IshikawaHG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits IshikawaHG proliferation though IshikawaHG is resistant to Met. Furthermore, a reduction-sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06-NPs) for drug delivery. It is found that in vitro JX06-NPs have better inhibitory effect on the growth of IshikawaHG as well as patient-derived EC cells (PDC) than JX06. Additionally, it is found that JX06-NPs can accumulate to the tumor of EC-bearing mouse with diabetes (miceEC+/dia+ ) after intravenous injection, and JX06-NPs combined Met can significantly inhibit tumor growth of miceEC+/dia+ . Taken together, the study demonstrates that the combination of JX06-NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patientsEC+/dia+ .

Peripheral Tumor Location Predicts a Favorable Prognosis in Patients with Resected Small Cell Lung Cancer.

Background: Small cell lung cancer (SCLC) is an aggressive malignancy. Surgical resection is currently only recommended for clinical stage I patients who have been carefully staged. The clinical outcomes of patients with resected SCLCs vary because the disease is highly heterogeneous, suggesting that selected patients could be considered for surgical resection depending on their clinical and/or molecular characteristics. Methods: We collected data on a retrospective cohort of 119 limited-stage SCLC patients who underwent lobectomy with mediastinal lymph node dissection from March 2013 to March 2020 at Harbin Medical University Cancer Hospital. Correlations were derived using Fisher's exact test. Models of 2-year and 3-year survival were evaluated by deriving the area under receiver operating characteristic curves. Kaplan-Meier and Cox regression analyses were used to evaluate significant differences between the survival curves and hazard ratios. Results: The median disease-free survival (DFS) was 35.9 months (range 0.9-105.3 months), and the median overall survival (OS) was 45.2 months (range 4.8-105.3 months). Univariate analysis showed that TNM stage was significantly correlated with DFS and OS. The 2-year disease-free rates of patients with stage I, II, and III disease were 76.4%, 50.5%, and 36.1%, respectively, and the 3-year OS rates were 75.9%, 57.7%, and 34.4%, respectively. In pN + patients, multiple (or multiple-station) lymph node involvement significantly increased recurrence and reduced survival compared with patients with single or single-station metastases. Patients with peripheral SCLCs evidenced significantly better DFS and OS than did patients with central tumors. Multivariate analysis showed that TNM stage and tumor location were independently prognostic in Chinese patients with resected limited-stage SCLC. A combination of TNM stage and tumor location was helpful for prognosis. Conclusions: TNM stage and tumor location were independently prognostic in Chinese patients with resected SCLCs. Patient stratification by tumor location should inform the therapeutic strategy. The role of surgical resection for limited-stage SCLC patients must be reevaluated, as this may be appropriate for some patients.

The association between a metabolically healthy overweight/obesity phenotype and markers of inflammation among Chinese children and adolescents aged 10-18 years.

OBJECTIVES: The association between metabolically healthy overweight/obesity (MHO) and inflammatory markers remains controversial. The aim of the present study was to describe the prevalence of different metabolic phenotypes and to examine the relationship of different metabolic phenotypes with inflammatory markers among Chinese children and adolescents. METHODS: The study included 1,125 children and adolescents aged 10-18 years using a cross-sectional survey, and all subjects were classified into four groups based on a combination of BMI and metabolic status. In addition, the inflammatory markers we measured were high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). RESULTS: The prevalence of metabolically healthy with normal-weight (MHNW), MHO, metabolically unhealthy with normal-weight (MUNW), and metabolically unhealthy overweight/obesity (MUO) phenotypes was 38.76, 7.11, 38.67 and 15.47%, respectively. The results of logistic regression analysis showed that the MHO was associated with the z scores of hs-CRP in Chinese children and adolescents (OR=0.57, 95% CI: 0.39-0.83). Meanwhile, multivariate adjusted regression analysis showed that the relationship between hs-CRP and MHO among the overweight/obese was consistent with the results above, but among the normal-weight, only the highest quartile of TNF-α could increase the risk of MUNW (OR=1.65, 95% CI: 1.09-2.52). CONCLUSIONS: MHO phenotypes were not common in Chinese children and adolescents. Individuals with MHO had a more beneficial hs-CRP profile than those with MUO.

Biodegradable Polymersomes with Structure Inherent Fluorescence and Targeting Capacity for Enhanced Photo-Dynamic Therapy.

Biodegradable nanostructures displaying aggregation-induced emission (AIE) are desirable from a biomedical point of view, due to the advantageous features of loading capacity, emission brightness, and fluorescence stability. Herein, biodegradable polymers comprising poly (ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-P(CLgTMC)), with tetraphenylethylene pyridinium-TMC (PAIE) side chains have been developed, which self-assembled into well-defined polymersomes. The resultant AIEgenic polymersomes are intrinsically fluorescent delivery vehicles. The presence of the pyridinium moiety endows the polymersomes with mitochondrial targeting ability, which improves the efficiency of co-encapsulated photosensitizers and improves therapeutic index against cancer cells both in vitro and in vivo. This contribution showcases the ability to engineer AIEgenic polymersomes with structure inherent fluorescence and targeting capacity for enhanced photodynamic therapy.

Development and validation of predictive model for lymph node metastasis in endometrial cancer: a SEER analysis.

BACKGROUND: The purpose of this study was to develop a nomogram that can be used to predict lymph node metastasis (LNM) in patients with endometrial cancer (EC). METHODS: The clinical data of EC patients diagnosed between 2004 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results Program (SEER) registry. The nomogram was constructed using independent risk factors chosen by a multivariate logistic regression analysis. Accuracy was validated for both groups using discrimination analysis and calibration curves. RESULTS: The final study group consisted of 63,836 women that met specific inclusion criteria. The factors that were identified in the multivariate analysis to be significant predictors of LNM were age, tumor size, histological type, myometrial invasion, cervical stromal invasion, and tumor grade in training group (N=42,558). These variables were included in the nomogram. Discriminations of the nomogram and Mayo criteria were 0.848 (95% CI: 0.843-0.853) and 0.806 (95% CI: 0.801-0.812), respectively. In the validation group (N=21,278), the AUC values were 0.847 (95% CI: 0.840-0.857) and 0.804 (95% CI: 0.796-0.813) for the nomogram and the Mayo criteria, respectively (P<0.01). Calibration plots showed that training and validation cohorts were well-calibrated. CONCLUSIONS: A nomogram was developed to predict LNM in EC patients based on a large population-based analysis. The nomogram showed good performance for predicting LNM in patients with EC. This convenient predictive tool may help clinicians to formulate suitable individualized treatment.

A Novel Transcription Factor-Based Prognostic Signature in Endometrial Cancer: Establishment and Validation.

BACKGROUND: Endometrial cancer (EC) is a common malignancy of the female reproductive system worldwide. Increasing evidence has suggested that many transcription factors are aberrantly expressed in various cancers. This study aimed to develop a transcription factor-based prognostic signature for EC. METHODS: Gene expression data and clinical data of EC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression and Multivariate Cox regression analysis was used to construct a prognostic signature. Then, the efficacy of the prognostic signature was validated in a training cohort, testing cohort and then the entire cohort. Correlations between clinical features and the model were also analyzed, and a nomogram based on the multivariate Cox analysis was developed. Furthermore, we verified the effect of a key transcription factor, E2F1, on biological functions of EC in vitro. RESULTS: We developed a nine-transcription factor (MSX1, HOXB9, E2F1, DLX4, BNC2, DLX2, PDX1, POU3F2, and FOXP3) prognostic signature. Compared with those in the low-risk group, patients in the high-risk group had worse clinical outcomes. The area under the curve (AUC) of this prognostic signature for 5-year survival was 0.806 in the training cohort, 0.710 in the testing cohort and 0.761 in the entire cohort. Gene set enrichment analysis (GSEA) revealed a correlation between the prognostic signature and various cancer signaling pathways, and a hub transcription factor regulatory network was constructed. The prognostic signature was confirmed to have independent predictive value. Finally, a nomogram based on the prognostic signature and clinical independent prognostic factors was also established and performed well according to the calibration curves. Further, knockdown of E2F1 inhibited invasion and metastasis of EC cells. CONCLUSION: Our study developed and validated a transcription factor-based prognostic signature that accurately predicts prognosis of EC patients. Moreover, E2F1 may represent a potential target for the treatment of EC.

A ten-gene methylation signature as a novel biomarker for improving prediction of prognosis and indicating gene targets in endometrial cancer.

Endometrial cancer (EC) is a common female reproductive tumor worldwide. Nonetheless, the pathogenesis of EC still remains ambiguous and associated epigenetic mechanism still to be explored. The goal of this study is to investigate whether gene methylation signature is associated with overall survival (OS) for EC patients. In this study, a 10-gene methylation risk model was built and the OS in high- and low-risk groups was significant different. The area under the ROC curve (AUC) of this model was 0.856 at 5 years survival. The nomogram could accurately predict the OS in EC patients, with concordance index and AUC at 5 year survival reached 0.796 and 0.792, respectively. Furthermore, we verified the nomogram with 24 patients in our center and the Kaplan-Meier survival curve also proved to be significantly different (p < 0.01). WGCNA revealed a key gene group for the model and further bioinformatics analysis indicated 6 genes as the hub genes in the module. Knockdown of MMP12 inhibited the proliferation, invasion and metastasis of EC cells. After all, a methylation signature and a nomogram based on this signature were constructed, and they could both predict survival in patients with EC. Moreover, WGCNA model identified MMP12 as a potential target for the treatment of EC.

Integrated genomic analysis reveals regulatory pathways and dynamic landscapes of the tRNA transcriptome.

tRNAs and tRNA-derived RNA fragments (tRFs) play various roles in many cellular processes outside of protein synthesis. However, comprehensive investigations of tRNA/tRF regulation are rare. In this study, we used new algorithms to extensively analyze the publicly available data from 1332 ChIP-Seq and 42 small-RNA-Seq experiments in human cell lines and tissues to investigate the transcriptional and posttranscriptional regulatory mechanisms of tRNAs. We found that histone acetylation, cAMP, and pluripotency pathways play important roles in the regulation of the tRNA gene transcription in a cell-specific manner. Analysis of RNA-Seq data identified 950 high-confidence tRFs, and the results suggested that tRNA pools are dramatically distinct across the samples in terms of expression profiles and tRF composition. The mismatch analysis identified new potential modification sites and specific modification patterns in tRNA families. The results also show that RNA library preparation technologies have a considerable impact on tRNA profiling and need to be optimized in the future.

α3 integrin-binding peptide-functionalized polymersomes loaded with volasertib for dually-targeted molecular therapy for ovarian cancer.

Ovarian cancer (OC) is a high-mortality malignancy in women with a five-year survival rate of 30-40%. There is an urgent need to develop high-efficacy and low toxic treatments for OC. Herein, we report an appealing strategy that combines α3 integrin targeted polymersomes (A3-Ps) and targeted molecular drug, polo-like kinase 1 (PLK1) inhibitor volasertib (Vol) for dually targeted molecular therapy of OC in vivo. A3-Ps had good Vol loading of 7.7-8.0 wt.% and small size of 25-32 nm, depending on the density of α3 integrin binding peptide A3. Interestingly, cellular uptake studies using FITC-labeled Vol revealed that A3-Ps with 20% peptide gave 2.3 and 3.3-fold better internalization in SKOV-3 OC cells compared with non-targeted Ps and free Vol, respectively. Accordingly, Vol loaded in A3-Ps showed the best inhibitory activity to SKOV-3 cells with an IC50 of 49 nM, which was 3.5 times lower than free Vol. Importantly, the in vivo experiments demonstrated that A3-Ps-Vol proficiently repressed the growth of SKOV-3 tumors in mice while continuous tumor growth was observed for Ps-Vol and free Vol-treated mice. A3-Ps-Vol besides boosting anti-OC activity also reduced the systemic toxicity of Vol. This dually targeted molecular drug nanoformulation has appeared to be an especially potent and low toxic treatment modality for human ovarian cancers. STATEMENT OF SIGNIFICANCE: Volasertib provides a potential molecular therapy for PLK1-positive advanced OC patients. The initial clinical outcomes, nevertheless, showed a suboptimal efficacy, possibly resulting from its fast clearance, deficient tumor deposition and dose-limiting toxicities. Here, we show for the first time that dually targeted molecular therapy of OC using α3 integrin-binding peptide-modified polymersomes as a vehicle gives markedly improved potency, better toleration, and depleted adverse effects in SKOV-3 tumor models, greatly outperforming free volasertib. This dually targeted strategy has emerged as an appealing treatment for malignant PLK1-positive ovarian tumors.

Identification of an immune-related risk signature and nomogram predicting the overall survival in patients with endometrial cancer.

OBJECTIVE: Aimed to construct an immune-related risk signature and nomogram predicting endometrial cancer (EC) prognosis. METHODS: An immune-related risk signature in EC was constructed using the least absolute shrinkage and selection operator regression analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A nomogram integrating the immune-related genes and the clinicopathological characteristics was established and validated using the Kaplan-Meier survival curve and receiver operating characteristic (ROC) curve to predict the overall survival (OS) of EC patients. The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) R tool was used to explore the immune and stromal scores. RESULTS: CCL17, CTLA4, GPI, HDGF, HFE2, ICOS, IFNG, IL21R, KAL1, NR3C1, S100A2, and S100A9 were used in developing an immune-related risk signature evaluation model. The Kaplan-Meier curve indicated that patients in the low-risk group had better OS (p<0.001). The area under the ROC curve (AUC) values of this model were 0.737, 0.764, and 0.782 for the 3-, 5-, and 7-year OS, respectively. A nomogram integrating the immune-related risk model and clinical features could accurately predict the OS (AUC=0.772, 0.786, and 0.817 at 3-, 5-, and 7-year OS, respectively). The 4 immune cell scores were lower in the high-risk group. Forkhead box P3 (FOXP3) and basic leucine zipper ATF-like transcription factor (BATF) showed a potential significant role in the immune-related risk signature. CONCLUSION: Twelve immune-related genes signature and nomogram for assessing the OS of patients with EC had a good practical value.

Effects of Metabolic Syndrome and Its Components on the Prognosis of Endometrial Cancer.

Objective: To explore the effects of metabolic syndrome (MetS) on the prognosis of endometrial cancer (EC) and to identify key components of MetS associated with EC. Methods: A total of 506 patients surgically diagnosed with EC were analyzed in this study. These patients were diagnosed with EC in the Department of Obstetrics and Gynecology at the People's Hospital of Peking University between 2010 and 2016. The follow-up time was cut off at December 2019. MetS was characterized based on standards provided by the Chinese Diabetes Society in 2004. Results: Among the 506 EC patients analyzed, 153 patients were diagnosed with MetS. MetS patients were more likely to be older and postmenopausal. MetS was positively related to tumor grade, stage, LNM, LVSI, and MI. The univariate analysis showed that MetS was closely related to the OS (HR = 2.14; P = 0.032) and RFS (HR = 1.80; P = 0.045) of EC patients. K-M analysis also indicated that EC patients with MetS had shorter OS and RFS than EC patients without MetS. More specifically, patients that had ≥3 components showed a worse outcome compared with patients only having 0 or 1-2 components (P <0.05). In the multivariate-adjust model, after adjusting for age, histotype, tumor grade, and stage, HDL-C was found to be associated with increased risk of death related to EC (HR = 2.2, P = 0.034). However, MetS did not significantly correlate with this. ROC analysis revealed that the area under the ROC curve of combined factors (HDL-C + grade + stage) was better than traditional stage or grade at 1-, 3-, and 5-year survival rates. From this, a nomogram based on HDL-C, grade, and stage was constructed to predict survival of EC patients. Calibration curve analysis and decision curve analysis (DCA) showed the nomogram we constructed could better predict the survival of EC patients. Conclusion: MetS is closely related to poor prognosis in EC patients. The prevalence of individual MetS components increase with worse outcomes in EC patients. A nomogram based on HDL-C, grade, and stage has good ability to predict survival of EC patients.

Establishment and validation of a prognostic nomogram based on a novel five-DNA methylation signature for survival in endometrial cancer patients.

BACKGROUND: This study aimed to explore the prognostic role of DNA methylation pattern in endometrial cancer (EC) patients. METHODS: Differentially methylated genes (DMGs) of EC patients with distinct survival from The Cancer Genome Atlas (TCGA) database were analyzed to identify methylated genes as biomarkers for EC prognosis. The Least Absolute Shrinkage and Selection Operator (LASSO) analysis was used to construct a risk score model. A nomogram was built based on analysis combining the risk score model with clinicopathological signatures together, and then verified in the validation cohort and patients in our own center. RESULTS: In total, 157 DMGs were identified between different prognostic groups. Based on the LASSO analysis, five genes (GBP4, OR8K3, GABRA2, RIPPLY2, and TRBV5-7) were screened for the establishment of risk score model. The model outperformed in prognostic accuracy at varying follow-up times (AUC for 3 years: 0.824, 5 years: 0.926, and 7 years: 0.853). Multivariate analysis identified four independent risk factors including menopausal status (HR = 3.006, 95%CI: 1.062-8.511, p = 0.038), recurrence (HR = 2.116, 95%CI: 1.061-4.379, p = 0.046), lymph node metastasis (LNM, HR = 3.465, 95%CI: 1.225-9.807, p = 0.019), and five-DNA methylation risk model (HR = 3.654, 95%CI: 1.458-9.161, p = 0.006) in training cohort. The performance of the nomogram was good in the training (AUC = 0.828), validation (AUC = 0.866) and the whole cohorts (AUC = 0.843). Furthermore, we verified the nomogram with 24 patients in our center and the Kaplan-Meier survival curve also proved to be significantly different (p < 0.01). The subgroup analysis in different stratifications indicated that the accuracy was high in different subgroups for age, histological type, tumor grade, and clinical stage (all p < 0.01). CONCLUSIONS: Briefly, our work established and verified a five-DNA methylation risk model, and a nomogram merging the model with clinicopathological characteristics to facilitate individual prediction of EC patients for clinicians.

Calcium and TRPV4 promote metastasis by regulating cytoskeleton through the RhoA/ROCK1 pathway in endometrial cancer.

Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that has been associated with several types of cancer. However, its biological significance, as well as its related mechanism in endometrial cancer (EC) still remains elusive. In this study, we examined the function of calcium in EC, with a specific focus on TRPV4 and its downstream pathway. We reported here on the findings that a high level of serum ionized calcium was significantly correlated with advanced EC progression, and among all the calcium channels, TRPV4 played an essential role, with high levels of TRPV4 expression associated with cancer progression both in vitro and in vivo. Proteomic and bioinformatics analysis revealed that TRPV4 was involved in cytoskeleton regulation and Rho protein pathway, which regulated EC cell migration. Mechanistic investigation demonstrated that TRPV4 and calcium influx acted on the cytoskeleton via the RhoA/ROCK1 pathway, ending with LIMK/cofilin activation, which had an impact on F-actin and paxillin (PXN) levels. Overall, our findings indicated that ionized serum calcium level was significantly associated with poor outcomes and calcium channel TRPV4 should be targeted to improve therapeutic and preventive strategies in EC.