Development and validation of matrix metalloproteinase for predicting prognosis and tumour microenvironment immune profiles in uterine corpus endometrial carcinoma.

Background: Matrix metalloproteinases (MMPs) are involved in many processes of tumour progression and invasion. However, few studies have analysed the effects of MMP expression patterns on endometrial cancer (EC) development from the perspective of the tumour microenvironment (TME). we quantified MMP expression in individual by constructing an MMP score and found MMP score effectively predict the prognosis of EC patients. Methods: MMPs expression profiles were determined based on the differential expression of 12 MMP-related regulators. Principal component analysis (PCA) was used to construct an MMP scoring system which can quantify the MMPs expression patterns individually of EC patients. Kaplan-Meier analysis, the log-rank test, and time-dependent receiver operating characteristic (ROC) curve analysis were used to evaluate the value of MMPs expression in predicting prognosis. Single-cell RNA sequencing (scRNA-seq) dataset was used to verify correlation between MMPs and progression of EC. Gene Ontology (GO) analysis was used to investigate the pathways and functions underlying MMPs expression. Tumour immune dysfunction, exclusion prediction, and pharmacotherapy response analyses were performed to assess the potential response to pharmacotherapy based on MMPs patterns. Results: We downloaded the MMPs expression data, somatic mutation data and corresponding clinical information of EC patients from the TCGA website and ICGC portal. Based on the MMP-related differentially expressed genes (DEGs), the MMP score was constructed, and EC patients were divided into high and low MMP score groups. There was a positive correlation between MMP score and prognosis of EC patients. Patients with high MMP scores had better prognosis, more abundant immune cell infiltration and stronger antitumoor immunity. Although prognosis is worse with the lower group than the high, patients with low MMP score had better response to immunotherapy, which means they could prolong the survival time through Immunological checkpoint blockade (ICB) therapy. scRNA-seq analysis identified significant heterogeneity between MMP score and classical pathways in EC. Conclusion: Our work indicates that the MMP score could be a potential tool to evaluate MMP expression patterns, immune cell infiltration, response to pharmacotherapy, clinicopathological features, and survival outcomes in EC. This will provide the more effective guide to select immunotherapeutic strategies of EC in the future.

A Novel Conductive Polypyrrole-Chitosan Hydrogel Containing Human Endometrial Mesenchymal Stem Cell-Derived Exosomes Facilitated Sustained Release for Cardiac Repair.

Myocardial infarction (MI) results in cardiomyocyte necrosis and conductive system damage, leading to sudden cardiac death and heart failure. Studies have shown that conductive biomaterials can restore cardiac conduction, but cannot facilitate tissue regeneration. This study aims to add regenerative capabilities to the conductive biomaterial by incorporating human endometrial mesenchymal stem cell (hEMSC)-derived exosomes (hEMSC-Exo) into poly-pyrrole-chitosan (PPY-CHI), to yield an injectable hydrogel that can effectively treat MI. In vitro, PPY-CHI/hEMSC-Exo, compared to untreated controls, PPY-CHI, or hEMSC-Exo alone, alleviates H2O2-induced apoptosis and promotes tubule formation, while in vivo, PPY-CHI/hEMSC-Exo improves post-MI cardiac functioning, along with counteracting against ventricular remodeling and fibrosis. All these activities are facilitated via increased epidermal growth factor (EGF)/phosphoinositide 3-kinase (PI3K)/AKT signaling. Furthermore, the conductive properties of PPY-CHI/hEMSC-Exo are able to resynchronize cardiac electrical transmission to alleviate arrythmia. Overall, PPY-CHI/hEMSC-Exo synergistically combines the cardiac regenerative capabilities of hEMSC-Exo with the conductive properties of PPY-CHI to improve cardiac functioning, via promoting angiogenesis and inhibiting apoptosis, as well as resynchronizing electrical conduction, to ultimately enable more effective MI treatment. Therefore, incorporating exosomes into a conductive hydrogel provides dual benefits in terms of maintaining conductivity, along with facilitating long-term exosome release and sustained application of their beneficial effects.

Optimizing human endometrial mesenchymal stem cells for maximal induction of angiogenesis.

Human endometrial mesenchymal stem cells (hEMSCs) have been shown to promote neo-vascularization; however, its angiogenic function lessens with age. To determine the optimal conditions for maximizing hEMSC angiogenic capacity, we examined the effects of serial passaging on hEMSC activity. hEMSCs were cultured from passages (P) 3, 6, 9, and 12, and analyzed for proliferation, migration, differentiation and senescence, as well as their capacity to induce angiogenesis. The results showed that hEMSC proliferation and migration significantly decreased after P12. Furthermore, hEMSC differentiation into adipogenic and osteogenic lineages, as well as their proangiogenic capacity, gradually decreased from P9-12, while senescence only occurred after P12. Evaluation of angiogenic-related protein levels showed that both transforming growth factor ß2 and Tie-2 was significantly reduced in hEMSCs at P12, compared to P3, possibly serving as the basis behind their lowered angiogenic capacity. Furthermore, in vivo angiogenesis evaluation with Matrigel plug assay showed that the optimal hEMSC to HUVEC ratio, for maximizing vessel formation, was 1:4. This study showed that hEMSC passaging was associated with lowered cellular functioning, bringing them closer to a senescent phenotype, especially after P12, thereby defining the optimal time period for cultivating fully functional hEMSCs for therapeutic applications.

BPCN: bilateral progressive compensation network for lung infection image segmentation.

Lung infection image segmentation is a key technology for autonomous understanding of the potential illness. However, current approaches usually lose the low-level details, which leads to a considerable accuracy decrease for lung infection areas with varied shapes and sizes. In this paper, we propose bilateral progressive compensation network (BPCN), a bilateral progressive compensation network to improve the accuracy of lung lesion segmentation through complementary learning of spatial and semantic features. The proposed BPCN are mainly composed of two deep branches. One branch is the multi-scale progressive fusion for main region features. The other branch is a flow-field based adaptive body-edge aggregation operations to explicitly learn detail features of lung infection areas which is supplement to region features. In addition, we propose a bilateral spatial-channel down-sampling to generate a hierarchical complementary feature which avoids losing discriminative features caused by pooling operations. Experimental results show that our proposed network outperforms state-of-the-art segmentation methods in lung infection segmentation on two public image datasets with or without a pseudo-label training strategy.

The incidence of unexpected uterine malignancies in hysterectomies carried out for benign indications.

PURPOSE: The aim of the present study was to evaluate the incidence of unexpected uterine malignancies in patients undergoing hysterectomy for benign indications and to evaluate their clinical characteristics. METHODS: We conducted a retrospective review of patients who underwent benign hysterectomy in the Department of Gynecology, the First Hospital of Shanxi Medical University from January 2015 to December 2020. The clinical data of these patients were retrieved and collected. RESULTS: Their median age was 49.8 years (31-82 years). The mean parity was 1.86 ± 2.54. Their mean BMI was 27.5 ± 7.6 kg/m2. 42.90% were (2438/5683) postmenopausal. The benign indications of procedure were as follows: symptomatic uterine leiomyomas 2218/5683 (39.02%), pelvic organ prolapse 1406/5683 (24.74%), symptomatic endometriosis or adenomyosis 1132/5683 (19.91%), and 927/5683 (16.31%) to treat other benign conditions such as abnormal uterine bleeding, infection, polyps, and endometrial hyperplasia without atypia. In minimally invasive surgery subgroups, 1560/2621 (59.52%) specimens were removed by in-bag manual morcellation through vaginal cuff. The mean operative time of minimally invasive surgery with in-bag morcellation was shorter than abdominal hysterectomy (96.75 ± 35.7 vs. 140 ± 32.6, P < .001), and the estimated blood loss was also less than abdominal hysterectomy (47.35 ± 42.3 vs. 170 ± 60.4, P < .001). A total of 19/5683 (0.33%) unexpected uterine malignancies were recorded, of which 14/5683 (0.26%) were unexpected endometrial carcinomas and 5/5683 (0.08%) were unexpected uterine sarcomas. CONCLUSION: Preoperative examination in the context of benign hysterectomy must be undertaken with care, and patients should be educated about the very slight possibility of a malignant diagnosis.

The effect of color coding and layout coding on users' visual search on mobile map navigation icons.

Color and spatial layout are important factors that affect users' icon cognition and play a huge role in the visual search process of icons. Guided by the user's interactive needs, this paper aims to improve the visual search efficiency of mobile map navigation icons. The mixed design within and between subjects is adopted through the combination of theoretical and experimental research, and the subjective questionnaire method is used to explore the research. This paper explores the visual search problem of mobile map navigation icons based on color coding and layout coding. The experimental results mainly include reaction time, accuracy rate, user experience, and statistical and variance analysis. The results show that the layout of the mobile map navigation icons significantly impacts the user's visual search. The navigation icons that use color for layout coding have the highest visual search efficiency and better user experience. Among the icons, the layout with regular color distribution and a larger area of the same color has the highest visual search efficiency for users and the best user experience; the visual search efficiency of navigation icons using color for layout coding is significantly higher than that of mobile map navigation icons. Relevance to industry: The user scale of mobile information maps is huge and the usage rate is high, but the large number of navigation icons increases the burden of user information identification and acquisition. As a result, the efficiency of user information acquisition is low, and the user experience is reduced. A clear, easy-to-search navigation icon design can enhance the user experience of the entire product. The results of this research provide theoretical support and practical guidance for the design optimization and improvement of mobile map navigation icons.

Endometrial microbiota from endometrial cancer and paired pericancer tissues in postmenopausal women: differences and clinical relevance.

OBJECTIVE: The incidence of postmenopausal endometrial cancer (EC) is rising, and the uterine microbiota has recently been suggested to be an etiology of EC. However, the differences in microbiota profiles in paired EC and the adjacent non-EC endometrium, and the functional microbiota of clinical relevance remain largely unknown. Therefore, we examined the differences in microbiota profiles between EC and non-EC endometrium and investigated their clinical relevance to EC. METHODS: Twenty-eight EC-affected postmenopausal women undergoing hysterectomy were enrolled. Endometrial microbiome from paired EC and adjacent non-EC tissue samples were detected using 16S rRNA sequencing, and the data were analyzed using R language software. RESULTS: The α diversity and evenness of the endometrial bacterial community significantly increased in EC tissues than those in pericancer tissues ( P < 0.05 for all variables). Lactobacillus and Gardnerella were the main bacterial genera present in both EC and adjacent non-EC-invading endometrium, whereas Prevotella , Atopobium , Anaerococcus , Dialister , Porphyromonas , and Peptoniphilus were more commonly enriched in the EC endometrium (corrected P < 0.05 for all variables). Finally, the abundance of some observed endometrial bacteria was associated with clinical aspects, particularly the vaginal pH, vaginal Lactobacillus abundance, and EC clinical stage. CONCLUSIONS: Paired EC and adjacent non-EC endometrium harbor different endometrial microbiota, and the functional bacteria residing in the endometrium are clinically relevant but require further investigation.

Fractal dimension of retinal vasculature as an image quality metric for automated fundus image analysis systems.

Automated fundus screening is becoming a significant programme of telemedicine in ophthalmology. Instant quality evaluation of uploaded retinal images could decrease unreliable diagnosis. In this work, we propose fractal dimension of retinal vasculature as an easy, effective and explainable indicator of retinal image quality. The pipeline of our approach is as follows: utilize image pre-processing technique to standardize input retinal images from possibly different sources to a uniform style; then, an improved deep learning empowered vessel segmentation model is employed to extract retinal vessels from the pre-processed images; finally, a box counting module is used to measure the fractal dimension of segmented vessel images. A small fractal threshold (could be a value between 1.45 and 1.50) indicates insufficient image quality. Our approach has been validated on 30,644 images from four public database.

The RETA Benchmark for Retinal Vascular Tree Analysis.

Topological and geometrical analysis of retinal blood vessels could be a cost-effective way to detect various common diseases. Automated vessel segmentation and vascular tree analysis models require powerful generalization capability in clinical applications. In this work, we constructed a novel benchmark RETA with 81 labelled vessel masks aiming to facilitate retinal vessel analysis. A semi-automated coarse-to-fine workflow was proposed for vessel annotation task. During database construction, we strived to control inter-annotator and intra-annotator variability by means of multi-stage annotation and label disambiguation on self-developed dedicated software. In addition to binary vessel masks, we obtained other types of annotations including artery/vein masks, vascular skeletons, bifurcations, trees and abnormalities. Subjective and objective quality validations of the annotated vessel masks demonstrated significantly improved quality over the existing open datasets. Our annotation software is also made publicly available serving the purpose of pixel-level vessel visualization. Researchers could develop vessel segmentation algorithms and evaluate segmentation performance using RETA. Moreover, it might promote the study of cross-modality tubular structure segmentation and analysis.

Exosomal MiR-423-3p inhibits macrophage M2 polarization to suppress the malignant progression of cervical cancer.

BACKGROUND: Cervical cancer (CC) is the leading cause of death among women-related cancers. MicroRNAs (miRNAs) exerting important impacts in the development of CC is widely recognized. MiR-423-3p was found to be with low expression in the plasma exosomes of patients with CC. Exo-miRNAs have been documented to be potential modulators of cancer progression, and exosomes have been reported to be associated with macrophage polarization. AIM: We aim to verify the potential function exosomal miR-423-3p may exert in CC cells as well as its underlying mechanism. METHODS: A co-culture model of exosomes and CC cells was established and the function of exosomal miR-423-3p was verified through Transwell, colony formation and other assays. A co-culture model of exosomes and macrophages, together with mechanism experiments in vitro and in vivo was taken to verify the molecular mechanism of exosomal miR-423-3p in CC. RESULTS: Exosomal miR-423-3p inhibited macrophage M2 polarization so as to suppress CC cell progression as well as tumor growth. MiR-423-3p regulated macrophage M2 polarization by targeting cyclin-dependent kinase 4 (CDK4) mRNA, and it inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) via CDK4 to silence Interleukin 6 (IL-6) expression. CONCLUSION: Exosomal miR-423-3p inhibited macrophage M2 polarization to suppress the progression of CC cells.

Up-regulation of MTHFD2 is associated with clinicopathological characteristics and poor survival in ovarian cancer, possibly by regulating MOB1A signaling.

BACKGROUND: MTHFD2 is a folate-coupled metabolic enzyme, which has been proved to participant in the metabolic reprogramming and tumor cell-sustaining proliferative capacity. However, the function of MTHFD2 in the development of ovarian cancer and its potential molecular mechanisms is still unclear. MATERIALS AND METHODS: The expression, various mutations, prognosis, and related network signaling pathways of MTHFD2 were analyzed using bioinformatics-related websites, including Oncomine, GEPIA, UCSC, cBioPortal, KM Plotter, TISIDB and TIMER. The prognostic value of MTHFD2 expression was validated by our own ovarian cancer samples using RT-qPCR. The migration ad invasion of ovarian cancer cells were further analyzed by CCK-8 and transwell assay. The Western-blot assay was performed to explore the protein levels of MTHFD2 and MOB1A. RESULTS: We obtained the following important results. (1) MTHFD2 expression was markedly up-regulated in ovarian cancer than normal samples. (2) Among patients with ovarian cancer, those with higher MTHFD2 expression was associated with lower survival rate. (3) The major mutation type of MTHFD2 in ovarian cancer samples was missense mutation. (4) MTHFD2 knockdown inhibited proliferation, migration, invasion, as well as the expression of MOB1A in vitro. CONCLUSION: MTHFD2, as a NAD + -dependent enzyme, accelerated tumor progression by up-regulating MBO1A, suggesting that this protein may be an independent prognostic factor and a potential therapeutic target for future ovarian cancer treatments.

Genetic of preimplantation diagnosis of dysmorphic facial features and intellectual developmental disorder (CHDFIDD) without congenital heart defects.

BACKGROUND: Cyclin-dependent kinase 13 plays a critical role in the regulation of gene transcription. Recent evidence suggests that heterozygous variants in CDK13 are associated with a syndromic form of mental deficiency and developmental delay, which is inherited in an autosomal dominant manner. METHODS: A mentally retarded mother (33-year-old) and son (10-year-old boy) in our hospital with CDK13 variant (c.2149 (exon 4) G>A. p.Gly717Arg) were detected by whole-exome sequencing (WES). All published CDK13 variant syndrome cases as of November 11, 2021, were searched, and their clinical information was recorded and summarized. RESULTS: We studied two patients in a Chinese family with a heterozygous constitutional CDK13 variant (c.2149 (exon 4) G>A. p.Gly717Arg), exhibiting the classical characteristics of dysmorphic facial features and intellectual developmental disorder (CHDFIDD, OMIM # 617360), without congenital heart defects. This is the first reported case of an adult patient with a CDK13 variant that gave birth to the next generation with the same variant. Preimplantation genetic testing for monogenic disease (PGT-M) was performed for the proband and her husband with full informed consent and successfully blocked the inheritance of the disease. CONCLUSION: Our study is of great significance for molecular diagnosis and genetic counseling of patients with CDHFIDD and extends the variant spectrum of CDK13.

Fabrication of polymer-based self-assembly nanocarriers loaded with a crizotinib and gemcitabine: potential therapeutics for the treatment of endometrial cancer.

Combination therapy in cancer therapy has been widely used for its positive attributes, such as minimizing the undesirable side effects of chemotherapies and enhancing the therapeutic effects on different cancers. Compared with free drugs crizotinib (CRZ) and gemcitabine (GEM), CRZ@GEM-NPs could remarkably improve the cytotoxicity for endometrial cancer (EC) cells (Ishikawa cells and KLE cells) after treatment with MTT assay. In this study, CRZ and GEM were conjugated to tri-block copolymer poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, known as NPs). The fabricated nanoparticles were characterized by the high-resolution transmission electron microscopy (HR-TEM), and the particles size and zeta potential were investigated by the dynamic light scattering analysis. Further, the morphological features of the EC cell lines were examined by the biochemical staining assays. Morphological changes in endometrial cells morphology revealed by nuclear fragmentation and nuclear condensation (the hallmarks of apoptosis) were noted upon treatment with CRZ@GEM-NPs to the Ishikawa and KLE cancer cells. In addition, resulting in the highest ratio of apoptosis and mitochondrial membrane potential shows the cell death through the mitochondrial membrane potential. In vivo, systemic toxicity studies showed no histological changes and substantial blood biochemical with the near-normal appearance of the organs upon treatment with CRZ@GEM-NPs. Overall, the targeted combination suitable therapeutic framework may be a promising candidate for improved EC therapy.

Exploring the malnutrition status and impact of total parenteral nutrition on the outcome of patients with advanced stage ovarian cancer.

BACKGROUND: Ovarian cancer is a common cancer type in women and is often associated with onset of malnutrition. Total parenteral nutrition (TPN) is a nutritional intervention method that has been reported to have controversial effect on cancer patients. In the present retrospective study, we sought to explore the prevalence of malnutrition assessed by the Nutritional Risk Index (NRI) and its association with survival in advanced stage ovarian cancer patients. We also compared the post-operative outcome of the malnourished patients treated with either TPN or conservative management. RESULTS: A total of 415 patients with advanced stage ovarian cancer were separated into 4 nutrition groups based on the NRI scores. We found that a number of factors were significantly different among the 4 nutrition groups, including age, serum albumin level, BMI and NRI; among which serum albumin level and NRI were identified to be independent predictors of progression-free and overall survival. In the moderately and severely malnourished patients, those who were treated with TPN had significantly shorter hospitalization period, lower serum albumin level and lower BMI after surgery. In addition, serum albumin level, use of TPN and number of patients with complications were closely related to the hospital stay duration. CONCLUSION: Malnutrition status is closely associated with survival of advanced stage ovarian cancer patients. These patients may benefit from TPN treatment for reduced hospitalization, especially with the onset of hypoalbuminemia.

Human endometrium-derived stem cell improves cardiac function after myocardial ischemic injury by enhancing angiogenesis and myocardial metabolism.

BACKGROUND: The human endometrium in premenopausal women is an active site of physiological angiogenesis, with regenerative cells present, suggesting that the endometrium contains adult angiogenic stem cells. In the context of cardiac repair after ischemic injury, angiogenesis is a crucial process to rescue cardiomyocytes. We therefore investigated whether human endometrium-derived stem cells (hEMSCs) can be used for cardiac repair after ischemic injury and their possible underlying mechanisms. METHODS: Comparisons were made between hEMSCs successfully isolated from 22 premenopausal women and human bone marrow mesenchymal stem cells (hBMSCs) derived from 25 age-matched patients. Cell proliferation, migration, differentiation, and angiogenesis were evaluated through in vitro experiments, while the ability of hEMSCs to restore cardiac function was examined by in vivo cell transplantation into the infarcted nude rat hearts. RESULTS: In vitro data showed that hEMSCs had greater proliferative and migratory capacities, whereas hBMSCs had better adipogenic differentiation ability. Human umbilical cord vein endothelial cells, treated with conditioned medium from hEMSCs, had significantly higher tube formation than that from hBMSCs or control medium, indicating greater angiogenic potentials for hEMSCs. In vivo, hEMSC transplantation preserved cardiac function, decreased infarct size, and improved tissue repair post-injury. Cardiac metabolism, assessed by 18F-FDG uptake, showed that 18F-FDG uptake at the infarction area was significantly higher in both hBMSC and hEMSC groups, compared to the PBS control group, with hEMSCs having the highest uptake, suggesting hEMSC treatment improves cardiomyocyte metabolism and survival after injury. Mechanistic assessment of the angiogenic potential for hEMSCS revealed that angiogenesis-related factors angiopoietin 2, Fms-like tyrosine kinase 1, and FGF9 were significantly upregulated in hEMSC-implanted infarcted hearts, compared to the PBS control group. CONCLUSION: hEMSCs, compared to hBMSCs, have greater capacity to induce angiogenesis, and improved cardiac function after ischemic injury.

Total Parenteral Nutrition Treatment Improves the Nutrition Status of Gynecological Cancer Patients by Improving Serum Albumin Level.

BACKGROUND: Malnutrition is often observed in gynecological cancer patients, however its prevalence in these patients remains largely unexplored. Total parenteral nutrition (TPN) is a nutritional intervention method that has controversial treatment outcome on gynecological cancer patients. The present retrospective study is designed to evaluate the nutrition status and TPN treatment outcome on patients diagnosed with endometrial, cervical or ovarian malignant tumors. METHODS: Medical records of a total of 263 patients treated at the First Hospital of Shanxi Medical University, China were included. Nutrition status was assessed by patient-generated subjective global assessment (PG-SGA). Patients were grouped based on nutrition status, cancer type or treatment strategy for clinical characteristic comparison. Multivariable logistic regression analysis was used to identify predictors for malnutrition status and hospital stay duration. RESULTS: Presence of endometrial and cervical cancer, body weight before nutritional intervention and serum albumin level (P < 0.001 for all) were found to be significant predictors for malnutrition status in gynecological cancer patients. In the malnourished patients, those who were treated with TPN had significantly lower serum albumin levels before and after treatment (P < 0.001) and PG-SGA scores after treatment. Also, TPN treatment could significantly increase the serum albumin levels in these patients after 1 week. In addition, shorter hospitalization period was needed for TPN-treated endometrial (P = 0.019) and ovarian (P < 0.001) patients. Moreover, serum albumin levels (P < 0.001), use of TPN treatment (P = 0.025) and nutrition status (P = 0.010) were identified to be independent predictors for hospital stay duration. CONCLUSION: Our results suggest that malnutrition is a significant clinical manifestation in gynecological cancer patients who may benefit from TPN treatment for reduced hospitalization and improved serum albumin levels.

Circadian Clock Protein PERIOD2 Suppresses the PI3K/Akt Pathway and Promotes Cisplatin Sensitivity in Ovarian Cancer.

BACKGROUND: The mortality rate of ovarian cancer is the highest among gynecological tumors. The two factors leading to high mortality of ovarian cancer are late clinical stage and chemotherapy resistance. It is very important to reverse or intervene chemotherapy resistance. Abnormal circadian rhythm is related to the occurrence of tumor, and circadian clock protein PERIOD2 (PER2) acts as a tumor suppressor in cancer; however, little is known about its involvement in chemosensitivity. METHODS: This study aimed to investigate the role and underlying mechanisms of PER2 in ovarian cancer sensitivity to cisplatin. Overexpression and knockdown of PER2 were performed to explore its role in ovarian cancer cell sensitivity to cisplatin both in vitro and in vivo. The protein levels of PI3K, AKT, caspase 3, E-cadherin, and other drug resistance-related molecules were determined in parental SKOV3 and SKOV3/DDP cells as well as in xenograft tumor tissues. RESULTS: Compared with parental cells, SKOV3/DDP cells had dramatically decreased PER2 expression, possibly due to hypermethylation in the PER2 promoter. PER2 overexpression significantly inhibited proliferation while promoting cisplatin-induced apoptosis in SKOV3 and SKOV3/DDP cells. In agreement, PER2-overexpressing SKOV3/DPP cells yielded significantly reduced tumor mass in cisplatin-treated mice compared with control cells. Mechanistically, PER2 overexpression remarkably reduced the protein amounts of PI3K, AKT, and MDR1 while increasing those of caspase 3 and E-cadherin in tumor tissues. Knockdown of PER2 exhibited opposite effects. PER2 overexpression also reduced the serum levels of TNF-α and IL-6 in tumor-bearing mice before the initiation of cisplatin treatment. CONCLUSION: This study suggests that loss of PER2 contributes to cisplatin resistance in SKOV3 cells, possibly by activating the PI3K/AKT pathway and EMT, inhibiting apoptosis, and promoting drug efflux and inflammatory responses. Overexpression of PER2 could reverse these alterations and sensitize both parental SKOV3 and SKOV3/DDP cells to cisplatin.

The circadian rhythm and core gene Period2 regulate the chemotherapy effect and multidrug resistance of ovarian cancer through the PI3K signaling pathway.

BACKGROUND: Ovarian cancer is the most lethal cancer in the female reproductive system. It has been shown that 'time chemotherapy' of ovarian cancer has an important impact on the chemotherapy effect and prognosis of patients, but the specific mechanism is not known. METHODS: We designed a case-control study in strict accordance with epidemiological principles. We collected resection samples of ovarian cancer patients who worked night-shifts and those who did not, and analyzed the differences in protein expression. Through construction of a normal/circadian-rhythm disorder model of ovarian cancer in nude mice, we explored the molecular mechanism of a 'biological clock' rhythm on treatment of ovarian cancer. RESULTS: Expression of interleukin (IL)-6, programmed cell death receptor-1 (PD-1) and programmed death ligand 1 (PD-L1) increased, and expression of tumor necrosis factor (TNF)-α, Period 1 (Per1) and Period 2 (Per2) decreased in the night-shift group. Methylation of CpG islands in the promoter of Per2 could result in its decreased expression in SKOV3/DDP (Cisplatin) cells. Dysrhythmia of the circadian clock: (i) had a negative effect on the chemotherapy effect against ovarian cancer; (ii) affected expression of immune factors and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. CONCLUSION: The Per2 gene can affect the drug resistance of ovarian cancer by inhibiting the PI3K/Akt signaling pathway and then acting on its downstream drug-resistance factors, thereby providing a new target for ovarian cancer treatment.

Associated analysis of PER1/TUBB2B with endometrial cancer development caused by circadian rhythm disorders.

Endometrial cancer (EC) is one of the most common gynecologic malignancies, and the incidence rate of night shift among women workers is higher than that in the general population. Circadian rhythm disorder, mainly rhythm gene, is related to various tumor onset, including EC. This study described the sleep/night-shift features of EC patients, explored the mechanism of the circadian clock gene PER and investigated prognostic and functional values of Per1 caused by night shift. A total of 619 subjects were enrolled and divided into two groups according to night-shift duties (rhythm group and control group), analyzed for clinical risk factors and night shift features of endometrial carcinoma. Then samples were randomly selected for sequencing and western blot were performed, and the function of overexpressed PER1 in ishikawa cells was explored. We noticed that severer EC patients experienced night-shift more frequently and with longer durations. A total of 58,174 differentially expressed genes were discovered, mainly rhythm genes and related to up and downstream regulatory genes. Western blot showed that the rhythm group had elevated protein expression of BCAS4, TUBB2B and RSPO4, and decreased expression of PER1 and PER2 in night-shift. In TCGA-EC datasets, PER1 was decreased in the EC patients with a significantly positive correlation with PER2, and higher PER1 expression indicated longer survival, opposite to TUBB2B. The research of overexpressing PER1 gene in EC ishikawa cells found that PER1 can promote apoptosis, expression of TNF-a, IL-6 and PD-1/PD-L1, inhibit the tumor invasion and expression of TUBB2B gene. Together, EC severity was associated with night-shift and rhythm disorders. The rhythm relating factors PER1, TUBB2B and tumor immune factors may regulate the mechanisms of EC onset and progression.