ABSTRACT
Purpose: To study the effects of prior pelvic radiotherapy on bone marrow suppression in recurrent cervical cancer patients during chemotherapy. Methods and materials: The cases of 129 patients with recurrent cervical cancer were reviewed, of which 77 patients had pelvic radiotherapy history and another 52 patients with no pelvic radiotherapy history were used as control group. All patients received a chemotherapy regimen of paclitaxel combined with carboplatin (TC) per 21 days for 5-6 times. Hematologic toxicity, including count of red blood cell, white blood cell and neutrophil cell and platelet, was defined by using Common Terminology Criteria for Adverse Events (version 4.0). The relationship between age, body mass index, disease free survival, pathological types, FIGO stages, radiotherapy methods and the degree of bone marrow suppression during chemotherapy was statistically analyzed, respectively, for all recurrent cervical cancer patients. Results: Among 77 patients with previous radiotherapy history, 73 recurrent patients (94.8%) had bone marrow suppression followed by chemotherapy. Recurrent cervical cancer patients without prior radiotherapy (n=52) showed a lower risk of bone marrow suppression followed by chemotherapy (n=39, 75.0%, P < 0.05). The probability of severe bone marrow suppression (grade III-IV) after chemotherapy in recurrent cervical patients with or without history of radiotherapy was 41.6% and 13.5%, respectively (P < 0.05). In univariate analysis, radiotherapy methods were associated with the incidence of grade III-IV bone marrow suppression in recurrent cervical cancer patients (P=0.005). In multivariate analysis, radiotherapy methods and extended-field radiotherapy were the risk factor of grade III-IV bone marrow suppression (χ2=16.975, P=0.001). No significant differences in the counts of white blood cell, hemoglobin and platelet were observed before chemotherapy at relapse between patients with and without prior radiotherapy. Reduction of white blood cell counts, absolute value of neutrophil cell and platelet counts composited majority type of grade III and IV bone marrow suppression. Conclusions: The prior pelvic radiotherapy significantly increased the incidence of bone marrow suppression during chemotherapy in recurrent cervical cancer patients. When treating recurrent cervical cancer patients with chemotherapy who had prior radiotherapy, especially for those experienced external beam radiation therapy, essential attention and timely intervention are recommended to ensure completion of chemotherapy and clinical efficacy.
Subject(s)
Bone Marrow , Neoplasm Recurrence, Local , Uterine Cervical Neoplasms , Humans , Female , Uterine Cervical Neoplasms/radiotherapy , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/drug therapy , Middle Aged , Neoplasm Recurrence, Local/pathology , Bone Marrow/radiation effects , Bone Marrow/drug effects , Bone Marrow/pathology , Adult , Aged , Carboplatin/administration & dosage , Carboplatin/therapeutic use , Carboplatin/adverse effects , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Pelvis/radiation effects , Pelvis/pathology , Retrospective Studies , Disease-Free SurvivalABSTRACT
Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here, we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effectively reversed the effects of palmitic acid on cell proliferation, apoptosis, and invasive capacity in endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation and invasion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer.
Subject(s)
Apoptosis , Cell Proliferation , Endometrial Neoplasms , Lipid Droplets , Palmitic Acid , Female , Palmitic Acid/pharmacology , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/pathology , Humans , Lipid Droplets/metabolism , Lipid Droplets/drug effects , Animals , Cell Proliferation/drug effects , Mice , Apoptosis/drug effects , Cell Line, Tumor , Diacylglycerol O-Acyltransferase/metabolism , Mice, TransgenicABSTRACT
Ascorbate (vitamin C) is an essential vitamin for the human body and participates in various physiological processes as an important coenzyme and antioxidant. Furthermore, the role of ascorbate in the prevention and treatment of cancer including gynecological cancer has gained much more interest recently. The bioavailability and certain biological functions of ascorbate are distinct in males versus females due to differences in lean body mass, sex hormones, and lifestyle factors. Despite epidemiological evidence that ascorbate-rich foods and ascorbate plasma concentrations are inversely related to cancer risk, ascorbate has not demonstrated a significant protective effect in patients with gynecological cancers. Adequate ascorbate intake may have the potential to reduce the risk of human papillomavirus (HPV) infection and high-risk HPV persistence status. High-dose ascorbate exerts antitumor activity and synergizes with chemotherapeutic agents in preclinical cancer models of gynecological cancer. In this review, we provide evidence for the biological activity of ascorbate in females and discuss the potential role of ascorbate in the prevention and treatment of ovarian, endometrial, and cervical cancers.
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OBJECTIVE: Overweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential benefits of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC. METHODS: Lkb1fl/flp53fl/fl mice were fed HFD or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on a HFD or switched to a LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial cancer, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed. RESULTS: HFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment. CONCLUSION: In Lkb1fl/flp53fl/fl mice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as an EC prevention and treatment strategies in overweight/obesity women.
Subject(s)
Diet, High-Fat , Endometrial Neoplasms , Mice, Transgenic , Obesity , Paclitaxel , Animals , Female , Paclitaxel/pharmacology , Paclitaxel/administration & dosage , Endometrial Neoplasms/pathology , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/metabolism , Mice , Obesity/metabolism , Diet, High-Fat/adverse effects , Caloric Restriction/methods , Disease Models, Animal , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/administration & dosageABSTRACT
Objective: In current most observational studies, the prognosis of cervical adenocarcinoma is worse than that of cervical squamous cell carcinoma. However, most of the current studies are holistic and lack more detailed staging and grouping analysis of the prognosis of the two types of cervical tumors. Patients and Methods: Inclusion from the SEER database of stage IIB-IVA cervical squamous cell carcinoma and cervical adenocarcinoma patients who did not undergo surgery from 2000 to 2019, underwent radiotherapy/chemotherapy/radiotherapy and chemotherapy/no treatment, and then propensity score matching (PSM) was performed to eliminate confounding factors between cervical squamous cell carcinoma and cervical adenocarcinoma patients with the same stage and treatment method. After matching the original data and propensity score, logarithmic rank test and chi square test were used to evaluate the survival benefits of different stages and treatment methods for patients using Kaplan Meier curve. The prognosis of two types of cervical tumors under the same treatment method was compared, and factors that may cause poor prognosis were analyzed, excluding confounding factors. Results: A total of 10,057 patients were included in this study, and survival analysis showed a significant correlation between the treatment method used and patient prognosis (P<0.05). However, for patients who received radiotherapy or no special treatment, OS and CSS were only related to tumor stage and not to tumor type. In patients undergoing radiotherapy and chemotherapy, the OS and CSS of stage IIIA and IVA patients are not related to tumor pathological characteristics, while the OS of stage IIB patients is not related to tumor properties after PSM. Conclusion: In patients undergoing radiotherapy and chemotherapy, the OS and CSS of stage IIIA and IVA patients were not related to histological type, while the OS of stage IIB patients was not related to histological type after PSM.
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Lipid metabolism is widely reprogrammed in tumor cells. Lipid droplet is a common organelle existing in most mammal cells, and its complex and dynamic functions in maintaining redox and metabolic balance, regulating endoplasmic reticulum stress, modulating chemoresistance, and providing essential biomolecules and ATP have been well established in tumor cells. The balance between lipid droplet formation and catabolism is critical to maintaining energy metabolism in tumor cells, while the process of energy metabolism affects various functions essential for tumor growth. The imbalance of synthesis and catabolism of fatty acids in tumor cells leads to the alteration of lipid droplet content in tumor cells. Diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2, the enzymes that catalyze the final step of triglyceride synthesis, participate in the formation of lipid droplets in tumor cells and in the regulation of cell proliferation, migration and invasion, chemoresistance, and prognosis in tumor. Several diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 inhibitors have been developed over the past decade and have shown anti-tumor effects in preclinical tumor models and improvement of metabolism in clinical trials. In this review, we highlight key features of fatty acid metabolism and different paradigms of diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 activities on cell proliferation, migration, chemoresistance, and prognosis in tumor, with the hope that these scientific findings will have potential clinical implications.
Subject(s)
Diacylglycerol O-Acyltransferase , Neoplasms , Animals , Humans , Diacylglycerol O-Acyltransferase/genetics , Diacylglycerol O-Acyltransferase/metabolism , Triglycerides/metabolism , Lipid Metabolism , Lipogenesis , Cell Proliferation , Mammals/metabolismABSTRACT
OBJECTIVE: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells. METHODS: Cell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting. RESULTS: High-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells. CONCLUSIONS: Ascorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.
Subject(s)
Apoptosis , Ascorbic Acid , Carboplatin , Cystadenocarcinoma, Serous , Drug Synergism , Uterine Neoplasms , Ascorbic Acid/pharmacology , Ascorbic Acid/administration & dosage , Humans , Carboplatin/pharmacology , Carboplatin/administration & dosage , Female , Cell Line, Tumor , Uterine Neoplasms/drug therapy , Uterine Neoplasms/pathology , Uterine Neoplasms/metabolism , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/pathology , Cystadenocarcinoma, Serous/metabolism , Apoptosis/drug effects , Cell Proliferation/drug effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Reactive Oxygen Species/metabolism , DNA Damage/drug effects , Antioxidants/pharmacology , Antioxidants/administration & dosageABSTRACT
BACKGROUND: Cervical cancer survivors can experience vaginal length shortening, vaginal stenosis, vaginal elasticity deterioration, sexual frequency reduction and sexual dysfunction. This prospective, uncontrolled, monocentric clinical interventional study aimed to evaluate the effect of vaginal dilation therapy on vaginal condition and sexual function of cervical cancer survivors who had not received timely vaginal dilation. METHODS: A total of 139 patients completed the study. They received 6 months of vaginal dilation therapy. We evaluated their vaginal elasticity, vaginal diameter, vaginal length and sexual function before and after vaginal dilation therapy. Their vaginal conditions were evaluated by customised vaginal moulds, and the sexual function was assessed by female sexual function index. The SPSS 25 software was used to analyse all the data. RESULTS: Age, vaginal diameter and sexual intercourse frequency before diagnosis were significantly associated with female sexual dysfunction of the patients after cancer treatment. Vaginal dilation therapy improved vaginal stenosis, vaginal length and sexual function in all the patients; however, the vaginal elasticity and incidence of sexual dysfunction did not improve significantly. Sexual intercourse frequency before diagnosis, vaginal elasticity, time interval from last treatment and treatment modalities were significantly associated with the change in female sexual function index score before and after vaginal dilation therapy. Patients with a time interval from the last treatment less than 24 months or those who had moderate or good vaginal elasticity, benefitted more from vaginal dilatation therapy. CONCLUSIONS: Cervical cancer survivors who had not received timely vaginal dilation still benefitted from vaginal dilation therapy, irrespective of the treatment methods they received. Moreover, vaginal dilation therapy should be performed as early as possible after cervical cancer treatment.
Cervical cancer survivors can experience vaginal condition deterioration and sexual dysfunction after treatment. Vaginal dilation can help improve vaginal stenosis, vaginal length and sexual function of these patients. However, some medical institutions in China do not provide timely vaginal dilation for this population. This study aimed to explore whether vaginal dilation was still effective for cervical cancer survivors who had not received timely vaginal dilation. The results showed that these patients still benefitted from vaginal dilation, irrespective of the treatment methods they received. Patients with a time interval from the last treatment less than 24 months or those who had moderate or good vaginal elasticity, benefitted more from vaginal dilation. The findings of the study is an indication to developing countries that more attention should be given to sexual issue of cervical cancer survivors in clinical practice, and vaginal dilation therapy should be performed promptly after treatment.
Subject(s)
Cancer Survivors , Uterine Cervical Neoplasms , Humans , Female , Uterine Cervical Neoplasms/therapy , Vagina , Constriction, Pathologic/etiology , Constriction, Pathologic/therapy , Dilatation/adverse effects , Prospective Studies , ElasticityABSTRACT
Objective: Overweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential abilities of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC. Methods: Lkb1 fl/fl p53 fl/fl mice were fed high-fat diet (HFD) or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on HFD or switched to LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial tumor, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed. Results: HFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment. Conclusion: In Lkb1 fl/fl p53 fl/fl mice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as a EC prevention strategy in women with overweight/obesity.
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Premature ovarian insufficiency (POI) refers to the decline of ovarian function before the age of 40. POI causes a reduction in or loss of female fertility, accompanied by different degrees of menopausal symptoms, which increases the risk of chronic diseases related to early menopause and seriously affects patients' quality of life and health. It is conservatively estimated that at least one million prepubertal girls and women of reproductive age in China are at risk of iatrogenic POI caused by radiotherapy and chemotherapy every year. With the development of medical technology and the breakthrough of scientific and technological advances, preventing and treating iatrogenic POI have become possible. International and national guidelines consider cryopreserved ovarian tissue transplantation to be the most promising method of preserving the ovarian function and fertility of prepubertal girls and women of reproductive age who cannot delay radiotherapy and chemotherapy. In order to guide the clinical application of ovarian tissue cryopreservation and transplantation technology in China, the Guideline Working Group finally included 14 scientific questions and 18 recommendations through a questionnaire survey, field investigation, and consultation of a large number of Chinese and English literature databases in order to provide a reference for colleagues in clinical practice.
Subject(s)
Fertility Preservation , Menopause, Premature , Primary Ovarian Insufficiency , Female , Humans , Quality of Life , Cryopreservation , Primary Ovarian Insufficiency/etiology , Primary Ovarian Insufficiency/prevention & control , Iatrogenic Disease/prevention & controlABSTRACT
BACKGROUND: Deficits in response inhibition are associated with numerous psychiatric disorders. Previous studies have revealed the crucial role of the right inferior frontal gyrus (rIFG), pre-supplementary motor area (preSMA), and beta activity in these brain regions in response inhibition. Multi-channel transcranial alternating current stimulation (tACS) has garnered significant attention for its ability to modulate neural oscillations in brain networks. In this study, we employed multi-channel tACS targeting rIFG-preSMA network to investigate its impact on response inhibition in healthy adults. METHODS: In Experiment 1, 70 healthy participants were randomly assigned to receive 20 Hz in-phase, anti-phase, or sham stimulation over rIFG-preSMA network. Response inhibition was assessed using the stop-signal task during and after stimulation, and impulsiveness was measured via the Barratt Impulsiveness Scale. Additionally, 25 participants received stimulation at the left supraorbital area to account for potential effects of the "return" electrode. Experiment 2, consisting of 25 participants, was conducted to validate the primary findings of Experiment 1, including both in-phase and sham stimulation conditions, based on prior estimations derived from the results of Experiment 1. RESULTS: In Experiment 1, we found that in-phase stimulation significantly improved response inhibition compared with sham stimulation, whereas anti-phase stimulation did not. These findings were consistently replicated in Experiment 2. We also conducted an exploratory analysis of the multi-channel tACS impact, revealing that its effects primarily emerged during the post-stimulation phase. Furthermore, individuals with higher baseline attentional impulsiveness showed greater improvements in the in-phase stimulation group. CONCLUSIONS: These results demonstrate that in-phase beta-tACS over rIFG-preSMA network can effectively improve response inhibition in healthy adults and provides a new potential treatment for patients with deficits in response inhibition.
Subject(s)
Motor Cortex , Transcranial Direct Current Stimulation , Adult , Humans , Transcranial Direct Current Stimulation/methods , Motor Cortex/physiology , Brain , Prefrontal CortexABSTRACT
OBJECTIVE: This study aimed to evaluate the effect of vaginal dilation therapy on vaginal length, vaginal stenosis, vaginal elasticity, and sexual function of endometrial cancer patients treated with radiotherapy after surgery. METHODS: A total of 117 women were enrolled in this study. They received 6 months of vaginal dilation therapy. We evaluated their vaginal length, vaginal diameter, vaginal elasticity, and sexual function before radiotherapy, after radiotherapy, and after 6 months of vaginal dilation therapy. Their vaginal condition was assessed by customized vaginal dilating molds. Their sexual function was assessed by female sexual function index. The SPSS 25 software was used to analyze all the data. RESULTS: According to multivariate analysis, vaginal diameter (ß = 0.300, 95% CI [0.217-1.446], p = 0.010) and sexual intercourse frequency before diagnosis (ß = 0.424, 95% CI [0.164-0.733], p = 0.006) were significantly correlated with female sexual function after radiotherapy. Vaginal dilation therapy helped increase vaginal length, improve vaginal stenosis and sexual function (p < 0.05), though most of the figures at the end of the intervention did not fully return to those before radiotherapy. Noticeably, vaginal dilation therapy was ineffective in improving vaginal elasticity and the incidence rate of female sexual dysfunction (p > 0.05). Moreover, patients with medium or good vaginal elasticity benefited more from vaginal dilation therapy than patients with poor vaginal elasticity (p < 0.05). CONCLUSION: Vaginal dilation therapy should be carried out timely and preventatively in endometrial cancer patients treated with radiotherapy after surgery to improve their vaginal condition and sexual function.
Subject(s)
Endometrial Neoplasms , Mental Disorders , Humans , Female , Constriction, Pathologic/therapy , Dilatation/adverse effects , Vagina/surgery , Endometrial Neoplasms/radiotherapy , Endometrial Neoplasms/surgeryABSTRACT
Reprogramming of fatty acid metabolism promotes cell growth and metastasis through a variety of processes that stimulate signaling molecules, energy storage, and membrane biosynthesis in endometrial cancer. Oleic acid is one of the most important monounsaturated fatty acids in the human body, which appears to have both pro- and anti-tumorigenic activities in various pre-clinical models. In this study, we evaluated the potential anti-tumor effects of oleic acid in endometrial cancer cells and the LKB1fl/flp53fl/fl mouse model of endometrial cancer. Oleic acid increased lipogenesis, inhibited cell proliferation, caused cell cycle G1 arrest, induced cellular stress and apoptosis, and suppressed invasion in endometrial cancer cells. Targeting of diacylglycerol acyltransferases 1 and 2 effectively increased the cytotoxicity of oleic acid. Moreover, oleic acid significantly increased the expression of wild-type PTEN, and knockdown of PTEN by shRNA partially reversed the anti-proliferative and anti-invasive effects of oleic acid. Inhibition of the AKT/mTOR pathway by ipatasertib effectively increased the anti-tumor activity of oleic acid in endometrial cancer cells. Oleic acid treatment (10 mg/kg, daily, oral) for four weeks significantly inhibited tumor growth by 52.1% in the LKB1fl/flp53fl/fl mice. Our findings demonstrated that oleic acid exhibited anti-tumorigenic activities, dependent on the PTEN/AKT/mTOR signaling pathway, in endometrial cancer.
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BACKGROUND/AIM: Endometriosis is an estrogen-dependent disease characterized by the ectopic implantation and growth of endometrial tissue outside the uterus. Endometrial stromal cells (ESCs) play a crucial role in the pathogenesis of endometriosis. Epithelial-mesenchymal transition (EMT) has recently been described in endometriosis and was induced by estrogen. Metformin has been shown to inhibit EMT in various diseases, but its role in endometriosis remains unclear. MATERIALS AND METHODS: We collected endometrial tissue samples from patients with endometriosis and healthy controls and isolated primary ESCs. We performed gene expression analysis using the Gene Expression Omnibus (GEO) dataset and validated the results by immunohistochemistry in tissue samples. We also assessed the effects of metformin on the proliferation, migration and invasion of ectopic ESCs (EESCs) by Cell Counting Kit-8 and Transwell migration and invasion assays, respectively. We analyzed the protein expression of EMT-related markers (N-cadherin, vimentin, twist, and snail) and ß-catenin by Western blotting and immunohistochemistry. RESULTS: We found that vimentin was highly expressed in ectopic endometrial tissues compared to normal endometrial tissues. Metformin treatment inhibited the proliferation, migration and invasion of EESCs in a dose-dependent manner. Metformin treatment also downregulated the expression of EMT-related markers and reduced the expression and nuclear translocation of ß-catenin in EESCs. CONCLUSION: Our results suggest that metformin inhibits estrogen-induced EMT and regulates the expression of ß-catenin in EESCs. This study provides new insights into the potential therapeutic role of metformin in endometriosis.
Subject(s)
Endometriosis , beta Catenin , Female , Humans , beta Catenin/genetics , Vimentin/metabolism , Endometriosis/drug therapy , Endometriosis/genetics , Epithelial-Mesenchymal Transition/genetics , Cell Movement/genetics , Stromal Cells/metabolism , Estrogens/pharmacology , Estrogens/metabolism , Endometrium/pathology , Cell ProliferationABSTRACT
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B cell malignancies; however, some patients fail to respond due to poor autologous T cell fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of CTLA4 in preclinical models of leukemia and myeloma improved CAR T cell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR T cells. Mechanistically, CTLA4 deficiency permitted unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under conditions of high antigen load. In clinical studies, deletion of CTLA4 rescued the function of T cells from patients with leukemia that previously failed CAR T cell treatment. Thus, selective deletion of CTLA4 reinvigorates dysfunctional chronic lymphocytic leukemia (CLL) patient T cells, providing a strategy for increasing patient responses to CAR T cell therapy.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Receptors, Chimeric Antigen , Humans , Receptors, Antigen, T-Cell/metabolism , CTLA-4 Antigen/genetics , CTLA-4 Antigen/metabolism , T-Lymphocytes , Immunotherapy, Adoptive , Antigens, CD19ABSTRACT
PURPOSE: To investigate the prognostic indicators, develop and verify nomograms for predicting overall survival (OS) and cancer-specific survival (CSS) in elderly patients with uterine serous carcinoma (USC). METHODS: Data of eligible USC patients aged ≥ 65 years from 2004 to 2015 in the Surveillance, Epidemiology and End Results (SEER) database were collected for retrospective analysis. X-tile software was used to assess the optimal cut-off values. Univariate and multivariate Cox regression analyses were performed to explore the prognostic factors. Nomograms were developed to predict the probability of 1-, 3- and 5-year OS and CSS. Concordance indexes (c-index), receiver operating characteristic analysis and calibration curves were used to evaluate the model. Decision curve analysis (DCA) was introduced to examine the clinical value of the models. RESULTS: Age, Federation International of Gynecology and Obstetrics stage, N stage, tumor size, number of lymph nodes resected, and adjuvant therapy were independent prognostic factors for OS and CSS. The C-indexes were 0.736 (OS), 0.754 (CSS) in the training set and 0.731 (OS), 0.759 (CSS) in the validation set. The area under the curve (AUCs) of OS and CSS for 1-, 3-, and 5-years all exceeded 0.75. The calibration plots for the probability of survival were in good agreement. As shown in DCA curves, the nomograms showed better discrimination power and higher net benefits than the 6th American Joint Committee on Cancer staging system. CONCLUSIONS: The nomograms constructed based on prognostic risk factors could individually predict the prognosis of elderly USC patients and provide a reference for clinical decision-making.
Subject(s)
Cystadenocarcinoma, Serous , Nomograms , Aged , Female , Pregnancy , Humans , Retrospective Studies , Prognosis , Area Under Curve , Cystadenocarcinoma, Serous/therapy , SEER Program , Neoplasm StagingABSTRACT
OBJECTIVES: The effect of telomerase inhibitor BIBR1532 on endometriotic cells was investigated to explore the inhibitory effect of targeting telomerase on endometriosis. DESIGN: In vitro primary cell culture study. Participants/Materials: Primary endometrial cells derived from eutopic and ectopic endometrium in patients with endometriosis. SETTING: The study was conducted in the university hospital. METHODS: Paired eutopic and ectopic endometrial cells were collected from 6 patients from January 2018 to July 2021. A TRAP assay was performed to detect the telomerase activity of the cells. MTT, cell cycle, apoptosis, migration, and invasion assays were performed to study the inhibitory effect of BIBR1532. Enrichment analysis was performed to identify the key pathways involved in endometriosis progression and telomerase action. Then, Western blotting was used to investigate the expression of related proteins. RESULTS: BIBR1532 treatment significantly inhibited the growth of eutopic and ectopic endometrial cells, with apoptosis and cell cycle signaling involved. Migration and invasion, important characteristics for the establishment of ectopic lesions, were also inhibited by BIBR1532. The MAPK signaling cascade, related to telomerase and endometriosis, was decreased in eutopic and ectopic endometrial stromal cells with the treatment of BIBR1532. LIMITATIONS: The severe side effects of telomerase inhibitors might be the main obstacle to clinical application, so it is necessary to find better drug delivery methods in vivo. CONCLUSIONS: The telomerase inhibitor BIBR1532 affects endometrial cell proliferation, migration, and invasion in endometriosis.
Subject(s)
Endometrial Hyperplasia , Endometriosis , Telomerase , Female , Humans , Endometriosis/pathology , Telomerase/metabolism , Telomerase/pharmacology , Aminobenzoates/metabolism , Aminobenzoates/pharmacology , Endometrial Hyperplasia/pathology , Endometrium/pathology , Cell Proliferation , Stromal Cells/metabolismABSTRACT
Ovarian clear cell carcinomas (OCCCs) are a subtype of ovarian epithelial tumors that arise from the malignant transformation of endometriosis (EMs). These tumors have distinctive molecular features, high malignant potential, low sensitivity to conventional chemotherapy, and poor prognosis. The process and mechanism of malignant transformation from EMs to OCCCs remains elusive. Elucidation of the molecular pathogenesis and drug resistance mechanism of OCCCs is essential to guide the clinical management and basic research of this disease. This paper provides a comprehensive review of the mechanisms of malignant transformation, genomic characteristics, drug resistance and targeted therapy of OCCCs. The review aims to provide new insights for the clinical management of advanced OCCCs.
Subject(s)
Adenocarcinoma, Clear Cell , Endometriosis , Ovarian Neoplasms , Female , Humans , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Carcinoma, Ovarian Epithelial , Adenocarcinoma, Clear Cell/genetics , Adenocarcinoma, Clear Cell/therapy , Adenocarcinoma, Clear Cell/pathology , Endometriosis/drug therapy , Endometriosis/genetics , GenomicsABSTRACT
Carbon monoxide (CO) is a colourless, odourless, and toxic gas. Long-term exposure to high concentrations of CO causes poisoning and even death; therefore, CO removal is particularly important. Current research has focused on the efficient and rapid removal of CO via low-temperature (ambient) catalytic oxidation. Gold nanoparticles are widely used catalysts for the high-efficiency removal of high concentrations of CO at ambient temperature. However, easy poisoning and inactivation due to the presence of SO2 and H2S affect its activity and practical application. In this study, a bimetallic catalyst, Pd-Au/FeOx/Al2O3, with a Au:Pd ratio of 2:1 (wt%) was formed by adding Pd nanoparticles to a highly active Au/FeOx/Al2O3 catalyst. Its analysis and characterisation proved that it has improved catalytic activity for CO oxidation and excellent stability. A total conversion of 2500 ppm of CO at -30 °C was achieved. Furthermore, at ambient temperature and a volume space velocity of 13,000 h-1, 20,000 ppm CO was fully converted and maintained for 132 min. Density functional theory (DFT) calculations and in situ FTIR analysis revealed that Pd-Au/FeOx/Al2O3 exhibited stronger resistance to SO2 and H2S adsorption than the Au/FeOx/Al2O3 catalyst. This study provides a reference for the practical application of a CO catalyst with high performance and high environmental stability.
ABSTRACT
Purpose: Few studies have explored the association between sleep quality and depressive symptoms in perinatal women from the second trimester to the postpartum period. This study aims to explore this relationship using a longitudinal design. Patients and Methods: Participants were enrolled at 15 gestational weeks. Demographic information was collected. Perinatal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS). Sleep quality was measured employing the Pittsburgh Sleep Quality Index (PSQI) at five timepoints from enrollment to three months postpartum. Overall, 1416 women completed the questionnaires at least thrice. A Latent Growth Curve (LGC) model was performed to identify the relationship between the trajectories of perinatal depressive symptoms and sleep quality. Results: Of the participants, 23.7% screened positive at least once on the EPDS. The perinatal depressive symptoms trajectory, fitted by the LGC model, decreased at early pregnancy and increased from 15 gestational weeks to three months postpartum. The intercept of sleep trajectory positively affected the intercept of perinatal depressive symptoms' trajectory; the slope of sleep trajectory positively affected both the slope and the quadratic coefficient of perinatal depressive symptoms' trajectory. Conclusion: The trajectory of perinatal depressive symptoms increased from 15 gestational weeks to three months postpartum following a quadratic trend. Poor sleep quality was associated with depression symptoms beginning at the onset of pregnancy. Moreover, rapidly declining sleep quality could be a significant risk factor for perinatal depression (PND). These findings call for greater attention to perinatal women who report poor and persistently deteriorating sleep quality. Additional sleep-quality evaluations, depression assessments, and referrals to mental health care providers may benefit these women and support PND prevention, screening, and early diagnosis.