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Objective: This study aimed to explore the neurological adverse events of oxaliplatin through the Food and Drug Administration Adverse Event Reporting System (FAERS) database and to provide reference for safe clinical drug use. Methods: The adverse events report data of oxaliplatin from the first quarter of 2019 (1 January 2019) to the third quarter of 2023 (30 September 2023) were extracted from FAERS database, and the adverse events signal intensity was determined using the reporting odds ratio, proportional reporting ratio, information component, and empirical Bayes geometric mean methods. Time-to-onset and univariate logistic regression analysis were performed to describe the characteristics and risk factors of oxaliplatin-associated neurological adverse events. Results: A total of 4,471 cases of oxaliplatin-associated neurological adverse events were identified, with 318 neurological adverse events being documented, among which 87 adverse events satisfied the thresholds of four methodologies. The median time-to-onset of oxaliplatin-associated neurological adverse events was 2 days (interquartile range 0-36 days). Among the factors significantly influencing oxaliplatin-related neurological adverse events, male sex and combination medication decreased the risk of neurological adverse events, while higher cumulative dose increased the risk. Conclusion: The real-world neurotoxicity spectrum of oxaliplatin and its characteristics and influencing factors were obtained through data mining of FAERS, providing valuable insights for healthcare professionals to effectively manage the risk of neurological adverse events associated with oxaliplatin in clinical practice.
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Background: Sotorasib has been approved for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Due to the limitations of clinical trials, potential adverse events (AEs) and long-term safety issues cannot be detected. The presented study aimed to evaluate sotorasib-associated AEs using the FDA Adverse Event Reporting System (FAERS) database. Methods: Post-marketing AE reports of sotorasib in the database were collected for analysis. Disproportionality analyses, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC) and empirical bayes geometric mean (EBGM) algorithms, were performed to mine the signals of sotorasib-associated AEs. The median duration, quartiles and the Weibull shape parameter (WSP) test were used to assess the onset time data. Results: The database contained 1538 cases of sotorasib as primary suspect (PS), with 27 signals detected, scattering in 5 SOCs. The SOC of hepatobiliary disorders (182, ROR 4.48, PRR 4.07, IC 2.02, EBGM 4.07) met the four methodological thresholds. The median onset time of sotorasib-associated AEs was 42 days (interquartile range [IQR] 14-86.75 days). Different SOCs had different types of risk over time. Conclusion: After obtaining marketing authorization, the study identified all potentially relevant adverse event (AE) signals expected to have a reporting frequency higher than anticipated and characterized them during sotorasib treatment.
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Hinokiresinol synthase (HRS) from Asparagus officinalis consists of two subunits, α and ß, and catalyzes an unusual decarboxylative rearrangement reaction of 4-coumaryl 4-coumarate to generate (Z)-hinokiresinol with complete stereoselectivity. Herein, we describe the mechanism of rearrangement catalysis and the role played by the heterodimeric HRS, through structural and computational analyses. Our results suggest that the HRS reaction is unlikely to proceed via the previously hypothesized Claisen rearrangement mechanism. Instead, we propose that the 4-coumaryl 4-coumarate substrate is first cleaved into coumarate and an extended p-quinone methide, which then recombine to generate a new C-C bond. These processes are facilitated by proton transfers mediated by the basic residues (α-Lys164, α-Arg169, ß-Lys168, and ß-Arg173) in the cavity at the heterodimer interface. The active site residues, α-Asp165, ß-Asp169, ß-Trp17, ß-Met136, and ß-Ala171, play crucial roles in controlling the regioselectivity of the coupling between the fragmented intermediates as well as the stereoselectivity of the decarboxylation step, leading to the formation of the (Z)-hinokiresinol product.
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BACKGROUND: Rucaparib has been approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. However, the long-term safety of rucaparib in large sample population was unknown. The presented study aimed to evaluate rucaparib-associated adverse events (AEs) according to the real-world pharmacovigilance database. METHODS: Disproportionality analysis was conducted to assess the association between rucaparib and its AEs. Data were collected from the international pharmacovigilance database of US FDA Adverse Event Reporting System (FAERS) between January 2017 and June 2022. The characteristics of rucaparib-related AEs, and the onset time were further analyzed. RESULTS: A total of 9,296,694 AE reports were recorded in the FAERS during the study period, among which 7,087 reports were associated with rucaparib. About 135 rucaparib-related AE signals in 15 system organ class (SOCs) were identified. The most common AEs included anaemia, thrombocytopenia, nausea, vomiting, fatigue, blood creatinine increase, alanine aminotransferase increase, and aspartate aminotransferase increase, which were listed in the label for rucaparib. Of note, 21 new and unexpected significant AEs that off-label were also found in our study, such as preferred term (PTs) of intestinal obstruction, gastrooesophageal reflux disease, blood iron decreased, dehydration, and hypersomnia. The median onset time of rucaparib-related AEs was 12 days (interquartile range [IQR] 1-62 days), and had early failure types. CONCLUSION: Our study demonstrated potential new AEs of rucaparib, and further studies were expected to confirm the results.
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Indoles , Pharmacovigilance , Adult , Female , United States , Humans , Indoles/adverse effects , Databases, Factual , United States Food and Drug AdministrationABSTRACT
Preeclampsia (PE) is a common obstetric syndrome with an unclear etiology and pathogenesis. The study here aimed to investigate the role of Yin Yang 1 (YY1) in PE, and to reveal any YY1-regulated mechanisms in PE. Peripheral blood, placenta, and endometrial tissues of PE patients, healthy volunteers, and patients who had undergone an elective Cesarean section and had a scarred uterus (control group) were collected for analyses. Rat PE models were established by lipopolysaccharide induction. Subsets of these rats were then made to over-express YY1. At 18 d after the PE was established, urine, blood, and placental tissues from all rats were collected. Levels of regulatory-T (Treg) and helper T-type 17 (TH17) cells in both human and rat blood were measured by flow cytometry. ELISA kits were used to evaluate blood levels of inflammatory factors (i.e. IL-6, IL-10, and IL-17) as well. RT-qPCR and Western blot assays were performed to quantify levels of forkhead box P3 (Foxp3), retinoic acid-related orphan receptor C (RORc), and YY1 in the human and rat placenta and endometrial tissues. Expressions of PI3K/AKT pathway-related proteins were also evaluated by Western blots. The results indicated that the PE patients, relative to levels in control group and the healthy control subjects, had decreased circulating levels of Treg cells/increased TH17 cells; tissues from these patients also had relatively-decreased FoxP3 mRNA and protein expressions and elevated RORc mRNA and protein expressions. YY1 was expressed only at low levels in the PE patient placenta and endometrial tissues. In rats, PE rats treated with over-expressed YY1 had (relative to in PE rats without over-induced YY1) increased circulating levels of Treg cells/decreased TH17 cells; tissues from these rats had elevated FoxP3 mRNA and protein expressions and reduced mRNA and protein RORc expressions, as well as indications of alleviated inflammation. In the rat placenta samples, YY1 was also determined to activate the PI3K/AKT pathway. In summary, YY1 regulates the balance among Treg/TH17 cells and so affect the PE process in part through activation of the PI3K/AKT pathway.
Subject(s)
Pre-Eclampsia , Humans , Female , Rats , Pregnancy , Animals , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , T-Lymphocytes, Regulatory , Cesarean Section , Yin-Yang , Th17 Cells/metabolism , Th17 Cells/pathology , Placenta , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , RNA, Messenger/metabolismABSTRACT
BACKGROUND AND OBJECTIVE: Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Because of the limitations of clinical trials, which are not representative of large real-world populations, rare events and long-term safety concerns cannot be detected. The current study aimed to evaluate the adverse events of abemaciclib through data mining of the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: Reporting odds ratio and Bayesian confidence propagation neural network of information components were used to quantify the adverse event signals of abemaciclib from the third quarter of 2017 to the first quarter of 2022. Serious and non-serious cases were compared using the Mann-Whitney U test or Chi-squared test, and clinical priority was assigned to signals by scoring (range 0-10 points) five features using a rating scale. RESULTS: A total of 6125 reports of abemaciclib as the "primary suspected" and 72 significant adverse events of abemaciclib were identified. Common adverse events, such as diarrhea, neutropenia, alanine transaminase, aspartate transaminase, and serum creatinine increases, and other adverse events, including thrombosis, deep vein thrombosis, pulmonary embolism, interstitial lung disease, and pneumonitis were of high concern. Of note, 17 preferred terms were classified as unexpected adverse events that uncovered in the label. In addition, 1, 26, and 45 adverse events were identified as strong, moderate, and weak clinical priorities. The median time to onset for strong, moderate, and weak clinical priority signals was 49, 22, and 28 days, respectively. All of the disproportionality signals had early failure type features, suggesting that adverse events of abemaciclib gradually decreased over time. CONCLUSIONS: The discovery of disproportionality signals could potentially prompt improved awareness of toxicities for abemaciclib, and the results of time to onset, serious and non-serious reports, and clinical priority analyses provided some supporting evidence for clinicians to manage adverse events.
Subject(s)
Breast Neoplasms , Drug-Related Side Effects and Adverse Reactions , United States , Humans , Female , Pharmacovigilance , Drug-Related Side Effects and Adverse Reactions/epidemiology , Bayes Theorem , Adverse Drug Reaction Reporting Systems , Breast Neoplasms/drug therapy , United States Food and Drug AdministrationABSTRACT
Background: Risankizumab, a humanized IgG1 monoclonal antibody that selectively inhibits IL-23, is currently approved for the treatment of moderate-to-severe plaque psoriasis and Crohn's disease. The real-world safety study of risankizumab in a large- sample population is currently lacking. The aim of this study was to evaluate risankizumab-associated adverse events (AEs) and characterize the clinical priority through the data mining of the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: Disproportionality analyses were performed by calculating the reporting odds ratios (RORs), deemed significant when the lower limit of the 95% confidence interval was greater than 1, to quantify the signals of risankizumab-related AEs from the second quarter (Q2) of 2019 to 2022 Q3. Serious and non-serious cases were compared, and signals were prioritized using a rating scale. Results: Risankizumab was recorded in 10,235 reports, with 161 AEs associated with significant disproportionality. Of note, 37 PTs in at least 30 cases were classified as unexpected AEs, which were uncovered in the drug label, such as myocardial infarction, cataract, pancreatitis, diabetes mellitus, stress, and nephrolithiasis. 74.68%, 25.32%, and 0% PTs were graded as weak, moderate, and strong clinical priorities, respectively. A total of 48 risankizumab-related AEs such as pneumonia, cerebrovascular accident, cataract, loss of consciousness, cardiac disorder, hepatic cirrhosis, and thrombosis, were more likely to be reported as serious AEs. The median TTO of moderate and weak signals related to risankizumab was 115 (IQR 16.75-305) and 124 (IQR 29-301) days, respectively. All of the disproportionality signals had early failure type features, indicating that risankizumab-associated AEs gradually decreased over time. Conclusion: Our study found potential new AE signals and provided valuable evidence for clinicians to mitigate the risk of risankizumab-associated AEs based on an extensive analysis of a large-scale postmarketing international safety database.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Pharmacovigilance , United States/epidemiology , Humans , Adverse Drug Reaction Reporting Systems , United States Food and Drug Administration , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/epidemiology , Antibodies, Monoclonal , Antibodies, Monoclonal, HumanizedABSTRACT
OBJECTIVE: Quetiapine, an atypical second-generation antipsychotic drug, is approved for treatment of schizophrenia, bipolar disorder, and depression. Due to the limitations of clinical trials, the association between quetiapine and rare cardiac adverse events (AEs) is still unclear. This study is to evaluate quetiapine-associated cardiac AEs through data mining of FDA Adverse Event Reporting System (FAERS). METHODS: Reporting odds ratio (ROR) was used to quantify the signals of quetiapine-related cardiac AEs from the first quarter (Q1) of 2018-2022 Q1. Serious and nonserious cases were compared, and signals were prioritized using a rating scale. RESULTS: A total of 1004 cases of quetiapine-associated cardiac AEs were identified, with 31 signals being detected, among which 13 AEs were identified as new and unexpected signals. Besides, nine and 22 cardiac AEs were identified as moderate and weak clinical priority. The median TTO for moderate and weak clinical priority signals were 0 and 4 days, respectively. All of the cardiac AEs had early failure type characteristics, suggesting that most of the patients developed cardiac AEs in a few days after quetiapine treatment, and that the risk of cardiac AEs occurrence would be gradually decreased over time. CONCLUSION: Our study provided valuable evidence for health-care professionals to mitigate the risk of quetiapine-associated cardiac AEs based on an extensive analysis of a real-world, large-sample FAERS database, and prioritize cardiac AE signals.
Subject(s)
Antipsychotic Agents , Bipolar Disorder , United States/epidemiology , Humans , Quetiapine Fumarate/adverse effects , Adverse Drug Reaction Reporting Systems , United States Food and Drug Administration , Antipsychotic Agents/adverse effects , Bipolar Disorder/drug therapyABSTRACT
PURPOSE: In this study, we explored the relationship of genes in HIF-1 signaling pathway with preeclampsia and establish a logistic regression model for diagnose preeclampsia using bioinformatics analysis. METHOD: Two microarray datasets GSE75010 and GSE35574 were downloaded from the Gene Expression Omnibus database, which was using for differential expression analysis. DEGs were performed the Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene set enrichment analysis (GSEA). Then we performed unsupervised consensus clustering analysis using genes in HIF-1 signaling pathway, and clinical features and immune cell infiltration were compared between these clusters, as well as the least absolute shrinkage and selection operator (LASSO) method to screened out key genes to constructed logistic regression model, and receiver operating characteristic (ROC) curve was plotted to evaluate the accuracy of the model. RESULTS: 57 DEGs were identified, of which GO, KEGG and analysis GSEA showed DEGs were mostly involved in HIF-1 signaling pathway. Two subtypes were identified of preeclampsia and 7 genes in HIF1-signaling pathway were screened out to establish the logistic regression model for discrimination preeclampsia from controls, of which the AUC are 0.923 and 0.845 in training and validation datasets respectively. CONCLUSION: Seven genes (including MKNK1, ARNT, FLT1, SERPINE1, ENO3, LDHA, BCL2) were screen out to build potential diagnostic model of preeclampsia.
Subject(s)
Pre-Eclampsia , Female , Humans , Pregnancy , Cluster Analysis , Databases, Factual , Intracellular Signaling Peptides and Proteins , Logistic Models , Protein Serine-Threonine Kinases , Signal Transduction , Hypoxia-Inducible Factor 1, alpha Subunit/metabolismABSTRACT
Background: Sintilimab plus chemotherapy significantly prolongs overall survival (OS) for patients with advanced or metastatic oesophageal squamous cell carcinoma (OSCC). However, the cost-effectiveness of this high-priced therapy is currently unknown. We evaluated the cost-effectiveness of sintilimab plus chemotherapy vs chemotherapy alone as fist-line therapy in patients with advanced or metastatic OSCC from the perspective of Chinese healthcare system. Methods: A partitioned survival model consisting of 3 discrete health states was constructed to assess the cost and effectiveness of sintilimab plus chemotherapy vs chemotherapy as first-line treatment of OSCC. Key clinical data in the model came from the ORIENT-15 trial. Costs and utilities were collected from published sources. Life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were calculated for the two treatment strategies. One-way and probabilistic sensitivity analyses were conducted to account for uncertainty and model stability. Additional subgroup and scenario analyses were performed. Results: Treatment with sintilimab plus chemotherapy provided an additional 0.37 QALYs and an incremental cost of $8,046.58 compared with chemotherapy, which resulted in an ICER of $21,782.24 per QALY gained. One-way sensitivity analysis revealed that the model was most sensitive to utility of progression-free survival (PFS) and the cost of sintilimab. The probabilistic sensitivity analysis indicated that the probability of sintilimab plus chemotherapy being cost-effective was 0.01%, 76.80% and 98.60% at the threshold of 1, 2 or 3 times GDP per capita per QALY, respectively. Subgroup analysis found that all subgroups other than PD-L1 expression combined positive scores < 1 subgroup favored sintilimab plus chemotherapy treatment due to its association with positive INHBs by varying the hazard ratios for OS and PFS. The scenario analyses showed altering the time horizon of the model or fitting survival curves separately did not reverse results of the model. Conclusion: Sintilimab plus chemotherapy was associated with improved QALYs and an additional cost but was estimated to be cost-effective compared with chemotherapy alone as a first-line treatment for patients with advanced or metastatic OSCC at the commonly adopted willingness-to-pay threshold of 3 times GDP per capita per QALY in China.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Cost-Benefit Analysis , Esophageal Squamous Cell Carcinoma/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Esophageal Neoplasms/drug therapyABSTRACT
We aimed to explore whether the effect of progesterone on preeclampsia via the PI3K/AKT signaling pathway. First, we studied the role of progesterone in preeclampsia patients and HTR-8/Svneo cells by adding progesterone. Then PI3K inhibitor LY294002 was added. The effects of progesterone on preeclampsia were also studied in animals by constructing a preeclampsia rat model. CCK-8 and Transwell assay were applied to measure cell viability and invasion ability. ELISA was performed to measure progesterone, MMP-2, MMP-9, pro-inflammatory factors TNF-α, IL-1ß, and anti-inflammatory factors IL-4, IL-10, and IL-13 levels. HE staining was used to detect the pathological changes in uterine spiral artery. Western blot was performed to detect Cyclin D1, PCNA, MMP-2, MMP-9, inflammatory factors TNF-α, IL-1ß, IL-4, IL-10, IL-13, and PI3K/AKT signaling pathway related proteins AKT, p-AKT, PI3K, and p-PI3K expressions. Progesterone could reduce blood pressure and urine protein in pregnant women with preeclampsia. TNF-α and IL-1ß levels were decreased, but IL-4, IL-10, IL-13, cyclin D1, and PCNA levels were increased in pregnant women with preeclampsia after using progesterone. After the use of progesterone, the symptoms of the PE model group were improved. Among them, the lumen of the placental uterine spiral artery was enlarged, and the fibrinoid necrosis of the uterine wall and acute atherosclerotic lesions were relieved. In addition, progesterone promoted HTR-8/Svneo cells proliferation and invasion. However, high expression of MMP-2, MMP-9, p-AKT, and p-PI3K in Normal and preeclampsia groups caused by progesterone was weakened after adding LY294002, indicating that progesterone could activate PI3K/AKT signaling pathway to regulate HTR-8/Svneo cells. Progesterone decreased urine protein and blood pressure of preeclampsia rats in a concentration-dependent manner. Moreover, progesterone activated the PI3K/AKT signaling pathway and inhibited the inflammatory response in preeclampsia rats.
Subject(s)
Pre-Eclampsia , Trophoblasts , Female , Pregnancy , Humans , Rats , Animals , Trophoblasts/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Progesterone/pharmacology , Placenta/metabolism , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase 2/metabolism , Cyclin D1/metabolism , Interleukin-10/metabolism , Pre-Eclampsia/metabolism , Tumor Necrosis Factor-alpha/metabolism , Interleukin-13/metabolism , Interleukin-4/metabolism , Proliferating Cell Nuclear Antigen/metabolism , Signal Transduction/physiology , Cell MovementABSTRACT
OBJECTIVES: First-line treatment with nivolumab plus ipilimumab has been shown to improve overall survival (OS) and progression-free survival (PFS) for patients with advanced non-small cell lung cancer (NSCLC). The current study evaluated the cost-effectiveness of nivolumab plus ipilimumab versus chemotherapy in advanced NSCLC from the perspective of Chinese healthcare system. METHODS: A three state-transition Markov model was employed to evaluate the cost and effectiveness of nivolumab plus ipilimumab versus chemotherapy in the first-line treatment of advanced NSCLC. Key clinical data in the model were derived from Part 1 of the phase 3 CheckMate 227 trial (NCT02477826). Costs and utilities were obtained from published literatures. The main endpoints of the model were costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. RESULTS: Nivolumab plus ipilimumab was associated with an increase in overall cost of $95,867.82 and improved effectiveness of 0.98 QALYs compared with chemotherapy, yielding an ICER of $97,676.24 per QALY. In one-way sensitivity analysis, the variables that had the greatest influence on the ICER were hazard ratio for OS and body weight. In probabilistic analysis, nivolumab plus ipilimumab had a 0% probability of being cost-effective at a willingness-to-pay (WTP) threshold of $37,663.26/QALY in China. However, the combination therapy would become cost-effective when the cost of nivolumab and ipilimumab were discounted by 65%. CONCLUSION: First-line nivolumab plus ipilimumab treatment for advanced NSCLC was found to be not cost-effective compared with chemotherapy at a WTP threshold of $37,663.26/QALY in China.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Nivolumab/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Ipilimumab/therapeutic use , Cost-Benefit Analysis , Lung Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
This study investigated the implication of monitoring hypertensive disorders in pregnancy (HDP) to prevent preeclampsia (PE) in pregnant women of advanced maternal age. Between January 2016 and April 2021, 262 consecutive pregnant women aged ≥40 years were recruited. Extensive monitoring of hypertensive disorders in pregnancy, including blood hypercoagulability screening and subsequent interventions, was performed in 129 pregnant women in our university hospital. The remaining 133 patients from other centres, who did not receive antenatal maternal pregnancy screening and preventive intervention during the same period, constituted the non-intervention group enabling comparison to mimic a trial. The incidences of hypertensive disorders, mild and severe PE, eclampsia, and chronic hypertension complicated by PE in the intervention group were significantly lower than in the non-intervention group (10.08 versus 20.30%, 8.52 versus 18.80%, 7.75 versus 21.05%, 0 versus 3.01%, and 3.86 versus 15.04%, respectively; P < 0.05). Premature birth, low birth weight, and foetal loss were significantly rarer in the intervention group than in the non-intervention group (6.98 versus 24.81%, 7.75 versus 21.80%, and 0.78 versus 14.29% respectively; P < 0.001). The comparison of MP with routine blood coagulation biochemical examination found that the MP detection system of Beijing Yes Medical Devices Co., Ltd., had similar sensitivity as thromboelastogram. Still, it was significantly better than the routine biochemical indicators (P < 0.01). Based on MP parameters, early anticoagulant treatment with low-molecular-weight heparin or low-dose aspirin in pregnant women with hypercoagulability can effectively prevent the occurrence of PE and significantly improve the prognosis of both mothers and infants.
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BACKGROUND: Complex epithelial neoplasms of the ovary (CENO), an uncommon pathological histotype in ovarian cancer, comprises adenosquamous carcinoma and adenocarcinoma with metaplasia. Owing to the rarity of relevant reports, there are currently no statistics on outcomes based on large samples. Meanwhile high-grade serous ovarian cancer (HGSOC) is the most common histotype in ovarian cancer which has a recognized first-line treatment regimen and poor prognosis. Thus, we aimed to determine the characteristics, prognosis, and independent predictors of survival for CENO, compare them with those of HGSOC and construct prognostic predictive models and nomograms. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to determine patients diagnosed with CENO or HGSOC from 2000 to 2017. Clinical, demographic, and treatment characteristics were compared between these groups. Propensity score matching, Cox risk regression analysis, Kaplan-Meier survival curves, and the Least Absolute Shrinkage and Selection Operator regression analysis were employed for analyzing the data. RESULTS: Here, 31,567 patients with HGSOC and 216 patients with CENO between 2000 and 2017 in the SEER database were enrolled. Age < 57 years, unmarried, and early-stage diseases were more common in patients with CENO than in those with HGSOC. Women with CENO were less likely to receive adjuvant chemotherapy (65.7% vs. 79.4%) but more likely to receive radiotherapy (6.0% vs. 0.8%; both p < 0.001) than those with HGSOC. Year of diagnosis, surgery status, number of primary tumors, grade, and FIGO stage were independent prognostic factors for overall and cancer-specific survival in CENO. Overall survival rates were significantly lower for CENO than for more malignant HGSOC. CONCLUSIONS: In summary, CENO was rare in ovarian cancer, while the year of diagnosis, surgery status, number of primary tumors, grade, and FIGO stage were independent prognostic factors. Compared with other common malignant ovarian tumors, CENO had a poor prognosis. Prognostic predictive models and nomograms had been determined to predict the individual survival rates of patients with CENO. These methods could improve evaluations of survival and therapeutic decisions for patients.
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Adenocarcinoma , Ovarian Neoplasms , Humans , Female , Middle Aged , Retrospective Studies , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/therapy , Pelvis , Carcinoma, Ovarian Epithelial/therapyABSTRACT
Background: Pregnancy-induced Hypertension (PIH) is a disease that causes serious maternal and fetal morbidity and mortality. Alisma Orientale (AO) has a long history of use as traditional Chinese medicine therapy for PIH. This study explores its potential mechanism and biosafety based on network pharmacology, network toxicology, molecular docking and molecular dynamics simulation. Methods: Compounds of AO were screened in TCMSP, TCM-ID, TCM@Taiwan, BATMAN, TOXNET and CTD database; PharmMapper and SwissTargetPrediction, GeneCards, DisGeNET and OMIM databases were used to predict the targets of AO anti-PIH. The protein-protein interaction analysis and the KEGG/GO enrichment analysis were applied by STRING and Metascape databases, respectively. Then, we constructed the "herb-compound-target-pathway-disease" map in Cytoscape software to show the core regulatory network. Finally, molecular docking and molecular dynamics simulation were applied to analyze binding affinity and reliability. The same procedure was conducted for network toxicology to illustrate the mechanisms of AO hepatotoxicity and nephrotoxicity. Results: 29 compounds with 78 potential targets associated with the therapeutic effect of AO on PIH, 10 compounds with 117 and 111 targets associated with AO induced hepatotoxicity and nephrotoxicity were obtained, respectively. The PPI network analysis showed that core therapeutic targets were IGF, MAPK1, AKT1 and EGFR, while PPARG and TNF were toxicity-related targets. Besides, GO/KEGG enrichment analysis showed that AO might modulate the PI3K-AKT and MAPK pathways in treating PIH and mainly interfere with the lipid and atherosclerosis pathways to induce liver and kidney injury. The "herb-compound-target-pathway-disease" network showed that triterpenoids were the main therapeutic compounds, such as Alisol B 23-Acetate and Alisol C, while emodin was the main toxic compounds. The results of molecular docking and molecular dynamics simulation also showed good binding affinity between core compounds and targets. Conclusion: This research illustrated the mechanism underlying the therapeutic effects of AO against PIH and AO induced hepato-nephrotoxicity. However, further experimental verification is warranted for optimal use of AO during clinical practice.
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Objective: We aimed to evaluate the effectiveness of different triage strategies for high-risk human papillomavirus (hrHPV)-positive women in primary healthcare settings in China. Methods: This study was undertaken in 11 rural and 9 urban sites. Women aged 35-64 years old were enrolled. HrHPV-positive women were randomly allocated to liquid-based cytology (LBC), visual inspection with acetic acid and Lugol's iodine (VIA/VILI) (rural only) triage, or directly referred to colposcopy (direct COLP). At 24 months, hrHPV testing, LBC and VIA/VILI were conducted for combined screening. Results: In rural sites, 1,949 hrHPV-positive women were analyzed. A total of 852, 218 and 480 women were randomly assigned to direct COLP, LBC and VIA/VILI. At baseline, colposcopy referral rates of LBC or VIA/VILI triage could be reduced by 70%-80%. LBC (n=3 and n=7) or VIA/VILI (n=8 and n=26) could significantly decrease the number of colposcopies needed to detect one cervical intraepithelial neoplasia (CIN) 2 or worse and CIN3+ compared with direct COLP (n=14 and n=23). For the 24-month cumulative detection rate of CIN2+, VIA/VILI triage was 0.50-fold compared with LBC triage and 0.46-fold with the direct COLP. When stratified by age, baseline LBC triage+ performed best (P<0.001), peaking among women aged 35-44 years (Ptrend=0.002). In urban sites, 1,728 women were hrHPV genotyping test positive. A total of 408, 571 and 568 women were randomly assigned to direct COLP for HPV16/18+, direct COLP for other hrHPV subtypes+, and LBC triage for other hrHPV subtypes+. LBC (n=12 and n=31) significantly decreased the number of colposcopies needed to detect one CIN2+ and CIN3+ compared with direct COLP (n=14 and n=44). HPV16/18+ increased the 24-month cumulative detection rate of CIN2+ (17.89%, P<0.001). Conclusions: LBC triage for hrHPV-positive women in rural settings and direct COLP for HPV16/18+ women and LBC triage for other hrHPV subtype+ women in urban settings might be feasible strategies.
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INTRODUCTION: Recently, ferroptosis has been reported to be closely related to preeclampsia (PE). However, the mechanisms associated with ferroptosis in PE have been poorly studied. METHODS: A PE rat model was established via reduced uterine perfusion pressure (RUPP) surgery. A Ferroptosis inhibitor was used to treat the model rats. Blood pressure, urine protein, sFlt-1, GSH, GSH-PX, MDA, total Fe, Fe (II), and Fe (â ¢) levels were detected. Placenta morphological changes and fetal survival rate were observed and counted, respectively. miRNA sequencing and bioinformatical analysis were conducted to establish the ferroptosis-related interaction network of miRNAs-mRNAs in PE. After hypoxia treatment, cells were silenced glutamic-oxaloacetic transaminase1 (GOT1) or overexpressed miR-2115-3p/GOT1. Cellular proliferation, invasion, and reactive oxygen species (ROS) were determined. The ferroptosis-related factors levels (ACSL4, TfR1, GPX4, SCL7A11, GSH, GSH-PX, Fe (II), and MDA) were quantified. RESULTS: In vivo, ferrostatin-1 attenuated ferroptosis in the PE models, significantly increasing fetal survivability. The miR-2115-3p/GOT1 pathway was screened for possible association with abnormal ferroptosis in PE. miR-2115-3p was discovered to interact with the mRNA of GOT1. Inhibition of GOT1 and overexpression of miR-2115-3p reversed the decrease in cell proliferation capacity, GSH, GSH-PX, and GPX4 levels, and the increase in ROS, ACSL4, TfR1, MDA, total Fe, and Fe (II) levels induced by hypoxia. However, simultaneous overexpression of miR-2115-3p and GOT1 reversed the above results of overexpression of miR-2115-3p. DISCUSSION: miR-2115-3p might interact with the GOT1 mRNA to downregulate its expression, further inhibiting the hypoxia-promoted ferroptosis in a PE model.
Subject(s)
Ferroptosis , MicroRNAs , Pre-Eclampsia , Humans , Pregnancy , Female , Rats , Animals , Pre-Eclampsia/genetics , Pre-Eclampsia/metabolism , Aspartate Aminotransferases , Ferroptosis/genetics , Reactive Oxygen Species , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Messenger , HypoxiaABSTRACT
[This corrects the article DOI: 10.3389/fmolb.2021.763958.].
ABSTRACT
AIMS: Clinical evidence indicated the activation of endoplasmic reticulum stress (ERS) in pregnant women with preeclampsia (PE), and the regulatory role of melatonin (MT) in ERS. This study aims to explore the possible effect and mechanism of MT on ERS and on the infiltration of trophoblasts in PE. METHODS: The serum expression levels of MT and GRP78 in pregnant women with PE were measured. The cell proliferation, invasion, migration and apoptosis of trophoblasts were also determined. The trophoblast cell infiltration in placenta tissues was detected in EVOS image system. The expressions of ERS related proteins were measured by RT-qPCR and western blot. KEY RESULTS: The PE-serum treatment on HTR-8/SVneo cells led to activated ERS and suppressed cell biological functions. PE mouse models after MT treatment or 4-PBA treatment had reduced blood pressure, proteinuria, apoptosis and increased foetus and placenta weight, in addition to enhanced cell infiltration. CONCLUSIONS: In vivo and in vitro evidence demonstrated MT can simultaneously suppress ERS and ASK1/JNK signal pathway in PE to promote the infiltration of trophoblasts.
Subject(s)
Melatonin , Pre-Eclampsia , Animals , Apoptosis/physiology , Cell Movement/physiology , Cell Proliferation/physiology , Endoplasmic Reticulum Stress , Female , Humans , Melatonin/pharmacology , Mice , Placenta/metabolism , Pre-Eclampsia/metabolism , Pregnancy , Trophoblasts/physiologyABSTRACT
Most international academic papers are written in English, and the use of tenses in English academic papers often follows some conventional rules. Automatically extracting and analyzing English tenses in scientific papers have begun to attract researchers' attention for the global environment. In the analysis of the English tense of scientific papers, consider that the neural network model that combines attention mechanism and sequential input network such as Long Short-Term Memory (LSTM) network has a long training time, low extraction accuracy, and cannot parallelize text input. We propose an environmental affection-driven English tense analysis model, which includes an attention mechanism and LSTM model and conducts a temporal analysis of English texts based on an affective computing model. In this paper, our proposed method is verified based on the self-built healthcare exercise-based corpus over public English environment. By comparison, the experimental results show that the method proposed in this paper has better performance than ordinary Convolutional Neural Network (CNN), Support Vector Machine (SVM), and LSTM based on attention mechanism.