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Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
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In the meiotic prophase, programmed DNA double-strand breaks are repaired by meiotic recombination. Recombination-defective meiocytes are eliminated to preserve genome integrity in gametes. BRCA1 is a critical protein in somatic homologous recombination, but studies have suggested that BRCA1 is dispensable for meiotic recombination. Here we show that BRCA1 is essential for meiotic recombination. Interestingly, BRCA1 also has a function in eliminating recombination-defective oocytes. Brca1 knockout (KO) rescues the survival of Dmc1 KO oocytes far more efficiently than removing CHK2, a vital component of the DNA damage checkpoint in oocytes. Mechanistically, BRCA1 activates chromosome asynapsis checkpoint by promoting ATR activity at unsynapsed chromosome axes in Dmc1 KO oocytes. Moreover, Brca1 KO also rescues the survival of asynaptic Spo11 KO oocytes. Collectively, our study not only unveils an unappreciated role of chromosome asynapsis in eliminating recombination-defective oocytes but also reveals the dual functions of BRCA1 in safeguarding oocyte genome integrity.
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Proteína BRCA1 , Proteínas de Ciclo Celular , Ratones Noqueados , Oocitos , Oocitos/metabolismo , Animales , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Femenino , Ratones , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Meiosis/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/deficiencia , Roturas del ADN de Doble Cadena , Emparejamiento Cromosómico/genética , Endodesoxirribonucleasas/metabolismo , Endodesoxirribonucleasas/genética , Quinasa de Punto de Control 2/genética , Quinasa de Punto de Control 2/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Recombinación Genética , Recombinación Homóloga , Inestabilidad GenómicaRESUMEN
CAR-T cell therapies hold great potential in achieving long-term remission in patients suffering from malignancies. However, their efficacy in treating solid tumors is impeded by challenges such as limited infiltration, compromised cancer recognition, decreased cytotoxicity, heightened exhaustion, absence of memory phenotypes, and inevitable toxicity. To surmount these obstacles, researchers are exploring innovative strategies, including the integration of CAR-T cells with targeted inhibitors. The combination of CAR-T therapies with specific targeted drugs has shown promise in enhancing CAR-T cell infiltration into tumor sites, boosting their tumor recognition capabilities, strengthening their cytotoxicity, alleviating exhaustion, promoting the development of a memory phenotype, and reducing toxicity. By harnessing the synergistic potential, a wider range of patients with solid tumors may potentially experience favorable outcomes. To summarize the current combined strategies of CAR-T therapies and targeted therapies, outline the potential mechanisms, and provide insights for future studies, we conducted this review by collecting existing experimental and clinical evidence.
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Inmunoterapia Adoptiva , Neoplasias , Humanos , Neoplasias/terapia , Inmunoterapia Adoptiva/métodos , Terapia Combinada/métodos , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéutico , Terapia Molecular Dirigida/métodosRESUMEN
The use of low-sodium salt substitute (LSSS) has the potential to reduce sodium and increase potassium intake. LSSS has been available in the Chinese market for years. However, its real-world use and impact on sodium/potassium intake is unclear. Baseline data of 4000 adult individuals who participated in three similarly designed randomized controlled trials were pooled together for this analysis. Self-reported awareness and use of LSSS were collected using a standardized questionnaire, and the participants' 24-h urinary sodium and potassium excretion was used to estimate their dietary intake. Mixed-effects models were developed to assess the relationship between LSSS and 24-h urinary sodium and potassium excretion. 32.0% of the participants reported awareness of LSSS and 11.7% reported its current use. After adjusting for location, sex, age, and education, compared with the group of participants unaware of LSSS, participants who were aware of but not using LSSS and those who were using LSSS had a lower 24-h urinary sodium excretion by -356.1 (95% CI: -503.9, -205.9) mg/d and -490.6 (95% CI: -679.2, -293.7) mg/d, respectively (p < 0.001). No significant difference was found for 24-h urinary potassium excretion or sodium-to-potassium ratio among the three groups (p > 0.05). In conclusion, the findings of low usage of LSSS and the reduced urinary sodium excretion associated with the awareness and use of LSSS provide further support for the prometon of LSSS as a key salt reduction strategy in China.
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Hipertensión , Sodio en la Dieta , Adulto , Humanos , Estudios Transversales , Dieta Hiposódica , Potasio , Sodio , Cloruro de Sodio Dietético , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: To investigate the prognostic relevance of the time to interval debulking surgery (TTS) and the time to postoperative adjuvant chemotherapy (TTC) after the completion of neoadjuvant chemotherapy (NACT). METHODS: A retrospective real-word study included 658 patients with histologically confirmed advanced epithelial ovarian cancer who received NACT at seven tertiary hospitals in China from June 2008 to June 2020. TTS was defined as the time interval from the completion of NACT to the time of interval debulking surgery (IDS). TTC was defined as the time interval from the completion of NACT to the initiation of postoperative adjuvant chemotherapy (PACT). RESULTS: The median TTS and TTC were 25 (IQR, 20-29) and 40 (IQR, 33-49) days, respectively. Patients with TTS > 25 days were older (55 vs. 53 years, P = 0.012) and received more NACT cycles (median, 3 vs. 2, P = 0.002). Similar results were observed in patients with TTC > 40 days. In the multivariate analyses, TTS and TTC were not associated with PFS when stratified by median, quartile, or integrated as continuous variables (all P > 0.05). However, TTS and TTC were significantly associated with worse OS when stratified by median (P = 0.018 and 0.018, respectively), quartile (P = 0.169, 0.014, 0.027 and 0.012, 0.001, 0.033, respectively), or integrated as continuous variables (P = 0.018 and 0.011, respectively). Similarly, increasing TTS and TTC intervals were associated with a higher risk of death (Ptrend = 0.016 and 0.031, respectively) but not with recurrence (Ptrend = 0.103 and 0.381, respectively). CONCLUSION: The delays of IDS and PACT after the completion of NACT have adverse impacts on OS but no impacts on PFS, which indicates that reducing delays of IDS and PACT might ameliorate the outcomes of ovarian cancer patients treated with NACT.
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Terapia Neoadyuvante , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/cirugía , Carcinoma Epitelial de Ovario/etiología , Estudios Retrospectivos , Procedimientos Quirúrgicos de Citorreducción/métodos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/patología , Quimioterapia Adyuvante , Estadificación de NeoplasiasRESUMEN
BACKGROUND: Mucinous epithelial ovarian cancer (mEOC) is a relatively uncommon subtype of ovarian cancer with special prognostic features, but there is insufficient research in this area. This study aimed to develop a nomogram for the cancer-specific survival (CSS) of mEOC based on Surveillance, Epidemiology, and End Results (SEER) database and externally validate it in National Union of Real World Gynecological Oncology Research and Patient Management (NUWA) platform from China. METHODS: Patients screened from SEER database were allocated into training and internal validation cohort in a ratio of 7: 3, with those from NUWA platform as an external validation cohort. Significant factors selected by Cox proportional hazard regression were applied to establish a nomogram for 3-year and 5-year CSS. The performance of nomogram was assessed by concordance index, calibration curves and Kaplan-Meier (K-M) curves. RESULTS: The training cohort (n = 572) and internal validation cohort (n = 246) were filtered out from SEER database. The external validation cohort contained 186 patients. Baseline age, tumor stage, histopathological grade, lymph node metastasis and residual disease after primary surgery were significant risk factors (p < 0.05) and were included to develop the nomogram. The C-index of nomogram in training, internal validation and external validation cohort were 0.869 (95% confidence interval [CI], 0.838-0.900), 0.839 (95% CI, 0.787-0.891) and 0.800 (95% CI, 0.738-0.862), respectively. The calibration curves of 3-year and 5-year CSS in each cohort showed favorable agreement between prediction and observation. K-M curves of different risk groups displayed great discrimination. CONCLUSION: The discrimination and goodness of fit of the nomogram indicated its satisfactory predictive value for the CSS of mEOC in SEER database and external validation in China, which implies its potential application in different populations.
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Nomogramas , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/cirugía , Procedimientos Quirúrgicos de Citorreducción , Neoplasias Ováricas/cirugía , ChinaRESUMEN
Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
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Plaquetas , Neoplasias Ováricas , Humanos , Femenino , Plaquetas/patología , Biomarcadores de Tumor/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , ChinaRESUMEN
OBJECTIVE: To explore the impact of the primary treatment sequence (primary debulking surgery, PDS, versus neoadjuvant chemotherapy and interval debulking surgery, NACT-IDS) on post-relapse survival (PRS) and recurrence characteristics of recurrent epithelial ovarian cancer (REOC). DESIGN: Real-world retrospective study. SETTING: Tertiary hospitals in China. POPULATION: A total of 853 patients with REOC at International Federation of Gynaecology and Obstetrics stages IIIC-IV from September 2007 to June 2020. Overall, 377 and 476 patients received NACT-IDS and PDS, respectively. METHODS: Propensity score-based inverse probability of treatment weighting (IPTW) was performed to balance the between-group differences. MAIN OUTCOME MEASURES: Clinicopathological factors related to PRS. RESULTS: The overall median PRS was 29.3 months (95% CI 27.0-31.5 months). Multivariate analysis before and after IPTW adjustment showed that NACT-IDS and residual R1/R2 disease were independent risk factors for PRS (p < 0.05). Patients with diffuse carcinomatosis and platinum-free interval (PFI) ≤ 12 months had a significantly worse PRS (p < 0.001). Logistic regression analysis revealed that NACT-IDS was an independent risk factor for diffuse carcinomatosis (OR 1.36, 95% CI 1.01-1.82, p = 0.040) and PFI ≤ 12 months (OR 1.59, 95% CI 1.08-2.35, p = 0.019). In IPTW analysis, NACT-IDS was still significantly associated with diffuse carcinomatosis (OR 1.29, 95% CI 1.05-1.58, p = 0.015) and PFI ≤ 12 months (OR 1.90, 95% CI 1.52-2.38, p < 0.001). CONCLUSIONS: The primary treatment sequence may affect the PRS of patients with REOC by altering the recurrence pattern and PFI duration.
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Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/patología , Estudios Retrospectivos , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/tratamiento farmacológico , Quimioterapia Adyuvante , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/patología , Procedimientos Quirúrgicos de Citorreducción , Neoplasia ResidualRESUMEN
OBJECTIVE: To produce high-quality, real-world evidence for oncologists by collating scattered gynaecologic oncology (GO) medical records in China. DESIGN: Retrospective study. SETTING: The National Union of Real-world Gynaecological Oncology Research and Patient Management Platform (NUWA platform). SAMPLE: Patient-centred data pool. METHODS: The NUWA platform integrated inpatient/outpatient clinical, gene and follow-up data. Data of 11 456 patients with ovarian cancer (OC) were collected and processed using 91 345 electronic medical records. Structured and unstructured data were de-identified and re-collated into a patient-centred data pool using a predefined GO data model by technology-aided abstraction. MAIN OUTCOME MEASURES: Recent treatment pattern shifts towards precision medicine for OC in China. RESULTS: Thirteen first-tier hospitals across China participated in the NUWA platform up to 7 December 2021. In total, 3504 (30.59%) patients were followed up by a stand-alone patient management centre. The percentage of patients undergoing breast cancer gene (BRCA) mutation tests increased by approximately six-fold between 2017 and 2018. A similar trend was observed in the administration rate of poly(ADP-ribose) polymerase inhibitors as first-line treatment and second-line treatment after September 2018, when olaparib was approved for clinical use in China. CONCLUSION: The NUWA platform has great potential to facilitate clinical studies and support drug development, regulatory reviews and healthcare decision-making.
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Pueblos del Este de Asia , Neoplasias Ováricas , Femenino , Humanos , Estudios Retrospectivos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , ChinaRESUMEN
OBJECTIVES: Advancements in big data technology are reshaping the healthcare system in China. This study aims to explore the role of medical big data in promoting digital competencies and professionalism among Chinese medical students. DESIGN, SETTING AND PARTICIPANTS: This study was conducted among 274 medical students who attended a workshop on medical big data conducted on 8 July 2021 in Tongji Hospital. The workshop was based on the first nationwide multifunction gynecologic oncology medical big data platform in China, at the National Union of Real-World Gynecologic Oncology Research & Patient Management Platform (NUWA platform). OUTCOME MEASURES: Data on knowledge, attitudes towards big data technology and professionalism were collected before and after the workshop. We have measured the four skill categories: doctorâpatient relationship skills, reflective skills, time management and interprofessional relationship skills using the Professionalism Mini-Evaluation Exercise (P-MEX) as a reflection for professionalism. RESULTS: A total of 274 students participated in this workshop and completed all the surveys. Before the workshop, only 27% of them knew the detailed content of medical big data platforms, and 64% knew the potential application of medical big data. The majority of the students believed that big data technology is practical in their clinical practice (77%), medical education (85%) and scientific research (82%). Over 80% of the participants showed positive attitudes toward big data platforms. They also exhibited sufficient professionalism before the workshop. Meanwhile, the workshop significantly promoted students' knowledge of medical big data (p<0.05), and led to more positive attitudes towards big data platforms and higher levels of professionalism. CONCLUSIONS: Chinese medical students have primitive acquaintance and positive attitudes toward big data technology. The NUWA platform-based workshop may potentially promote their understanding of big data and enhance professionalism, according to the self-measured P-MEX scale.
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Neoplasias de los Genitales Femeninos , Estudiantes de Medicina , Macrodatos , Estudios Transversales , Femenino , Humanos , Relaciones Médico-Paciente , ProfesionalismoRESUMEN
BACKGROUND: Ovarian clear cell carcinoma (OCCC) has an abysmal prognosis with a median overall survival (OS) of 25.3 months because of a low response to chemotherapy. The 5-year disease-specific survival rate after recurrence is 13.2%, with more than two-thirds of the patients dying within a year. Therefore, it is urgent to explore new therapeutic options for OCCC. Based on the characteristic immune-suppressive tumour microenvironment derived from the gene expression profile of OCCC, the combination of immunoantiangiogenesis therapy might have certain efficacy in recurrent/persistent OCCC. This trial aims to evaluate the efficacy and safety of sintilimab and bevacizumab in patients who have failed platinum-containing chemotherapy with recurrent or persistent OCCC. METHOD AND ANALYSIS: In this multicentre, single-arm, open-label, investigator-initiated clinical trial, 38 patients will be assigned to receive sintilimab 200 mg plus bevacizumab 15 mg/kg every 3 weeks. The eligibility criteria include histologically diagnosed patients with recurrent or persistent OCCC who have been previously treated with at least one-line platinum-containing chemotherapy; patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-2 with an expected survival greater than 12 weeks. The exclusion criteria include patients previously treated with immune checkpoint inhibitor and patients with contraindications of bevacizumab and sintilimab. The primary endpoint is the objective response rate. The secondary endpoints are progression-free survival, time to response, duration of response, disease control rate, OS, safety and quality of life. Statistical significance was defined as p<0.05. ETHICS AND DISSEMINATION: This trial was approved by the Research Ethics Commission of Tongji Medical College of Huazhong University of Science and Technology (2020-S337). The protocol of this study is registered at www. CLINICALTRIALS: gov. The trial results will be published in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: NCT04735861; Clinicaltrials. gov.
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Adenocarcinoma de Células Claras , Anticuerpos Monoclonales Humanizados , Neoplasias Ováricas , Platino (Metal) , Adenocarcinoma de Células Claras/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/uso terapéutico , Femenino , Humanos , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Calidad de Vida , Microambiente TumoralRESUMEN
BACKGROUND: Ultrasound is a critical non-invasive test for preoperative diagnosis of ovarian cancer. Deep learning is making advances in image-recognition tasks; therefore, we aimed to develop a deep convolutional neural network (DCNN) model that automates evaluation of ultrasound images and to facilitate a more accurate diagnosis of ovarian cancer than existing methods. METHODS: In this retrospective, multicentre, diagnostic study, we collected pelvic ultrasound images from ten hospitals across China between September 2003, and May 2019. We included consecutive adult patients (aged ≥18 years) with adnexal lesions in ultrasonography and healthy controls and excluded duplicated cases and patients without adnexa or pathological diagnosis. For DCNN model development, patients were assigned to the training dataset (34â488 images of 3755 patients with ovarian cancer, 541â442 images of 101â777 controls). For model validation, patients were assigned to the internal validation dataset (3031 images of 266 patients with ovarian cancer, 5385 images of 602 with benign adnexal lesions), external validation datasets 1 (486 images of 67 with ovarian cancer, 933 images of 268 with benign adnexal lesions), and 2 (1253 images of 166 with ovarian cancer, 5257 images of 723 benign adnexal lesions). Using these datasets, we assessed the diagnostic value of DCNN, compared DCNN with 35 radiologists, and explored whether DCNN could augment the diagnostic accuracy of six radiologists. Pathological diagnosis was the reference standard. FINDINGS: For DCNN to detect ovarian cancer, AUC was 0·911 (95% CI 0·886-0·936) in the internal dataset, 0·870 (95% CI 0·822-0·918) in external validation dataset 1, and 0·831 (95% CI 0·793-0·869) in external validation dataset 2. The DCNN model was more accurate than radiologists at detecting ovarian cancer in the internal dataset (88·8% vs 85·7%) and external validation dataset 1 (86·9% vs 81·1%). Accuracy and sensitivity of diagnosis increased more after DCNN-assisted diagnosis than assessment by radiologists alone (87·6% [85·0-90·2] vs 78·3% [72·1-84·5], p<0·0001; 82·7% [78·5-86·9] vs 70·4% [59·1-81·7], p<0·0001). The average accuracy of DCNN-assisted evaluations for six radiologists reached 0·876 and were significantly augmented when they were DCNN-assisted (p<0·05). INTERPRETATION: The performance of DCNN-enabled ultrasound exceeded the average diagnostic level of radiologists matched the level of expert ultrasound image readers, and augmented radiologists' accuracy. However, these observations warrant further investigations in prospective studies or randomised clinical trials. FUNDING: National Key Basic Research Program of China, National Sci-Tech Support Projects, and National Natural Science Foundation of China.
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Aprendizaje Profundo , Neoplasias Ováricas , Adolescente , Adulto , China , Femenino , Humanos , Neoplasias Ováricas/diagnóstico por imagen , Estudios Prospectivos , Estudios Retrospectivos , Ultrasonografía/métodosRESUMEN
Corticosteroid has been proved to be one of the few effective treatments for COVID-19 patients. However, not all the patients were suitable for corticosteroid therapy. In this study, we aimed to propose a machine learning model to forecast the response to corticosteroid therapy in COVID-19 patients. We retrospectively collected the clinical data about 666 COVID-19 patients receiving corticosteroid therapy between January 27, 2020, and March 30, 2020, from two hospitals in China. The response to corticosteroid therapy was evaluated by hospitalization time, oxygen supply duration, and the outcomes of patients. Least Absolute Shrinkage and Selection Operator (LASSO) was applied for feature selection. Five prediction models were applied in the training cohort and assessed in an internal and an external validation dataset, respectively. Finally, two (C reactive protein, lymphocyte percent) of 36 candidate immune/inflammatory features were finally used for model development. All five models displayed promising predictive performance. Notably, the ensemble model, PRCTC (prediction of response to corticosteroid therapy in COVID-19 patients), derived from three prediction models including Gradient Boosted Decision Tree (GBDT), Neural Network (NN), and logistic regression (LR), achieved the best performance with an area under the curve (AUC) of 0.810 (95% confidence interval [CI] 0.760-0.861) in internal validation cohort and 0.845 (95% CI 0.779-0.911) in external validation cohort to predict patients' response to corticosteroid therapy. In conclusion, PRCTC proposed with universality and scalability is hopeful to provide tangible and prompt clinical decision support in management of COVID-19 patients and potentially extends to other medication predictions.
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Corticoesteroides/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Aprendizaje Automático , Anciano , Algoritmos , COVID-19/virología , China , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Redes Neurales de la Computación , Estudios Retrospectivos , SARS-CoV-2/fisiología , Resultado del TratamientoRESUMEN
Benzophenone-3 (BP-3), one of the most commonly utilized ultraviolet filters in personal care products, has aroused public concern in recent years for its high chances of human exposure. Previous studies have found that BP-3 can impair testes development and spermatogenesis, but the targets of BP-3 are still unknown. In this study, primary Sertoli cells from 20-day-old mice were treated in vitro with 0-100 µM BP-3 for 24 h to identify its toxicity on Sertoli cells and Sertoli cell barrier. Results demonstrated that BP-3 could induce a notable change in cell morphology and impair Sertoli cell viability. The analysis of transepithelial electrical resistance showed that the integrity of the Sertoli cell barrier was destroyed by BP-3 (100 µM). Some structural proteins of the barrier including ZO-1, Occludin, and Connexin43 were lower expressed and the localization of basal ectoplasmic specializations protein ß-catenin was altered because of BP-3 treatment. Further exploration suggested that BP-3 led to Sertoli cell F-actin disorganization by affecting the expression of Rictor, a key component of the mTORC2 complex. Moreover, although increased DNA damage marker γH2A.X was observed in the treatment group, the cell apoptosis rate was changeless which was further confirmed by increased BAX and stable Bcl-2 (two primary apoptosis regulating proteins). In conclusion, this study revealed that BP-3 had the potential to perturb the Sertoli cell barrier through altered junction proteins and disorganized F-actin, but it could hardly evoke Sertoli cell apoptosis.
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Actinas , Células de Sertoli , Animales , Apoptosis , Benzofenonas , Barrera Hematotesticular , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Espermatogénesis , Uniones EstrechasRESUMEN
Perfluorononanoic acid (PFNA), a member of PFAS, is frequently detected in human blood and tissues, even in follicular fluid of women. The exposure of PFNA, but not PFOA and PFOS, is positively correlated with miscarriage and increased time to pregnancy. Toxicological studies indicated that PFNA exposure is associated with immunotoxicity, hepatotoxicity, developmental toxicity, and reproductive toxicity in animals. However, there is little information regarding the toxic effects of PFNA on oocyte maturation. In this study, we investigated the toxic effects of PFNA exposure on mouse oocyte maturation in vitro. Our results showed that 600 µM PFNA significantly inhibited germinal vesicle breakdown (GVBD) and polar body extrusion (PBE) in mouse oocytes. Our further study revealed that PFNA induced abnormal metaphase I (MI) spindle assembly, evidenced by malformed spindles and mislocalization of p-ERK1/2 in PFNA-treated oocytes. We also found that PFNA induced abnormal mitochondrial distribution and increased mitochondrial membrane potential. Consequently, PFNA increased reactive oxygen species (ROS) levels, leading to oxidative stress, DNA damage, and eventually early-stage apoptosis in oocytes. In addition, after 14 h culture, PFNA disrupted the formation of metaphase II (MII) spindle in most PFNA-treated oocytes with polar bodies. Collectively, our results indicate that PFNA interferes with oocyte maturation in vitro via disrupting spindle assembly, damaging mitochondrial functions, and inducing oxidative stress, DNA damage, and early-stage apoptosis.
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Ácidos Grasos/toxicidad , Fluorocarburos/toxicidad , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/fisiología , Animales , Femenino , Metafase , Ratones , Oocitos/efectos de los fármacos , Oogénesis , Estrés Oxidativo/efectos de los fármacosRESUMEN
Ribonucleic acid export 1 (Rae1) is an important nucleoporin that participates in mRNA export during the interphase of higher eukaryotes and regulates the mitotic cell cycle. In this study, small RNA interference technology was used to knockdown Rae1, and immunofluorescence, immunoblotting, and chromosome spreading were used to study the role of Rae1 in mouse oocyte meiotic maturation. We found that Rae1 is a crucial regulator of meiotic maturation of mouse oocytes. After the resumption of meiosis (GVBD), Rae1 was concentrated on the kinetochore structure. The knockdown of Rae1 by a specific siRNA inhibited GVBD progression at 2 h, finally leading to a decreased 14 h polar body extrusion (PBE) rate. However, a comparable 14 h PBE rate was found in the control, and the Rae1 knockdown groups that had already undergone GVBD. Furthermore, we found elevated PBE after 9.5 h in the Rae1 knockdown oocytes. Further analysis revealed that Rae1 depletion significantly decreased the protein level of securin. In addition, we detected weakened kinetochore-microtubule (K-MT) attachments, misaligned chromosomes, and an increased incidence of aneuploidy in the Rae1 knockdown oocytes. Collectively, we propose that Rae1 modulates securin protein levels, which contribute to chromosome alignment, K-MT attachments, and aneuploidy in meiosis.
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Meiosis/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Matriz Nuclear/genética , Proteínas de Transporte Nucleocitoplasmático/genética , Oocitos/metabolismo , Animales , Técnicas de Silenciamiento del Gen , Técnicas de Maduración In Vitro de los Oocitos , Cinetocoros/metabolismo , Ratones , Oocitos/crecimiento & desarrollo , Cuerpos Polares/metabolismo , ARN Mensajero/genética , ARN Interferente Pequeño/genéticaRESUMEN
The adsorption performance of pyridine onto polyaluminium chloride (PAC) and anionic polyacrylamide (APAM) water treatment residuals (WTRs) was investigated by batch experiments. This study confirmed the assumption that PAC-APAM WTRs had the ability to remove pyridine. The non-linear Dubinin-Radushkevich model and non-linear Freundlich model better described the isotherms, indicating that the adsorption was a chemically controlled multilayer process. The pyridine adsorption rate was simultaneously controlled by external film diffusion and intraparticle diffusion. The adsorption of pyridine was an endothermic reaction with randomness increase. The pyridine adsorption decreased with pH increase. Pyridine removal was observed to be a linear increase from 6.16% to 96.18%, with the increase of dosage from 2.5 g/L to 15 g/L. The Langmuir maximum adsorption capacity was 3.605 mg/g while the theoretical isotherm saturation capacity was 9.823 mg/g. Therefore, PAC-APAM WTRs recycled into contaminated soils for remediation is expected to be an innovative alternative disposal method. More research is recommended in the future to identify detailed adsorption mechanisms and the most appropriate mixing ratio of PAC-APAM WTRs to contaminated soils under various climatic conditions.
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Contaminantes Químicos del Agua , Purificación del Agua , Resinas Acrílicas , Adsorción , Hidróxido de Aluminio , Concentración de Iones de Hidrógeno , Cinética , Piridinas , Soluciones , TermodinámicaRESUMEN
A dynamically adjustable ultra-wideband metamaterial perfect absorber (MPA) is proposed which consists of three resonance rings based on vanadium dioxide (VO2) and a metal ground layer separated by a dielectric spacer. The simulation results show that the terahertz (THz) absorption bandwidth of more than 90% absorptance reaches 3.30 THz, which covers from 2.34 to 5.64 THz, under different incident polarization angles. The range is better than that of previous VO2-based reports. Moreover, when the conductivity of VO2 changes from 200 S/m to 2×105 S/m, the absorption peak intensity can be adjusted continuously from 4% to 100%. The key is to optimize the geometric structure through interference cancellation and impedance matching theory, to achieve better absorption bandwidth and efficiency. Besides, the terahertz absorber has a wide-angle absorption effect both in TE and TM waves. Thus, the designed absorber may have many potential applications in modulating, sensing and imaging technology.
Asunto(s)
Antiinflamatorios/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Glucocorticoides/uso terapéutico , Terapia por Inhalación de Oxígeno/métodos , Insuficiencia Respiratoria/terapia , Anciano , COVID-19/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Respiración Artificial/métodos , Insuficiencia Respiratoria/virología , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Disinfection by-products (DBPs) are compounds produced during the water disinfection process. Iodoacetic acid (IAA) is one of the unregulated DBPs in drinking water, with potent cytotoxicity and genotoxicity in animals. However, whether IAA has toxic effects on oocyte maturation remains unclear. Here, we show that IAA exposure resulted in metaphase I (MI) arrest and polar-body-extrusion failure in mouse oocytes, indicating that IAA had adverse effects on mouse oocyte maturation in vitro. Particularly, IAA treatment caused abnormal spindle assembly and chromosome misalignment. Previous studies reported that IAA is a known inducer of oxidative stress in non-germline cells. Correspondingly, we found that IAA exposure increased the reactive oxygen species (ROS) levels in oocytes in a dose-dependent manner, indicating IAA exposure could induce oxidative stress in oocytes. Simultaneously, DNA damage was also elevated in the nuclei of these IAA-exposed mouse oocytes, evidenced by increased γ-H2AX focus number. In addition, the un-arrested oocytes entered metaphase II (MII) with severe defects in spindle morphologies and chromosome alignment after 14-h IAA treatment. An antioxidant, N-acetyl-L-cysteine (NAC), reduced the elevated ROS level and restored the meiotic maturation in the IAA-exposed oocytes, which indicates that IAA-induced maturation failure in oocytes was mainly mediated by oxidative stress. Collectively, our results indicate that IAA exposure interfered with mouse oocyte maturation by elevating ROS levels, disrupting spindle assembly, inducing DNA damage, and causing MI arrest.