Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors.

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.

BRCA1 safeguards genome integrity by activating chromosome asynapsis checkpoint to eliminate recombination-defective oocytes.

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.

Does the primary treatment sequence affect post-relapse survival in recurrent epithelial ovarian cancer? A real-world multicentre retrospective study.

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.

The first Chinese National Union of Real-world Gynaecological Oncology Research and Patient Management Platform: A retrospective study.

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.

Benzophenone-3 breaches mouse Sertoli cell barrier and alters F-actin organization without evoking apoptosis.

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.

Ultra-wideband tunable metamaterial perfect absorber based on vanadium dioxide.

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.

WDR62 is a novel participator in spindle migration and asymmetric cytokinesis during mouse oocyte meiotic maturation.

In female meiosis, oocyte meiotic maturation is a form of asymmetric cell division, producing the first polar body and a large oocyte, in which the asymmetry of oocyte meiotic division depends on spindle migration and positioning, and cortical polarization. In this study, we conclude that WDR62 (WD40-repeat protein 62) plays an important role in asymmetric meiotic division during mouse oocyte maturation. Our initial study demonstrated that WDR62 mainly co-localized with chromosomes during mouse oocyte meiotic maturation. Interference of Wdr62 by siRNA microinjection did not affect germinal vesicle breakdown (GVBD) but compromised the first polar body extrusion (PBE) with the large polar bodies generated, which is coupled with a higher incidence of spindle abnormality and chromosome misalignment. Further analysis concluded that loss of WDR62 blocked asymmetric spindle positioning and actin cap formation, which should be responsible for large polar body extrusion. Moreover, WDR62 decline intervened with the Arp2/3 complex, an upstream regulator for the cortical actin. Besides for p-MAPK, a critical regulator for the asymmetric division of oocyte, WDR62-depleted oocytes showed perturbation only in localization pattern but not expression level. In summary, our study defines WDR62 as an essential cytoskeletal regulator of spindle migration and asymmetric division during mouse oocyte meiotic maturation.

Ribonucleic Acid Export 1 Is a Kinetochore-Associated Protein That Participates in Chromosome Alignment in Mouse Oocytes.

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.

Adsorption of pyridine from aqueous solutions onto polyaluminium chloride and anionic polyacrylamide water treatment residuals.

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.

The toxic effects of Fluorene-9-bisphenol on porcine oocyte in vitro maturation.

Fluorene-9-bisphenol (9,9-bis(4-hydroxyphenyl)-fluorene [BHPF]) is a bisphenol A (BPA) substitute used in the production of "BPA-free" plastics, now has been identified is harmful to living organisms. Our previous study showed that BHPF impaired mouse denuded oocyte in vitro maturation. However, there is a question that whether BHPF is still able to affect oocyte maturation in the presence of dense cumulus cells. In the present study, we checked the toxic effects of BHPF on porcine oocyte maturation which is derived from COCs in vitro culture. Our results showed that BHPF (50 µM) inhibited the expansion of cumulus cells, led to a significant decrease in polar body extrusion (PBE). Importantly, BHPF resulted in abnormal spindle assembly, ATP level decrease, reactive oxygen species (ROS) accumulation and early apoptosis in porcine oocytes, which are all negative to oocyte maturation. Furthermore, BHPF also declined porcine oocyte quality by disturbing the cortical granules (CGs) distribution. In conclusion, our study showed that BHPF still inhibited oocyte maturation even in the presence of cumulus cells leading to abnormal spindle assembly, ATP decrease, increased ROS level, early apoptosis, and disturbed CGs distribution in porcine oocytes, and also indicates that BHPF has a wide range toxic effects on oocyte in different species.

Research on treatment and mechanism of salicylhydroxamic acid flotation wastewater by O3-BAF process.

Salicylhydroxamic acid is an effective and selective collector for tungsten and molybdenum ores. However, the salicylhydroxamic acid flotation wastewater discharge may cause damage to the water environment for the residual processing reagents with poor biodegradability. Combined O3 and biological aerated filter (BAF) has a well-known potential for removing refractory or toxic organic pollutants. Combined process of O3 and BAF (O3-BAF) was applied to treat the simulated wastewater from W-Mo mineral processing in this study. Compared single ozonation to O3-BAF, various influencing factors were discussed like O3 dosage, reaction time, initial pH value, gas-water ratio and organic loading. Meanwhile, degradation mechanism of salicylhydroxamic acid was reduced. Under the optimal experiment conditions as pH value 8, O3 dosage 1.3 mg·L-1, reaction time 15 min, the five-day biochemical oxygen demand (BOD5)/chemical oxygen demand of potassium dichromate (CODCr) value increased to from 0.19 to 0.35. The effluent was pumped to the following BAF process, when the optimal experiment conditions was organic load = 0.82 kgCODCr (m-3·d-1), gas-water ratio = 6:1, CODCr concentration of effluent was 28.92 mg·L-1 and the removal ratio was 86.26%, while the removal ratio could higher to 91.12% for the O3-BAF combined process. The effluent could meet the discharge and reuse emission standards requirements in China. UV-vis absorption spectra and high performance liquid chromatography showed the degradation pathway of salicylhydroxamic acid by ozone oxidation was salicylhydroxamic acid → salicylic acid + hydroxylamine → catechol → maleic → small molecular organic acid → carbon dioxide + water.

Nucleoporin35 is a novel microtubule associated protein functioning in oocyte meiotic spindle architecture.

Nucleoporins (Nups) are a large and diverse family of proteins that mediate nucleocytoplasmic transport at interphase of vertebrate cells. Nups also function in mitosis progression. However, whether Nups are involved in oocyte meiosis progression is still rarely known. In this study, we delineated the roles and regulatory mechanisms of Nucleoporin35 (Nup35) during oocyte meiotic maturation. The immunofluorescent signal of Nup35 was localized in the nuclear membrane at germinal vesicle (GV) stage, the microtubules and spindle at pro-metaphase I (pro-MI), metaphase I (MI), and metaphase II (MII), but to the spindle poles at anaphase I (AI) and telophase I (TI). The dynamic localization pattern of Nup35 during oocyte meiotic maturation implied its specific roles. We also found that Nup35 existed as a putatively phosphorylated form after resumption of meiosis (GVBD), but not at GV stage, implying its functional switch from nuclear membrane to meiotic progression. Further study uncovered that knockdown of Nup35 by specific siRNA significantly compromised the extrusion of first polar body (PBE), but not GVBD, with defects of spindle assembly and chromosome alignment and dissociated some localization signal of p-ERK1/2 from spindle poles to cytoplasm. A defective kinetochore - microtubule attachment (K-MT) was also identified in oocytes after knockdown of Nup35, which activates spindle assembly checkpoint. In conclusion, our results suggest that Nup35 is putatively phosphorylated and released to the cytoplasm after resumption of meiosis, and regulates spindle assembly and chromosome alignment.

Maternal SENP7 programs meiosis architecture and embryo survival in mouse.

Understanding the mechanisms underlying abnormal egg production and pregnancy loss is significant for human fertility. SENP7, a SUMO poly-chain editing enzyme, has been regarded as a mitotic regulator of heterochromatin integrity and DNA repair. Herein, we report the roles of SENP7 in mammalian reproductive scenario. Mouse oocytes deficient in SENP7 experienced meiotic arrest at prophase I and metaphase I stages, causing a substantial decrease of mature eggs. Hyperaceylation and hypomethylation of histone H3 and up-regulation of Cdc14B/C accompanied by down-regulation of CyclinB1 and CyclinB2 were further recognized as contributors to defective M-phase entry and spindle assembly in oocytes. The spindle assembly checkpoint activated by defective spindle morphogenesis, which was also caused by mislocalization and ubiquitylation-mediated proteasomal degradation of γ-tubulin, blocked oocytes at meiosis I stage. SENP7-depleted embryos exhibited severely defective maternal-zygotic transition and progressive degeneration, resulting in nearly no blastocyst production. The disrupted epigenetic landscape on histone H3 restricted Rad51C loading onto DNA lesions due to elevated HP1α euchromatic deposition, and reduced DNA 5hmC challenged the permissive status for zygotic DNA repair, which induce embryo death. Our study pinpoints SENP7 as a novel determinant in epigenetic programming and major pathways that govern oocyte and embryo development programs in mammals.

CAR-T therapy and targeted treatments: Emerging combination strategies in solid tumors.

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.

Awareness and Use of Low-Sodium Salt Substitutes and Its Impact on 24-h Urinary Sodium and Potassium Excretion in China-A Cross-Sectional Study.

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.

Timing of interval debulking surgery and postoperative chemotherapy after neoadjuvant chemotherapy in advanced epithelial ovarian cancer: a multicenter real-world study.

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.

Development and validation of a nomogram to predict cancer-specific survival of mucinous epithelial ovarian cancer after cytoreductive surgery.

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.

Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.

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.

PRCTC: a machine learning model for prediction of response to corticosteroid therapy in COVID-19 patients.

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.

Sintilimab combined with bevacizumab in relapsed/persistent ovarian clear cell carcinoma (INOVA): an investigator-initiated, multicentre clinical trial-a study protocol of clinical trial.

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.