Plasmodium vivax tryptophan-rich antigen reduces type I collagen secretion via the NF-κBp65 pathway in splenic fibroblasts.

BACKGROUND: The spleen plays a critical role in the immune response against malaria parasite infection, where splenic fibroblasts (SFs) are abundantly present and contribute to immune function by secreting type I collagen (collagen I). The protein family is characterized by Plasmodium vivax tryptophan-rich antigens (PvTRAgs), comprising 40 members. PvTRAg23 has been reported to bind to human SFs (HSFs) and affect collagen I levels. Given the role of type I collagen in splenic immune function, it is important to investigate the functions of the other members within the PvTRAg protein family. METHODS: Protein structural prediction was conducted utilizing bioinformatics analysis tools and software. A total of 23 PvTRAgs were successfully expressed and purified using an Escherichia coli prokaryotic expression system, and the purified proteins were used for co-culture with HSFs. The collagen I levels and collagen-related signaling pathway protein levels were detected by immunoblotting, and the relative expression levels of inflammatory factors were determined by quantitative real-time PCR. RESULTS: In silico analysis showed that P. vivax has 40 genes encoding the TRAg family. The C-terminal region of all PvTRAgs is characterized by the presence of a domain rich in tryptophan residues. A total of 23 recombinant PvTRAgs were successfully expressed and purified. Only five PvTRAgs (PvTRAg5, PvTRAg16, PvTRAg23, PvTRAg30, and PvTRAg32) mediated the activation of the NF-κBp65 signaling pathway, which resulted in the production of inflammatory molecules and ultimately a significant reduction in collagen I levels in HSFs. CONCLUSIONS: Our research contributes to the expansion of knowledge regarding the functional role of PvTRAgs, while it also enhances our understanding of the immune evasion mechanisms utilized by parasites.

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial.

Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Postmenopausal endometrial non-benign lesion risk classification through a clinical parameter-based machine learning model.

OBJECTIVE: This study aimed to develop and evaluate a machine learning model utilizing non-invasive clinical parameters for the classification of endometrial non-benign lesions, specifically atypical hyperplasia (AH) and endometrioid carcinoma (EC), in postmenopausal women. METHODS: Our study collected clinical parameters from a cohort of 999 patients with postmenopausal endometrial lesions and conducted preprocessing to identify 57 relevant characteristics from these irregular clinical data. To predict the presence of postmenopausal endometrial non-benign lesions, including atypical hyperplasia and endometrial cancer, we employed various models such as eXtreme Gradient Boosting (XGBoost), Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), Back Propagation Neural Network (BPNN), as well as two ensemble models. Additionally, a test set was performed on an independent dataset consisting of 152 patients. The performance evaluation of all models was based on metrics including the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, precision, and F1 score. RESULTS: The RF model demonstrated superior recognition capabilities for patients with non-benign lesions compared to other models. In the test set, it attained a sensitivity of 88.1% and an AUC of 0.93, surpassing all alternative models evaluated in this study. Furthermore, we have integrated this model into our hospital's Clinical Decision Support System (CDSS) and implemented it within the outpatient electronic medical record system to continuously validate and optimize its performance. CONCLUSIONS: We have trained a model and deployed a system with high discriminatory power that may provide a novel approach to identify patients at higher risk of postmenopausal endometrial non-benign lesions who may benefit from more tailored screening and clinical intervention.

Genome-based classification of the family Haloferacaceae and description of five novel species of Halobaculum.

The taxonomic status of some species of Halobellus, Haloferax, Halogranum, and Haloplanus within the family Haloferacaceae was elucidated by phylogenetic, phylogenomic, and comparative genomic analyses. The relative species of each genus should constitute a single species based on the overall genome-related indexes proposed for species demarcation. The cutoff values of AAI (72.1%), ANI (82.2%), and rpoB' gene similarity (90.7%) were proposed to differentiate genera within the family Haloferacaceae. According to these standards, a novel genus related to the genus Halobaculum was proposed to accommodate Halobaculum halophilum Gai3-2 T and Halobaculum salinum NJ-3-1 T. Five halophilic archaeal strains, DT31T, DT55T, DT92T, SYNS20T, and YSMS11T, isolated from a tidal flat and a marine solar saltern in China, were subjected to polyphasic classification. The phenotypic, phylogenetic, phylogenomic, and comparative genomic analyses revealed that strains DT31T (= CGMCC 1.18923 T = JCM 35417 T), DT55T (= CGMCC 1.19048 T = JCM 36147 T), DT92T (= CGMCC 1.19057 T = JCM 36148 T), SYNS20T (= CGMCC 1.62628 T = JCM 36154 T), and YSMS11T (= CGMCC 1.18927 T = JCM 34912 T) represent five novel species of the genus Halobaculum, for which the names, Halobaculum lipolyticum sp. nov., Halobaculum marinum sp. nov., Halobaculum litoreum sp. nov., Halobaculum halobium sp. nov., and Halobaculum limi sp. nov., are proposed.

Genome-based classification of genera Halosegnis and Salella, and description of four novel halophilic archaea isolated from a tidal flat.

The current species of Halosegnis and Salella within the class Halobacteria are closely related based on phylogenetic, phylogenomic, and comparative genomic analyses. The Halosegnis species showed 99.8-100.0% 16S rRNA and 96.6-99.6% rpoB' gene similarities to the Salella species, respectively. Phylogenetic and phylogenomic analyses showed that Salella cibi CBA1133T, the sole species of Salella, formed a single tight cluster with Halosegnis longus F12-1T, then with Halosegnis rubeus F17-44T. The average nucleotide identity (ANI), digital DNA-DNA hybridization (dDDH), and average amino acid identity (AAI) values between Salella cibi CBA1133T and Halosegnis longus F12-1T were 99.2, 94.2, and 98.6%, respectively, much higher than the thresholds for species demarcation. This genome-based classification revealed that the genus Salella should be merged with Halosegnis, and Salella cibi should be a later heterotypic synonym of Halosegnis longus. Halophilic archaeal strains DT72T, DT80T, DT85T, and DT116T, isolated from the saline soil of a tidal flat in China, were subjected to polyphasic taxonomic characterization. The phenotypic, chemotaxonomic, phylogenetic, and phylogenomic features indicated that strains DT72T (= CGMCC 1.18925T = JCM 35418T), DT80T (= CGMCC 1.18926T = JCM 35419T), DT85T (= CGMCC 1.19049T = JCM 35605T), and DT116T (= CGMCC 1.19045T = JCM 35606T) represent four novel species of the genera Halorussus, Halosegnis and Haloglomus, respectively, for which the names, Halorussus caseinilyticus sp. nov., Halorussus lipolyticus sp. nov., Halosegnis marinus sp. nov., and Haloglomus litoreum sp. nov., are proposed.

Effect of laser beam incidence angle on weld formation mechanism and corrosion resistance of T2 copper/304 stainless steel.

Over the last 20 years, industry interest in copper has increased. Its application in the petrochemical, automotive, and nuclear power industries highlights the need for new research directions especially in the joining of copper to other metals. In this work, lap joint of 304 stainless steel and T2 copper precoated with Cu-Mn-Ni filler metal was performed by laser brazing. The aim of this study is to characterize the influence of laser beam incidence angle on the welded joint forming mode, microstructure, elements diffusion and corrosion resistance. According to the findings, the joint is classified as a welded joint when the laser beam incidence angle is 80°, and as a welded-brazed joint when it's 90°, 70°, or 60°. The microstructure is mainly composed of Cu-rich and Fe-rich phases, Mn in the Cu-rich phase aggregation and Cr in the Fe-rich phase aggregation. In the fusion zone (FZ) the content of less than 50% of the liquid will be in the form of supersaturated droplets in the matrix of the other side. The local corrosion pair that the copper steel matrix and liquid drop produce in the FZ speeds up the dissolution of the Cu-rich phase, which effected corrosion resistance of the joint.

ECM1 promotes migration and invasion in endometriosis.

Extracellular matrix protein 1 (ECM1) is a glycoprotein that may be a key player in tumorigenesis and tumor progression. However, knowledge regarding the role of ECM1 in endometriosis (EM) is still lacking. Microarray analyses were performed to compare the mRNA expression patterns between paired EU tissues and ectopic endometrial (EC) tissues (n = 4) from EM patients. ECM1 expression was significantly increased in the eutopic endometrial (EU) tissues than paired EC tissues of endometriotic patients and normal endometrial (NE) tissues of controls without EM. Blocking ECM1 with siRNA attenuated the migration and invasion of hEM15A cells and modified the distribution of the F-actin cytoskeleton. We conducted microarray analyses and bioinformatics analyses to investigate the differentially expressed genes (DEGs) and related pathways regulated by ECM1. A total of 161 DEGs between the siECM1 and the negative control (siNC) treatments were identified, consisting of 79 downregulated genes and 82 upregulated genes. Enriched DEGs were associated with 9 gene ontology (GO) terms. Moreover, a protein-protein interaction (PPI) network was constructed for the hub genes and modules. Radixin (RDX) was the second most downregulated gene in the siECM1 group compared with the siNC group. ECM1 knockdown significantly decreased the expression of RDX, RhoC, ROCK1, N-cadherin and ß-catenin but not ROCK2. ECM1 showed high tissue-specific expression in EU tissues from EM patients, and may contribute to the migration, invasion and reorganization of the F-actin cytoskeleton in eutopic endometrial stromal cells via the RhoC/ROCK1 signaling pathway in EM.

Domain-Adversarial Transformer Network for Multiphase Liver Tumor Segmentation.

Accurate liver tumor segmentation is a prerequisite for data-driven tumor analysis. Multiphase computed tomography (CT) with extensive liver tumor characteristics is typically used as the most crucial diagnostic basis. However, the large variations in contrast, texture, and tumor structure between CT phases limit the generalization capabilities of the associated segmentation algorithms. Inadequate feature integration across phases might also lead to a performance decrease. To address these issues, we present a domain-adversarial transformer (DA-Tran) network for segmenting liver tumors from multiphase CT images. A DA module is designed to generate domain-adapted feature maps from the non-contrast-enhanced (NC) phase, arterial (ART) phase, portal venous (PV) phase, and delay phase (DP) images. These domain-adapted feature maps are then combined with 3D transformer blocks to capture patch-structured similarity and global context attention. The experimental findings show that DA-Tran produces cutting-edge tumor segmentation outcomes, making it an ideal candidate for this co-segmentation challenge.

Phase Difference Network for Efficient Differentiation of Hepatic Tumors with Multi-Phase CT.

Liver cancer has been one of the top causes of cancer-related death. For developing an accurate treatment strategy and raising the survival rate, the differentiation of liver cancers is essential. Multiphase CT recently acts as the primary examination method for clinical diagnosis. Deep learning techniques based on multiphase CT have been proposed to distinguish hepatic cancers. However, due to the recurrent mechanism, RNN-based approaches require expensive calculations whereas CNN-based models fail to explicitly establish temporal correlations among phases. In this paper, we proposed a phase difference network, termed as Phase Difference Network (PDN), to identify two liver cancer, hepatocellular carcinoma and intrahepatic cholangiocarcinoma, from four-phase CT. Specifically, the phase difference was used as interphase temporal information in a differential attention module, which enhanced the feature representation. Additionally, utilizing a multihead self-attention module, a transformer-based classification module was employed to explore the long-term context and capture the temporal relation between phases. Clinical datasets are used in experiments to compare the performance of the proposed strategy versus conventional approaches. The results indicate that the proposed method outperforms the traditional deep learning based methods.

Immunization with Embryonic Stem Cells/Induced Pluripotent Stem Cells Induces Effective Immunity against Ovarian Tumor-Initiating Cells in Mice.

Cancer stem cells (CSCs) express pluripotent markers and share many features with normal pluripotent stem cells. It is possible that immunity induced by embryonic stem cells (ESCs) and induced pluripotent stem cells- (IPSCs-) based vaccines may selectively target CSCs. In our study, cells expressing the pluripotent marker CD133 in the murine ovarian cancer cell-line ID8 were isolated and identified as CSCs. We investigated the preventive efficacy of ESCs and IPSCs-based vaccines against the development of ovarian cancer in vivo and evaluated the humoral and cellular immunities targeting CSCs in vitro. Our study showed that preimmunization with both mouse-derived embryonic stem cells (mESCs) and mouse-induced pluripotent stem cells (mIPSCs) lysates, combined with an immunostimulatory adjuvant CpG, elicited strong humoral and cellular responses. These responses effectively suppressed the development of CSC-derived tumors. Immune sera collected from mESCs and mIPSCs-vaccinated mice contained antibodies that were capable of selectively targeting CSCs, resulting in the lysis of CSCs in the presence of complement. Cytotoxic T-lymphocytes generated from splenocytes of mESCs and mIPSCs-vaccinated hosts could secrete interferon- (IFN-) γ in response to CSCs and kill CSCs in vitro. These findings indicate that vaccines based on mESCs and mIPSCs can elicit effective antitumor immunities. These immunities are related to the conferring of humoral and cellular responses that directly target CSCs.

Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease. Objective: To evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted). Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months. Interventions: Patients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of <77 kg and/or platelet count of <150 ×103/µL [to convert to ×109/µL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy. Main Outcomes and Measurements: The primary end point was blinded, independent central review-assessed PFS in the intention-to-treat population. Results: A total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P < .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events. Conclusion and Relevance: This randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting. Trial Registration: ClinicalTrials.gov Identifier: NCT03709316.

Salinilacihabitans rarus gen. nov., sp. nov., Natrononativus amylolyticus gen. nov., sp. nov., Natronobeatus ordinarius gen. nov., sp. nov., and Halovivax gelatinilyticus sp. nov., halophilic archaea, isolated from a salt lake and soda lakes.

Four halophilic archaea strains, AD-4T, CGA30T, CGA73T, and WLHSJ27T, were isolated from a salt lake and two soda lakes located in different regions of China. The 16S rRNA and rpoB' gene sequence similarities among strains AD-4T, CGA30T, CGA73T, WLHSJ27T, and the current species of the family Natrialbaceae were 90.9-97.5% and 83.1-91.8%, respectively. The phylogenetic and phylogenomic analyses revealed that these four strains separated from existing genera in the family Natrialbaceae and formed distant branches. The ANI, isDDH, and AAI values among these four strains and the current members of the family Natrialbaceae were 72-79%, 20-25%, and 63-73%, respectively, much lower than the threshold values for species demarcation. Strains AD-4T, CGA73T, and WLHSJ27T may represent three novel genera of the family Natrialbaceae according to the cutoff value of AAI (≤ 76%) proposed to differentiate genera within the family Natrialbaceae. These four strains could be distinguished from the related genera according to differential phenotypic characteristics. The major phospholipids of these four strains were identical while their glycolipid profiles were diverse. DGD-1 is a major glycolipid found in strain AD-4T, trace glycolipids, DGD-1, and S-DGD-1, and (or) S-TGD-1 was found in the other three strains. The major respiratory quinones detected in the four strains were menaquinone MK-8 and MK-8(H2). This polyphasic classification indicated that strains AD-4T, CGA73T, and WLHSJ27T represent three novel species of three new genera with the family Natrialbaceae, and strain CGA30T represents a novel species of Halovivax.

Characterization of candidate factors associated with the metastasis and progression of high-grade serous ovarian cancer.

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the biggest cause of gynecological cancer-related mortality because of its extremely metastatic nature. This study aimed to explore and evaluate the characteristics of candidate factors associated with the metastasis and progression of HGSOC. METHODS: Transcriptomic data of HGSOC patients' samples collected from primary tumors and matched omental metastatic tumors were obtained from three independent studies in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were selected to evaluate the effects on the prognosis and progression of ovarian cancer using data from The Cancer Genome Atlas (TCGA) database. Hub genes' immune landscapes were estimated by the Tumor Immune Estimation Resource (TIMER) database. Finally, using 25 HGSOC patients' cancer tissues and 10 normal fallopian tube tissues, immunohistochemistry (IHC) was performed to quantify the expression levels of hub genes associated with International Federation of Gynecology and Obstetrics (FIGO) stages. RESULTS: Fourteen DEGs, ADIPOQ , ALPK2 , BARX1 , CD37 , CNR2 , COL5A3 , FABP4 , FAP , GPR68 , ITGBL1 , MOXD1 , PODNL1 , SFRP2 , and TRAF3IP3 , were upregulated in metastatic tumors in every database while CADPS , GATA4 , STAR , and TSPAN8 were downregulated. ALPK2 , FAP , SFRP2 , GATA4 , STAR , and TSPAN8 were selected as hub genes significantly associated with survival and recurrence. All hub genes were correlated with tumor microenvironment infiltration, especially cancer-associated fibroblasts and natural killer (NK) cells. Furthermore, the expression of FAP and SFRP2 was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage, and their increased protein expression levels in metastatic samples compared with primary tumor samples and normal tissues were confirmed by IHC ( P = 0.0002 and P = 0.0001, respectively). CONCLUSIONS: This study describes screening for DEGs in HGSOC primary tumors and matched metastasis tumors using integrated bioinformatics analyses. We identified six hub genes that were correlated with the progression of HGSOC, particularly FAP and SFRP2 , which might provide effective targets to predict prognosis and provide novel insights into individual therapeutic strategies for HGSOC.

Single-Cell Dissection of the Multiomic Landscape of High-Grade Serous Ovarian Cancer.

High-grade serous cancer (HGSC) is the most common subtype of ovarian cancer. HGSC is highly aggressive with poor patient outcomes, and a deeper understanding of HGSC tumorigenesis could help guide future treatment development. To systematically characterize the underlying pathologic mechanisms and intratumoral heterogeneity in human HGSC, we used an optimized single-cell multiomics sequencing technology to simultaneously analyze somatic copy-number alterations (SCNA), DNA methylation, chromatin accessibility, and transcriptome in individual cancer cells. Genes associated with interferon signaling, metallothioneins, and metabolism were commonly upregulated in ovarian cancer cells. Integrated multiomics analyses revealed that upregulation of interferon signaling and metallothioneins was influenced by both demethylation of their promoters and hypomethylation of satellites and LINE1, and potential key transcription factors regulating glycolysis using chromatin accessibility data were uncovered. In addition, gene expression and DNA methylation displayed similar patterns in matched primary and abdominal metastatic tumor cells of the same genetic lineage, suggesting that metastatic cells potentially preexist in the subclones of primary tumors. Finally, the lineages of cancer cells with higher residual DNA methylation levels and upregulated expression of CCN1 and HSP90AA1 presented greater metastatic potential. This study characterizes the critical genetic, epigenetic, and transcriptomic features and their mutual regulatory relationships in ovarian cancer, providing valuable resources for identifying new molecular mechanisms and potential therapeutic targets for HGSC. SIGNIFICANCE: Integrated analysis of multiomic changes and epigenetic regulation in high-grade serous ovarian cancer provides insights into the molecular characteristics of this disease, which could help improve diagnosis and treatment.

Fuzuloparib Maintenance Therapy in Patients With Platinum-Sensitive, Recurrent Ovarian Carcinoma (FZOCUS-2): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial.

PURPOSE: This phase III trial aimed to explore the efficacy and safety of fuzuloparib (formerly fluzoparib) versus placebo as a maintenance treatment after response to second- or later-line platinum-based chemotherapy in patients with high-grade, platinum-sensitive, recurrent ovarian cancer. PATIENTS AND METHODS: Patients with platinum-sensitive, recurrent ovarian cancer previously treated with at least two platinum-based regimens were assigned (2:1) to receive fuzuloparib (150 mg, twice daily) or matching placebo for 28-day cycles. The primary end points were progression-free survival (PFS) assessed by blinded independent review committee (BIRC) in the overall population and PFS by BIRC in the subpopulation with germline BRCA 1/2 mutation. RESULTS: Between April 30, 2019, and January 10, 2020, 252 patients were randomly assigned to the fuzuloparib (n = 167) or placebo (n = 85). As of July 1, 2020, the median PFS per BIRC assessment in the overall population was significantly improved with fuzuloparib treatment (hazard ratio [HR], 0.25; 95% CI, 0.17 to 0.36; one-sided P < .0001) compared with that with placebo. The HR derived from a prespecified subgroup analysis showed a consistent trend of benefit in patients with germline BRCA 1/2 mutations (HR, 0.14; 95% CI, 0.07 to 0.28) or in those without mutations (HR, 0.46; 95% CI, 0.29 to 0.74). The most common grade ≥ 3 treatment-emergent adverse events reported in the fuzuloparib group were anemia (25.1%), decreased platelet count (16.8%), and decreased neutrophil count (12.6%). Only one patient (0.6%) discontinued fuzuloparib because of treatment-related toxicity (concurrent decreased white blood cell count and neutrophil count). CONCLUSION: Fuzuloparib as maintenance therapy achieved a statistically significant and clinically meaningful improvement in PFS for patients with platinum-sensitive, recurrent ovarian cancer versus placebo, regardless of germline BRCA 1/2 mutation, and showed a manageable safety profile.

[Identification of Cordyceps cicadae and Tolypocladium dujiaolongae based on ITS sequences and chemical pattern recognition method].

Based on ITS sequences, the molecular identification of Cordyceps cicadae and Tolypocladium dujiaolongae was carried out, and high-performance liquid chromatography(HPLC) fingerprint combined with chemical pattern recognition method was established to differentiate C. cicadae from its adulterant T. dujiaolongae. The genomic DNA from 10 batches of C. cicadae and five batches of T. dujiaolongae was extracted, and ITS sequences were amplified by PCR and sequenced. The stable differential sites of these two species were compared and the phylogenetic tree was constructed via MEGA 7.0. HPLC was used to establish the fingerprints of C. cicadae and T. dujiaolongae, and similarity evaluation, cluster analysis(CA), principal component analysis(PCA), and partial least squares discriminant analysis(PLS-DA) were applied to investigate the chemical pattern recognition. The result showed that the sources of these two species were different, and there were 115 stable differential sites in ITS sequences of C. cicadae and T. dujiao-longae. The phylogenetic tree could distinguish them effectively. HPLC fingerprints of 18 batches of C. cicadae and 5 batches of T. dujiaolongae were established. The results of CA, PCA, and PLS-DA were consistent, which could distinguish them well, indicating that there were great differences in chemical components between C. cicadae and T. dujiaolongae. The results of PLS-DA showed that six components such as uridine, guanosine, adenosine, and N~6-(2-hydroxyethyl) adenosine were the main differential markers of the two species. ITS sequences and HPLC fingerprint combined with the chemical pattern recognition method can serve as the identification and differentiation methods for C. cicadae and T. dujiaolongae.

Preliminary Safety and Potential Effect of 6B11-OCIK Adoptive Cell Therapy Against Platinum-Resistant Recurrent or Refractory Ovarian Cancer.

Ovarian cancer is a leading cause of death among gynecological malignancies, and novel therapies are urgently needed. Here we report preliminary findings on the potential safety and efficacy of 6B11-OCIK, an adoptive cell therapy of autologous T cells induced by the humanized anti-idiotypic antibody 6B11 minibody plus dendritic cells and cytokines, against platinum-resistant recurrent or refractory ovarian cancer in three patients. We found that 6B11-OCIK treatment was safe and well tolerated after five cycles of intravenous infusion with an initial dose of 1-2×109 cells and a dose-climbing strategy. Hemoglobin, platelets, white cell count, creatinine or liver enzyme values, coagulation function, kidney and heart function were not significantly affected over the duration of therapy. Two of the three enrolled patients showed potentially drug-related grade 1 and 2 weakness, and no other adverse events were observed. Of the three enrolled patients, one had stable disease and two showed disease progression. The patient with favorable clinical efficacy had better immune response as measured by 6B11-OCIK proliferation capacity, activation ability of CD3+CD8+ tumor-specific cytotoxic T lymphocytes and CD3+CD56+ cytokine-induced killer cells, and tumor cell killing efficiency. Changes in circulating tumor cells after treatment were consistent with serum level CA125 in the patient with stable disease (both decreased), while differences were observed in the two patients with disease progression (increased CA125 in both and decreased CTC in the patient with better immune response), suggesting that variation of circulating tumor cells was more consistent with immune response and reflected efficacy directly. This preliminary study suggested that autologous 6B11-OCIK treatment was safe and had potential clinical efficacy against ovarian cancer. Patients with better immune response had more favorable efficacy. In addition to imaging, CA125 and immunophenotypes, CTC monitoring may represent a potential indicator of immunotherapy response.

Real-world Experience of Olaparib Treatment in Patients with Ovarian Cancer: A Chinese Multicenter Study.

The objective of this study was to evaluate the real-world application, efficacy, and safety data of olaparib for maintenance therapy and active treatment in patients with ovarian cancer in China. Patients with ovarian cancer from 17 institutions in China treated with olaparib as maintenance or active therapy from January 2018 to March 2020 were included in this study. The medical records were reviewed, and follow-up information was collected for analysis of the patients' clinicopathologic characteristics as well as the effectiveness and safety of olaparib. A total of 251 patients receiving olaparib were included, with 84 as maintenance therapy after first-line chemotherapy (FL-M), 97 as maintenance therapy after platinum-sensitive recurrence (PSR-M), and 70 as active treatment (AT). The probability of progression-free survival (PFS) at 12 months was 87.6% in the FL-M group and 63.8% in the PSR-M group. According to the multivariate analysis, complete response (CR) to chemotherapy for the PSR-M patients was the only factor affecting the PFS (HR = 0.414, P = 0.014), and platinum sensitivity was the only factor affecting PFS improvement in the AT group (HR = 0.317, P = 0.009). In the AT group, the objective response rate was 37.1%, the CR rate was 7.1%, and 30% of the patients had stable disease. Eight (3.2%) patients discontinued olaparib due to toxicity. Anemia was the most common adverse event. In conclusion, olaparib is effective and well tolerated in the real-world setting of ovarian cancer treatment. Platinum sensitivity is positively correlated to the effectiveness of olaparib in both maintenance and active treatment.

Combined detection and subclass characteristics analysis of CTCs and CTECs by SE-iFISH in ovarian cancer.

OBJECTIVE: Hematogenous metastasis is essential for the progression of ovarian cancer (OC), and circulating tumor cells (CTCs) are part of the metastatic cascade. However, the detection rate of CTC is low due to the use of less sensitive detection methods. Therefore, this study aimed to detect CTCs and circulating tumorigenic endothelial cells (CTECs) in patients with OC using subtraction enrichment and immunostaining and fluorescence in situ hybridization (SE-iFISH). METHODS: We enrolled a total of 56 subjects, including 20 OC patients and 36 ovarian benign tumor patients. CTCs and CTECs were captured by subtraction enrichment (SE) and counted and classified according to immunofluorescence staining of tumor markers (TMs) carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) combined with fluorescence in situ hybridization (iFISH) of chromosome 8 (Chr8) aneuploidy. The diagnostic value and subtype characteristics of CTCs and CTECs were investigated. RESULTS: The detection rate of CTCs by SE-iFISH was high. Compared with CA125 and HE4, Chr8 aneuploidy was the major identification feature of CTC. CTC counts in OC were statistically higher than those in benign groups. CTC and CTEC with ≥pentaploidy were detected in both groups, illustrating the poor diagnostic value of CTC or CTEC. Distributions of triploid and tetraploid CTC subtypes were significantly different, and combined detection of triploid and tetraploid CTCs showed the best diagnostic value. In contrast, the distribution of CTECs in the OC and benign groups had no statistically significant difference. Small CTCs accounted for over 1/3 of the total CTC count. We also found that small CTCs and CTECs primarily comprised triploid cells, while large CTCs and CTECs mainly comprised pentaploidy and beyond. CONCLUSIONS: The application of SE-iFISH offered a more comprehensive understanding of heterogeneous CTCs and CTECs in OC. Analysis of subclass characteristics of the CTCs and CTECs according to Chr8 aneuploidy and cell size may broaden their potential clinical utility and deepen mechanistic studies in OC.

Ovarian endometrioid carcinoma and clear cell carcinoma: A 21-year retrospective study.

OBJECTIVE: This study aimed to identify the clinical characteristics of Chinese patients with ovarian endometrioid carcinoma (EC) and clear cell carcinoma (CCC) and to assess the impact of concurrent endometriosis on this group. METHODS: The present study reviewed the medical records of patients who received initial treatment and a postoperative pathological diagnosis of EC or CCC at our center in China between 1998 and 2018. RESULTS: Of 211 patients, 73 had pure EC, and 91 had pure CCC, and the remaining 47 had mixed cancer. The proportion of EC and CCC remained stable over past 21 years. The proportion of EC declined with aging and the age of EC onset to incline to the young. And the age of CCC onset had two peaks, namely, 36 and 77 years. After review by the pathologist, the number of endometriosis cases found in the pathological section of the analysis increased to 114, accounting for 54% of patients. As the stage progressed, the appearance of endometriosis became increasingly scarce in pathological sections(p = 0.001). Compared with CCC, EC had a higher frequency of concurrent endometrial cancer (independent endometrial lesions) and estrogen and progesterone receptor expression(p = 0.000). And more patients were in premenopausal state in EC group(p = 0.040). In the pure group, multivariate analysis showed that correlation existed between relevance to endometriosis and worse outcomes(p = 0.041). In patients with mixed cancer, mixed endometrioid histology was associated with better survival than other subtypes, even with stage III or poorly differentiated tumors(p = 0.001). CONCLUSIONS: CCC and EC which are common in ovarian cancer patients who have associated with endometriosis have distinct clinicopathological characteristics. Attention should be paid to ovarian cancer patients with a history of endometriosis and those with concurrent endometriosis in pathological sections.