The Prevalence and Associated Factors of Post-COVID-19 Fatigue: A Systematic Review and Meta-Analysis.

After the coronavirus disease 2019 (COVID-19) pandemic, numerous individuals experienced the enduring consequences of infection. One of the psychological symptoms that patients report most frequently is persistent fatigue, which is also called post-COVID-19 fatigue. This persistent fatigue can prolong recovery time for hospitalized patients and reduce exercise motivation for residents, affecting their health and working conditions. To determine the prevalence and associated factors, we conducted searches in PubMed, Embase, Web of Science, and Cochrane Library, from inception to 27 March 2023, and a total of 38 studies and 17,738 patients were included in this analysis. We analyzed data and estimated publication bias by Egger's test and funnel plot by STATA 14. We summarized the prevalence of post-COVID-19 fatigue and calculated the pooled OR to determine associated factors. This study revealed that the prevalence of fatigue in post-COVID-19 syndrome was 46.6% (95% CI: 38.5%-54.7%). Being female (OR: 0.40, 95% CI: 0.24-0.56), older age (OR: 0.04, 95% CI: 0.01-0.07), clinical severity (OR: 0.66, 95% CI: 0.24-1.09), the number of acute COVID symptoms (OR: 3.23, 95% CI: 1.83-5.69), preexisting hypertension (OR: 1.24, 95% CI: 1.08-1.42), lung disease (OR: 2.71, 95% CI: 1.07-6.89), and depression (OR: 1.55, 95% CI: 1.01-2.39) were risk factors for post-COVID-19 fatigue. By revealing the association of these factors with fatigue, it can help us to identify and treat post-COVID-19 fatigue early.

The influence of eight cognitive training regimes upon cognitive screening tool performance in post-stroke survivors: a network meta-analysis.

Background: Traditional meta-analysis offers only direct comparative evidence. The optimal cognitive training for poststroke cognitive impairment (PSCI) remains largely undetermined. Objectives: This study aims to assess and compare the effectiveness of selected cognitive training methods for PSCI patients and to identify and rank the most effective intervention programs. Methods: Searches were conducted in PubMed, Embase, Cochrane Library, Web of science, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biomedical Database for randomized controlled trials up to September 30, 2023. Two researchers independently performed literature screening, data extraction, and quality assessment. Network meta-analysis was utilized to synthesize the main findings. The primary outcome focused on the intervention's impact on subjective cognitive function, with secondary outcomes including effects on activities of daily living, motor function, and functional independence. This study is registered with PROSPERO (CRD42023463282). Results: Fifty eligible randomized controlled trials were identified, revealing eight distinct interventions. These interventions collectively demonstrate efficacy in enhancing cognition. Traditional cognitive training significantly improves overall cognitive function, daily living function, motor function, and functional independence. In Loewenstein Occupational Therapy Cognitive Assessment, Barthel Index, Fugl-Meyer Assessment, and Functional Independence Measure scales, a combination of computer-based and traditional cognitive training outperformed the conventional control group MD = 29.97 (95%CI: 16.3, 44.2), MD = 18.67 (95%CI: 9.78, 27.45), MD = 28.76 (95%CI: 5.46, 51.79) and MD = 42.2 (95%CI: 5.25, 78.99). In the MMSE scale, virtual reality cognitive training combined with traditional training was most effective MD = 8.01 (95%CI: 3.6, 12.4). On the MoCA scale, the combination of exercise and cognitive training showed superior results MD = 6.68 (95%CI: 2.55, 10.78). Only the combined computer-based and traditional cognitive training, as well as traditional cognitive training alone, significantly enhanced functional independence, with no notable differences in other pairwise interventions. Conclusion: The network meta-analysis suggests that augmenting traditional training with other modalities may enhance overall effectiveness. Specifically, interventions incorporating computer-based cognitive training appear to surpass other methods in improving cognition, daily living function, motor skills, and functional independence. The findings of this network meta-analysis provide evidence-based guidance for clinical decision-making. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier in PROSPERO (CRD42023463282).

A Saturation Artifacts Inpainting Method Based on Two-Stage GAN for Fluorescence Microscope Images.

Fluorescence microscopic images of cells contain a large number of morphological features that are used as an unbiased source of quantitative information about cell status, through which researchers can extract quantitative information about cells and study the biological phenomena of cells through statistical and analytical analysis. As an important research object of phenotypic analysis, images have a great influence on the research results. Saturation artifacts present in the image result in a loss of grayscale information that does not reveal the true value of fluorescence intensity. From the perspective of data post-processing, we propose a two-stage cell image recovery model based on a generative adversarial network to solve the problem of phenotypic feature loss caused by saturation artifacts. The model is capable of restoring large areas of missing phenotypic features. In the experiment, we adopt the strategy of progressive restoration to improve the robustness of the training effect and add the contextual attention structure to enhance the stability of the restoration effect. We hope to use deep learning methods to mitigate the effects of saturation artifacts to reveal how chemical, genetic, and environmental factors affect cell state, providing an effective tool for studying the field of biological variability and improving image quality in analysis.

The transcription factor ERF110 promotes cold tolerance by directly regulating sugar and sterol biosynthesis in citrus.

ERFs (ethylene-responsive factors) are known to play a key role in orchestrating cold stress signal transduction. However, the regulatory mechanisms and target genes of most ERFs are far from being well deciphered. In this study, we identified a cold-induced ERF, designated as PtrERF110, from trifoliate orange (Poncirus trifoliata L. Raf., also known as Citrus trifoliata L.), an elite cold-hardy plant. PtrERF110 is a nuclear protein with transcriptional activation activity. Overexpression of PtrERF110 remarkably enhanced cold tolerance in lemon (Citrus limon) and tobacco (Nicotiana tabacum), whereas VIGS (virus-induced gene silencing)-mediated knockdown of PtrERF110 drastically impaired the cold tolerance. RNA sequence analysis revealed that PtrERF110 overexpression resulted in global transcriptional reprogramming of a range of stress-responsive genes. Three of the genes, including PtrERD6L16 (early responsive dehydration 6-like transporters), PtrSPS4 (sucrose phosphate synthase 4), and PtrUGT80B1 (UDP-glucose: sterol glycosyltransferases 80B1), were confirmed as direct targets of PtrERF110. Consistently, PtrERF110-overexpressing plants exhibited higher levels of sugars and sterols compared to their wild type counterparts, whereas the VIGS plants had an opposite trend. Exogenous supply of sucrose restored the cold tolerance of PtrERF110-silencing plants. In addition, knockdown of PtrSPS4, PtrERD6L16, and PtrUGT80B1 substantially impaired the cold tolerance of P. trifoliata. Taken together, our findings indicate that PtrERF110 positively modulates cold tolerance by directly regulating sugar and sterol synthesis through transcriptionally activating PtrERD6L16, PtrSPS4, and PtrUGT80B1. The regulatory modules (ERF110-ERD6L16/SPS4/UGT80B1) unraveled in this study advance our understanding of the molecular mechanisms underlying sugar and sterol accumulation in plants subjected to cold stress.

Polyamines: pleiotropic molecules regulating plant development and enhancing crop yield and quality.

Polyamines (PAs) are pleiotropic bioorganic molecules. Cellular PA contents are determined by a balance between PA synthesis and degradation. PAs have been extensively demonstrated to play vital roles in the modulation of plant developmental processes and adaptation to various environmental stresses. In this review, the latest advances on the diverse roles of PAs in a range of developmental processes, such as morphogenesis, organogenesis, growth and development, and fruit ripening, are summarized and discussed. Besides, the crosstalk between PAs and phytohormones or other signalling molecules, including H2O2 and NO, involved in these processes is dwelled on. In addition, the attempts made to improve the yield and quality of grain and vegetable crops through altering the PA catabolism are enumerated. Finally, several other vital questions that remain unanswered are proposed and discussed. These include the mechanisms underlying the cooperative regulation of developmental processes by PAs and their interplaying partners like phytohormones, H2O2 and NO; PA transport for maintaining homeostasis; and utilization of PA anabolism/catabolism for generating high-yield and good-quality crops. This review aims to gain new insights into the pleiotropic role of PAs in the modulation of plant growth and development, which provides an alternative approach for manipulating and engineering valuable crop varieties that can be used in the future.

Efficacy and safety of adrenal arterial embolization for primary aldosteronism: a systematic review and meta-analysis.

Background: Primary aldosteronism (PA) is related with resistant hypertension and cardiovascular events. Adrenal artery embolization (AAE) is a choice for patients who refused surgery and medical therapy. However, whether AAE can effectively and safely treat PA is unclear. We performed this meta-analysis to determine the efficacy and safety of AAE for patients with PA. Methods: Databases including Cochrane Library, Embase, PubMed and Web of Science were used to obtain relevant articles published before July 30, 2023. The primary outcome was blood pressure before and after AAE. The second outcomes included changes in plasma aldosterone level, serum potassium level, and plasma cortisol level. Results: Finally, 7 prospective studies with 222 patients were included. The results showed that systolic and diastolic blood pressure was reduced by 21.68 mmHg (P<0.001) and 10.54 mmHg (P=0.007) respectively after AAE. The change in plasma aldosterone and serum potassium level was -11.52 ng/dL and 0.61 mmol/L respectively (P<0.001), whereas the reduction in cortisol level was not apparent. Moreover, AAE is a relatively safe procedure which only causes some minor complications such as back pain and fever. Conclusions: This meta-analysis indicated that AAE could effectively and safely treat PA. It is a good choice for patients that are not suitable for adrenalectomy or drug therapy.

Astrocytic 5-HT1A receptor mediates age-dependent hippocampal LTD and fear memory extinction in male mice.

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice. In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively. Furthermore, the astrocytic 5-HT1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders.

Bacmethy: A novel and convenient tool for investigating bacterial DNA methylation pattern and their transcriptional regulation effects.

DNA methylation serves as the primary mode of epigenetic regulation in prokaryotes, particularly through transcriptional regulation. With the rapid implementation of third-generation sequencing technology, we are currently experiencing a golden age of bacterial epigenomics. However, there has been a lack of comprehensive research exploring the versatility and consequential impact of bacterial DNA methylome on cellular and physiological functions. There is a critical need for a user-friendly bioinformatics tool that can effectively characterize DNA methylation modification features and predict the regulation patterns. To address this gap, the current study introduces Bacmethy, an innovative tool that utilizes SMRT-seq data and offers a range of analytical modules. First, the tool classifies methylation sites in the genome, highlighting the distinct regulations present under varying modification fractions and location enrichment. Furthermore, this tool enables us to identify regulatory region methylation and potential cis and trans interactions between methylation sites and regulatory effectors. Using benchmark data sets and our data, we show that our tool facilitates the understanding of the distinctive traits of DNA methylation modifications and predicts transcriptional regulation effects on important physiological and pathological functions. Bacmethy code is freely available, and the Docker image is downloadable. Bacmethy has been made available as a user-friendly web server interface at https://bacmethy.med.sustech.edu.cn.

Surgery versus no surgery in platinum-sensitive relapsed ovarian cancer: final overall survival analysis of the SOC-1 randomized phase 3 trial.

Surgery for platinum-sensitive, relapsed ovarian cancer (PSROC) is widely practiced but had contradictory survival outcomes in previous studies. In this multicenter, open-label, phase 3 trial, women with PSROC, and having had one previous therapy and no platinum-based chemotherapy (platinum-free interval) of 6 months or more, were randomly assigned to either the surgery group (182 patients) or the no-surgery group (control) (175 patients). Patients with resectable diseases were eligible according to the international model (iMODEL), combined with a positron emission tomography-computed tomography imaging. Overall survival (OS) and progression-free survival were coprimary endpoints in hierarchical testing, and a significantly longer progression-free survival with surgery was previously reported. Final analysis of OS was planned at data maturity of 59%. Between 19 July 2012 and 3 June 2019, 357 patients were enrolled. Median follow-up was 82.5 months. Median OS was 58.1 months with surgery and 52.1 months for control (hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.61-1.05, P = 0.11). The predefined threshold for statistical significance was not met, but prespecified sensitivity analysis was performed. Overall, 61 of 175 (35%) patients in control had crossed over to surgery following subsequent relapse, and adjusted HR for death in the surgery group compared with control was 0.76, 95% CI 0.58-0.99. In subgroup analysis of relapse sites by imaging, median survival was not estimable in the surgery group and was 69.5 months in control in patients with <20 sites (HR 0.69, 95% CI 0.46-1.03). Patients with a complete resection had the most favorable outcome, with a median OS of 73.0 months. Twenty-four of 182 (13.2%) patients remained relapse free and alive >60 months in the surgery group as compared with five of 175 (2.9%) patients in the control group. In patients with PSROC, surgery did not increase OS in the intention-to-treat population but resulted in a prolongation of survival following adjustment of crossover.ClinicalTrials.gov registration: NCT01611766 .

Genome-wide identification, expression analysis of WRKY transcription factors in Citrus ichangensis and functional validation of CiWRKY31 in response to cold stress.

BACKGROUND: Ichang papeda (Citrus ichangensis), a wild perennial plant of the Rutaceae family, is a cold-hardy plant. WRKY transcription factors are crucial regulators of plant growth and development as well as abiotic stress responses. However, the WRKY genes in C. ichangensis (CiWRKY) and their expression patterns under cold stress have not been thoroughly investigated, hindering our understanding of their role in cold tolerance. RESULTS: In this study, a total of 52 CiWRKY genes identified in the genome of C. ichangensis were classified into three main groups and five subgroups based on phylogenetic analysis. Comprehensive analyses of motif features, conserved domains, and gene structures were performed. Segmental duplication plays a significant role in the CiWRKY gene family expansion. Cis-acting element analysis revealed the presence of various stress-responsive elements in the promoters of the majority of CiWRKYs. Gene ontology (GO) analysis and protein-protein interaction predictions indicate that the CiWRKYs exhibit crucial roles in regulation of both development and stress response. Expression profiling analysis demonstrates that 14 CiWRKYs were substantially induced under cold stress. Virus-induced gene silencing (VIGS) assay confirmed that CiWRKY31, one of the cold-induced WRKYs, functions positively in regulation of cold tolerance. CONCLUSION: Sequence and protein properties of CiWRKYs were systematically analyzed. Among the 52 CiWRKY genes 14 members exhibited cold-responsive expression patterns, and CiWRKY31 was verified to be a positive regulator of cold tolerance. These findings pave way for future investigations to understand the molecular functions of CiWRKYs in cold tolerance and contribute to unravelling WRKYs that may be used for engineering cold tolerance in citrus.

Fusarium pseudograminearum biomass and toxin accumulation in wheat tissues with and without Fusarium crown rot symptoms.

Fusarium crown rot (FCR) is an important and devastating disease of wheat (Triticum aestivum) caused by the fungus Fusarium pseudograminearum and related pathogens. Using two distinct susceptible cultivars, we investigated the isolation frequencies of F. pseudograminearum and quantified its biomass accumulation and the levels of the associated toxins deoxynivalenol (DON) and DON-3-glucoside (D3G) in inoculated field-grown wheat plants. We detected F. pseudograminearum in stem, peduncle, rachis, and husk tissues, but not in grains, whereas DON and D3G accumulated in stem, rachis, husk, and grain tissues. Disease severity was positively correlated with the frequency of pathogen isolation, F. pseudograminearum biomass, and mycotoxin levels. The amount of F. pseudograminearum biomass and mycotoxin contents in asymptomatic tissue of diseased plants were associated with the distance of the tissue from the diseased internode and the disease severity of the plant. Thus, apparently healthy tissue may harbor F. pseudograminearum and contain associated mycotoxins. This research helps clarify the relationship between F. pseudograminearum occurrence, F. pseudograminearum biomass, and mycotoxin accumulation in tissues of susceptible wheat cultivars with or without disease symptoms, providing information that can lead to more effective control measures.

Exploring the pyro-phototronic effect for giant lateral photoresponse in an ITO/CdS/Si heterojunction position-sensitive detector.

The demand for a high-performance position sensitive detector (PSD), a novel type of photoelectric sensor, is increasing due to advancements in digitization and automation technology. Cadmium sulfide (CdS), a non-centrosymmetric material, holds significant potential in photoelectric devices. However, the pyroelectric effect of CdS in PSDs and its influence on lateral photoresponse are still unknown. In this work, we fabricated an ITO/CdS/Si heterojunction using chemical bath deposition (CBD) and investigated the pyro-phototronic effect under nonuniform illumination. The theory of electron-hole pairs' generation, separation, and carrier diffusion was carefully considered to understand the underlying mechanisms. Our experimental findings revealed that the device exhibited an exceptionally high position sensitivity (PS) of 1061.3 mV/mm, surpassing the generally observed PS of 655.1 mV/mm induced by single photovoltaic effect by 160.5%. Meanwhile, the PSD demonstrated rapid response times of 0.01 and 0.04 ms, respectively. Moreover, the influence of ambient temperature and electrode distance on the pyro-phototronic effect was well analyzed. Notably, the PSD exhibited remarkable stability even at ambient temperatures up to 150 °C. Despite the considerable working distance of 11 mm, the PS of the PSD remained at 128.99 mV/mm. These findings provide valuable theoretical and experimental foundations for optimizing the design and implementation of high-performance large working distance PSDs.

Transcriptome and metabolome atlas reveals contributions of sphingosine and chlorogenic acid to cold tolerance in Citrus.

Citrus is one of the most important fruit crop genera in the world, but many Citrus species are vulnerable to cold stress. Ichang papeda (Citrus ichangensis), a cold-hardy citrus species, holds great potential for identifying valuable metabolites that are critical for cold tolerance in Citrus. However, the metabolic changes and underlying mechanisms that regulate Ichang papeda cold tolerance remain largely unknown. In this study, we compared the metabolomes and transcriptomes of Ichang papeda and HB pummelo (Citrus grandis 'Hirado Buntan', a cold-sensitive species) to explore the critical metabolites and genes responsible for cold tolerance. Metabolomic analyses led to the identification of common and genotype-specific metabolites, consistent with transcriptomic alterations. Compared to HB pummelo under cold stress, Ichang papeda accumulated more sugars, flavonoids, and unsaturated fatty acids, which are well-characterized metabolites involved in stress responses. Interestingly, sphingosine and chlorogenic acid substantially accumulated only in Ichang papeda. Knockdown of CiSPT (C. ichangensis serine palmitoyltransferase) and CiHCT2 (C. ichangensis hydroxycinnamoyl-CoA: shikimate hydroxycinnamoyltransferase2), two genes involved in sphingosine and chlorogenic acid biosynthesis, dramatically decreased endogenous sphingosine and chlorogenic acid levels, respectively. This reduction in sphingosine and chlorogenic acid notably compromised the cold tolerance of Ichang papeda, whereas exogenous application of these metabolites increased plant cold tolerance. Taken together, our findings indicate that greater accumulation of a spectrum of metabolites, particularly sphingosine and chlorogenic acid, promotes cold tolerance in cold-tolerant citrus species. These findings broaden our understanding of plant metabolic alterations in response to cold stress and provide valuable targets that can be manipulated to improve Citrus cold tolerance.

First-line bevacizumab plus chemotherapy in Chinese patients with stage III/IV epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer: a phase III randomized controlled trial.

OBJECTIVE: First-line bevacizumab plus carboplatin and paclitaxel (CP) is approved for stage III/IV ovarian cancer treatment following initial surgical resection, based on global phase III GOG-0218 and ICON7 trials. This study evaluated the efficacy and safety of bevacizumab + CP as first-line ovarian cancer therapy in Chinese patients. METHODS: Patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer post-primary surgery were randomized 1:1 to receive 6 cycles of CP with bevacizumab/placebo, followed by bevacizumab/placebo maintenance until unacceptable toxicity or disease progression. Primary endpoint was investigator-assessed progression-free survival (PFS). Stratification factors were FIGO stage and debulking status (stage III optimally debulked vs stage III suboptimally debulked vs stage IV) and Eastern Cooperative Oncology Group performance status (0 vs 1 or 2). RESULTS: Of randomized patients, 51 received bevacizumab + CP and 49 received placebo + CP. Median PFS was 22.6 months with bevacizumab + CP (95% confidence interval [CI]=18.6, not estimable) and 12.3 months (95% CI=9.5, 15.0) with placebo + CP (stratified hazard ratio=0.30; 95% CI=0.17, 0.53). Treatment-related grade 3/4 adverse events occurred in 46 of 49 (94%) patients receiving bevacizumab + CP, and 34 of 50 (68%) receiving placebo + CP. CONCLUSION: Bevacizumab + CP showed clinically meaningful improvement in PFS vs placebo + CP, consistent with GOG-0218 results. Safety data were aligned with the known bevacizumab safety profile. These results support first-line bevacizumab + CP therapy in Chinese patients with ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03635489.

Rural-urban and racial differences in cesarean deliveries before and during the COVID-19 pandemic in South Carolina.

PROBLEM: Unnecessary cesarean delivery increases the risk of complications for birthing people and infants. BACKGROUND: Examining the intersectionality of rural and racial disparities in low-risk cesarean delivery is necessary to improve equity in quality obstetrics care. AIM: To evaluate rural and racial/ethnic differences in Nulliparous, Term, Singleton, Vertex (NTSV) and primary cesarean delivery rates before and during the COVID-19 pandemic in South Carolina. METHODS: This retrospective cohort study used birth certificates linked to all-payer hospital discharge data for South Carolina childbirths from 2018 to 2021. Multilevel logistic regressions examined differences in cesarean outcomes by rural/urban hospital location and race/ethnicity of birthing people during pre-pandemic (January 2018-February 2020) and peri-pandemic periods (March 2020-December 2021), adjusting for maternal, infant, and hospital characteristics among two low-risk pregnancy cohorts: 1) Nulliparous, Term, Singleton, Vertex (NTSV, n = 65,974) and 2) those without prior cesarean (primary, n = 167,928). FINDINGS: Black vs. White disparities remained for NTSV cesarean in adjusted models (urban pre-pandemic aOR = 1.34, 95 %CI 1.23-1.46) but were not significantly different for primary cesarean, apart from rural settings peri-pandemic (aOR = 0.87, 95 %CI 0.79-0.96). Hispanic individuals had higher adjusted odds of NTSV cesarean only for rural settings pre-pandemic (aOR = 1.28, 95 %CI 1.05-1.56), but this disparity was not significant during the pandemic (aOR = 1.13, 95 %CI 0.93-1.37). DISCUSSION AND CONCLUSION: Observed rural and racial/ethnic disparities in cesarean delivery outcomes were present before and during the COVID-19 pandemic. Strategies effective in reducing racial disparities in primary cesarean may be useful in also reducing Black vs. White NTSV cesarean disparities.

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.

Disulfidptosis-related signature elucidates the prognostic, immunologic, and therapeutic characteristics in ovarian cancer.

Introduction: Ovarian cancer (OC) is the deadliest malignancy in gynecology, but the mechanism of its initiation and progression is poorly elucidated. Disulfidptosis is a novel discovered type of regulatory cell death. This study aimed to develop a novel disulfidptosis-related prognostic signature (DRPS) for OC and explore the effects and potential treatment by disulfidptosis-related risk stratification. Methods: The disulfidptosis-related genes were first analyzed in bulk RNA-Seq and a prognostic nomogram was developed and validated by LASSO algorithm and multivariate cox regression. Then we systematically assessed the clinicopathological and mutational characteristics, pathway enrichment analysis, immune cell infiltration, single-cell-level expression, and drug sensitivity according to DRPS. Results: The DRPS was established with 6 genes (MYL6, PDLIM1, ACTN4, FLNB, SLC7A11, and CD2AP) and the corresponding prognostic nomogram was constructed based on the DRPS, FIGO stage, grade, and residual disease. Stratified by the risk score derived from DRPS, patients in high-risk group tended to have worse prognosis, lower level of disulfidptosis, activated oncogenic pathways, inhibitory tumor immune microenvironment, and higher sensitivity to specific drugs including epirubicin, stauroporine, navitoclax, and tamoxifen. Single-cell transcriptomic analysis revealed the expression level of genes in the DRPS significantly varied in different cell types between tumor and normal tissues. The protein-level expression of genes in the DRPS was validated by the immunohistochemical staining analysis. Conclusion: In this study, the DRPS and corresponding prognostic nomogram for OC were developed, which was important for OC prognostic assessment, tumor microenvironment modification, drug sensitivity prediction, and exploration of potential mechanisms in tumor development.

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].

Corrigendum to "SEMA4D acts as a novel oligogenic pathogenic gene of idiopathic hypogonadotropic hypogonadism through the PlexinB1/MET/RND1/RHOA/RAF1/MAPK signaling axis" [Genes & Diseases 10 (2023) 65-68].

[This corrects the article DOI: 10.1016/j.gendis.2022.05.030.].