Olaparib and niraparib as maintenance therapy in patients with newly diagnosed and platinum-sensitive recurrent ovarian cancer: A single-center study in China.

BACKGROUND: Poly adenosine-diphosphate-ribose polymerase (PARP) inhibitors (PARPi) have been approved to act as first-line maintenance (FL-M) therapy and as platinum-sensitive recurrent maintenance (PSR-M) therapy for ovarian cancer in China for >5 years. Herein, we have analyzed the clinical-application characteristics of olaparib and niraparib in ovarian cancer-maintenance therapy in a real-world setting to strengthen our understanding and promote their rational usage. METHODS: A retrospective chart review identified patients with newly diagnosed or platinum-sensitive recurrent ovarian cancer, who received olaparib or niraparib as maintenance therapy at Sichuan Cancer Hospital between August 1, 2018, and December 31, 2021. Patient medical records were reviewed. We grouped and analyzed patients based on the type of PARPi they used (the olaparib group and the niraparib group) and the line of PARPi maintenance therapy (the FL-M setting and the PSR-M setting). The primary endpoint was the 24-month progression-free survival (PFS) rate. RESULTS: In total, 131 patients (olaparib: n = 67, 51.1%; niraparib: n = 64, 48.9%) were enrolled. Breast cancer susceptibility genes (BRCA) mutations (BRCAm) were significantly less common in the niraparib group than in the olaparib group [9.4% (6/64) vs. 62.7% (42/67), P <0.001], especially in the FL-M setting [10.4% (5/48) vs. 91.4% (32/35), P <0.001]. The 24-month PFS rates in the FL-M and PSR-M settings were 60.4% and 45.7%, respectively. In patients with BRCAm, the 24-month PFS rates in the FL-M and PSR-M settings were 62.2% and 72.7%, respectively. CONCLUSIONS: Olaparib and niraparib were effective in patients with ovarian cancer without any new safety signals except for skin pigmentation. In patients with BRCAm, the 24-month PFS of the PARPi used in the PSR-M setting was even higher than that used in the FL-M setting.

Improvement of plant resistance to geminiviruses via protein de-S-acylation.

Geminiviruses are an important group of viruses that infect a variety of plants and result in heavy agricultural losses worldwide. The homologs of C4 (or L4) in monopartite geminiviruses and AC4 (or AL4) in bipartite geminiviruses are critical viral proteins. The C4 proteins from several geminiviruses are the substrates of S-acylation, a dynamic post-translational modification, for the maintenance of their membrane localization and function in virus infection. Here we initiated a screening and identified a plant protein ABAPT3 (Alpha/Beta Hydrolase Domain-containing Protein 17-like Acyl Protein Thioesterase 3) as the de-S-acylation enzyme of C4 encoded by BSCTV (Beet severe curly top virus). Overexpression of ABAPT3 reduced the S-acylation of BSCTV C4, disrupted its plasma membrane localization, inhibited its function in pathogenesis, and suppressed BSCTV infection. Because the S-acylation motifs are conserved among C4 from different geminiviruses, we tested the effect of ABAPT3 on the C4 protein of ToLCGdV (Tomato leaf curl Guangdong virus) from another geminivirus genus. Consistently, ABAPT3 overexpression also disrupted the S-acylation, subcellular localization, and function of ToLCGdV C4, and inhibited ToLCGdV infection. In summary, we provided a new approach to globally improve the resistance to different types of geminiviruses in plants via de-S-acylation of the viral C4 proteins and it can be extendedly used for suppression of geminivirus infection in crops.

S-acylation of a non-secreted peptide controls plant immunity via secreted-peptide signal activation.

Small peptides modulate multiple processes in plant cells, but their regulation by post-translational modification remains unclear. ROT4 (ROTUNDIFOLIA4) belongs to a family of Arabidopsis non-secreted small peptides, but knowledge on its molecular function and how it is regulated is limited. Here, we find that ROT4 is S-acylated in plant cells. S-acylation is an important form of protein lipidation, yet so far it has not been reported to regulate small peptides in plants. We show that this modification is essential for the plasma membrane association of ROT4. Overexpression of S-acylated ROT4 results in a dramatic increase in immune gene expression. S-acylation of ROT4 enhances its interaction with BSK5 (BRASSINOSTEROID-SIGNALING KINASE 5) to block the association between BSK5 and PEPR1 (PEP RECEPTOR1), a receptor kinase for secreted plant elicitor peptides (PEPs), thereby activating immune signaling. Phenotype analysis indicates that S-acylation is necessary for ROT4 functions in pathogen resistance, PEP response, and the regulation of development. Collectively, our work reveals an important role for S-acylation in the cross-talk of non-secreted and secreted peptide signaling in plant immunity.

Salicylic acid attenuates brassinosteroid signaling via protein de-S-acylation.

Brassinosteroids (BRs) are important plant hormones involved in many aspects of development. Here, we show that BRASSINOSTEROID SIGNALING KINASEs (BSKs), key components of the BR pathway, are precisely controlled via de-S-acylation mediated by the defense hormone salicylic acid (SA). Most Arabidopsis BSK members are substrates of S-acylation, a reversible protein lipidation that is essential for their membrane localization and physiological function. We establish that SA interferes with the plasma membrane localization and function of BSKs by decreasing their S-acylation levels, identifying ABAPT11 (ALPHA/BETA HYDROLASE DOMAIN-CONTAINING PROTEIN 17-LIKE ACYL PROTEIN THIOESTERASE 11) as an enzyme whose expression is quickly induced by SA. ABAPT11 de-S-acylates most BSK family members, thus integrating BR and SA signaling for the control of plant development. In summary, we show that BSK-mediated BR signaling is regulated by SA-induced protein de-S-acylation, which improves our understanding of the function of protein modifications in plant hormone cross talk.

Longitudinal Relation between Family Socio-Economic Status and Problem Behaviors in Chinese Children: The Roles of Sense of Coherence and Maternal Warmth.

Literature has well-documented the relation of family socio-economic status (SES) to children's problem behaviors, yet the complex mechanisms underlying the relation are not well understood. Therefore, the primary goal of this one-year longitudinal study was to explore the mediating role of children's sense of coherence and the moderating role of perceived maternal warmth in the association between family SES and externalizing and internalizing problems in Chinese children. The sample consisted of 913 children (493 boys; Mage = 11.50 years, SD = 1.04) in fourth to sixth grades in an urban area in mainland China. Data were obtained from multiple sources, including child self-reports, parental reports, and teacher ratings. The results indicated that children's sense of coherence mediated the association between family SES and internalizing problem behaviors, but not externalizing problem behaviors. This mediating role was also moderated by maternal warmth and specifically, family SES was negatively associated with internalizing problem behaviors via the sense of coherence for children who perceived high maternal warmth. Generally, these results highlighted the possible roles of a sense of coherence and maternal warmth in the longitudinal implications of family SES for Chinese children's internalizing problems.

APOBEC3B stratifies ovarian clear cell carcinoma with distinct immunophenotype and prognosis.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a challenging disease due to its intrinsic chemoresistance. Immunotherapy is an emerging treatment option but currently impeded by insufficient understanding of OCCC immunophenotypes and their molecular determinants. METHODS: Whole-genome sequencing on 23 pathologically confirmed patients was employed to depict the genomic profile of primary OCCCs. APOBEC3B expression and digital pathology-based Immunoscore were assessed by performing immunohistochemistry and correlated with clinical outcomes. RESULTS: An APOBEC-positive (APOBEC+) subtype was identified based on the characteristic mutational signature and prevalent kataegis events. APOBEC + OCCC displayed favourable prognosis across one internal and two external patient cohorts. The improved outcome was ascribable to increased lymphocytic infiltration. Similar phenomena of APOBEC3B expression and T-cell accumulation were observed in endometriotic tissues, suggesting that APOBEC-induced mutagenesis and immunogenicity could occur early during OCCC pathogenesis. Corroborating these results, a case report was presented for an APOBEC + patient demonstrating inflamed tumour microenvironment and clinical response to immune checkpoint blockade. CONCLUSIONS: Our findings implicate APOBEC3B as a novel mechanism of OCCC stratification with prognostic value and as a potential predictive biomarker that may inform immunotherapeutic opportunities.

Development and external validation of nomograms for predicting individual survival in patients with ovarian clear cell carcinoma.

PURPOSE: Ovarian clear cell carcinoma (OCCC) is a distinct and highly malignant subtype of ovarian cancer with high individual heterogeneity in survival that requires specific prognostic predictive tools. Thus, this study aimed to construct and validate nomograms for predicting individual survival in OCCC patients. METHODS: In total, 91 patients with OCCC who were diagnosed and treated at Renji Hospital between 2010 and 2020 were extracted as the training cohort, then 86 patients from the First Affiliated Hospital of USTC were used as the external validation cohort. Prognostic factors that affect survival were identified using least absolute shrinkage and selection operator regression. Nomograms of progression-free survival (PFS) and overall survival (OS) were then established with the Cox regression model and the performance was subsequently evaluated using the concordance index (C-index), calibration plots, decision curve analysis (DCA), and risk subgroup classification. RESULTS: Advanced tumor, ascites of >400 mL, lymph node-positive, CA199 of >142.3 IU/mL, and fibrinogen of >5.36 g/L were identified as risk factors for OS while advanced tumor, ascites of >400 mL, lymph node-positive, and fibrinogen of >5.36 g/L were risk factors for PFS. The C-indexes for the OS and PFS nomograms were 0.899 and 0.731 in the training cohort and 0.804 and 0.787 in the validation cohort, respectively. The calibration plots showed that nomograms could provide better consistency in predicting patient survival than the FIGO staging system. DCA also demonstrated that nomograms were more clinically beneficial than the FIGO staging system. Additionally, patients could be classified into two risk groups based on scores using nomograms, with significant survival differences. CONCLUSIONS: We developed nomograms that could more objectively and reliably predict the individual survival of patients with OCCC compared with the FIGO staging system. These tools might assist in clinical decision-making and management of patients with OCCC to improve their survival outcomes.

Space-Confined seeding and growth of ordered arrays of TiO2 hierarchical nanostructures.

Here, we report a facile approach to fabricate large area ordered arrays of TiO2 hierarchical nanostructures through space-confined seeding and growth on inverted pyramid templates. The mechanisms of space-confined seeding and growth have been systematically explored and studied. The drying TiO2 seed precursor solution prefers to accumulate on the narrow structures including the centre and edges of the inverted pyramid structures, which facilitates to reduce the free energy of the precursor solution surface and form crystal seeds. Followed by hydrothermal treatment, selective growth of TiO2 hierarchical nanostructures on desirable locations, such as only on the centre, only on the edges, or on the entire surface of the inverted pyramid templates, can be achieved. In addition, the growth temperature, duration and solvents affect the morphology of TiO2 hierarchical nanostructures. This work may provide a universal approach to obtain ordered arrays of metal oxide (e.g. ZnO and MnO2, etc.) nanostructures for applications in optics, electrics, energy, and catalysis.

ABA INSENSITIVE 5 confers geminivirus resistance via suppression of the viral promoter activity in plants.

Geminiviruses are a large group of plant viruses that have been a serious threat to worldwide agriculture. Transcription of the virus-encoded genes is necessary for geminiviruses to complete their life cycle, but the host proteins which directly target geminivirus promoters for suppression of viral gene transcription remain to be identified. Using Beet severe curly top virus (BSCTV) which causes severe plant symptoms as a system, we performed a yeast one-hybrid screening and identified ABA INSENSITIVE 5 (ABI5), a critical transcription factor in Abscisic acid (ABA) signaling transduction, as an interactor with the viral promoter. Further data showed that an ABA-responsive element in the viral promoter is necessary for its interaction with ABI5 and symptom development. Overexpression of ABI5 suppresses the transcription activity of the viral promoter and BSCTV infection in Nicotiana benthamiana and Arabidopsis; whilst depletion of ABI5 enhances the infection of BSCTV in Arabidopsis. Taken together, our study uncovered the function of ABI5 in the plant-virus interaction and will provide us with a new strategy to protect crops from geminivirus infection.

Prognostic Value of Pretreatment Glasgow Prognostic Score/Modified Glasgow Prognostic Score in Ovarian Cancer: A Systematic Review and Meta-Analysis.

To explore prognostic value of pretreatment Glasgow prognostic score (GPS) and modified Glasgow prognostic score (mGPS) in ovarian cancer patients.The PubMed, EMBASE (via OVID), and Web of Science databases were comprehensively searched for eligible studies. The hazard ratios (HRs) with 95% confidence intervals (CIs) were combined to evaluate the association of pretreatment GPS/mGPS with overall survival (OS) and progression-free survival (PFS) of ovarian cancer patients. STATA 12.0 version software was applied for statistical analysis.A total of eight retrospective studies involving 2260 were included into this systematic review and meta-analysis. The pooled results indicated that patients with elevated pretreatment GPS or mGPS had poorer OS (HR = 1.62, 95% CI: 1.38-1.91, P＜.001) and PFS (HR = 1.40, 95% CI: 1.02-1.93, P = .039) than patients with pretreatment GPS or mGPS 0. Subgroup analysis based on the type of score (GPS or mGPS) and tumor stage for OS were also performed and the results were consistent with above findings.Pretreatment GPS/mGPS might serve as promising prognostic indexes for ovarian cancer patients. More prospective studies with high-quality are needed to verify our findings.

An ABHD17-like hydrolase screening system to identify de-S-acylation enzymes of protein substrates in plant cells.

Protein S-acylation is an important post-translational modification in eukaryotes, regulating the subcellular localization, trafficking, stability, and activity of substrate proteins. The dynamic regulation of this reversible modification is mediated inversely by protein S-acyltransferases and de-S-acylation enzymes, but the de-S-acylation mechanism remains unclear in plant cells. Here, we characterized a group of putative protein de-S-acylation enzymes in Arabidopsis thaliana, including 11 members of Alpha/Beta Hydrolase Domain-containing Protein 17-like acyl protein thioesterases (ABAPTs). A robust system was then established for the screening of de-S-acylation enzymes of protein substrates in plant cells, based on the effects of substrate localization and confirmed via the protein S-acylation levels. Using this system, the ABAPTs, which specifically reduced the S-acylation levels and disrupted the plasma membrane localization of five immunity-related proteins, were identified respectively in Arabidopsis. Further results indicated that the de-S-acylation of RPM1-Interacting Protein 4, which was mediated by ABAPT8, resulted in an increase of cell death in Arabidopsis and Nicotiana benthamiana, supporting the physiological role of the ABAPTs in plants. Collectively, our current work provides a powerful and reliable system to identify the pairs of plant protein substrates and de-S-acylation enzymes for further studies on the dynamic regulation of plant protein S-acylation.

How Does Self-Concept Differentiation Work in Chinese Retirees: A Moderated Mediation Analysis.

Self-concept differentiation (SCD) is a sign of fragmentation of the self rather than specialization of role identities for its robust relationship with psychological adjustment. However, little is known about the mechanisms underlying the relationship between SCD and psychological adjustment. The aim of this study was to examine the mediating role of self-consistency and congruence (SCC) in the association between SCD and psychological adjustment (psychological well-being, depression, and anxiety), and the moderating role of age in the relationship between SCD and SCC. This moderated mediation model was examined among 158 Chinese retirees (mean age = 71.12, SD = 9.13), who completed measurements regarding SCD, SCC, psychological well-being, anxiety, and depression. The results showed that SCC partially mediated the links between SCD and the indices of psychological adjustment. Furthermore, age moderated this mediation effect, which was found in mean and high-age participants, but not in low-age ones. Our findings indicate that, at different age stages, the internal mechanisms of SCD affecting psychological adaptation are not the same, and a low differentiated or highly integrated self can serve as an adaptive resource to maintain high subjective well-being of the elderly and protect them from anxiety and depression.

Protein modification: A critical modulator in the interaction between geminiviruses and host plants.

Geminiviruses are a large group of single-stranded DNA viruses that infect plants and cause severe agricultural losses worldwide. Given geminiviruses only have small genomes that encode a few proteins, viral factors have to interact with host components to establish an environment suitable for virus infection, whilst the host immunity system recognizes and targets these viral components during infection. Post-translational protein modifications, such as phosphorylation, lipidation, ubiquitination, SUMOylation, acetylation and methylation, have been reported to be critical during the interplay between host plants and geminiviruses. Here we summarize the research progress, including phosphorylation and lipidation which usually control the activity and localization of viral factors; as well as ubiquitination and histone modification which are predominantly interfered with by viral components. We also discuss the dynamic competition on protein modifications between host defence and geminivirus efficient infection, as well as potential applications of protein modifications in geminivirus resistance. The summary and perspective of this topic will improve our understanding on the mechanism of geminivirus-plant interaction and contribute to further protection of plants from virus infection.

Danger peptide signaling enhances internalization of a geminivirus symptom determinant in plant cells during infection.

Geminiviruses are DNA viruses that cause severe diseases in diverse species of plants, resulting in considerable agricultural losses worldwide. C4 proteins are a major symptom determinant in several geminiviruses, including Beet severe curly top virus (BSCTV). Here, we uncovered a novel mechanism by which danger peptide signaling enhances the internalization of BSCTV C4 in plant cells. Previous studies showed that this signaling is important for activation of bacterium- and fungus-triggered immune responses, but its function in plant-virus interactions was previously unknown. Pep1 RECEPTOR1 (PEPR1) and PEPR2 are receptor kinases recognized by Peps (plant elicitor peptides) in the danger peptide pathway. We found that BSCTV C4 up-regulated and interacted with PEPR2 but not PEPR1. The Pep1-PEPR2 complex stimulated the internalization of C4 in both Arabidopsis and Nicotiana benthamiana cells. Furthermore, C4 induced callus formation in Arabidopsis, which was suppressed by PEPR2 overexpression but enhanced in the pepr2 mutants. In the presence of Pep1, overexpression of PEPR2 suppressed BSCTV infection in N. benthamiana. Exogenous Pep1 also reduced BSCTV infection in Arabidopsis in a PEPR2-dependent manner. Thus, PEPR2 recognizes the symptom determinant C4 and enhances its internalization mediated by danger peptides, suppressing BSCTV infection.

Biochar amendment immobilizes arsenic in farmland and reduces its bioavailability.

This study aimed to determine effects of biochar derived from wheat straw at 500 °C on arsenic immobilization in a soil-Brassica campestris L system. When the soils amended with 4% modified biochar (MBC), 0.5% Fe grit as zero-valent iron (ZVI), 0.5% Fe grit + 4% MBC (ZMBC), 0.5% ZVI + 4% biochar (ZBC), 4% biochar (BC), and control (without amendments), it confirmed that available arsenic concentration in soils occurred in the following order: ZMBC < MBC < ZVI < ZBC < Control < BC. Water-soluble As (WSAs) was reduced by 89.74% and 92.30% in MBC- and ZMBC-amended soils, respectively, compared to the control. When MBC applied into soil, As uptake of shoot and root decreased by 44.55% and 45.40%, respectively, and ZMBC resulted in 74.92% and 71.80% reduction in shoot and root As of Brassica campestris L. Immobilization effect of As in ZBC was also observed though BC elevated plant As uptake significantly. The immobilization effect of MBC was mainly attributed to Fe2O3 impregnation illustrated by x-ray diffraction (XRD) and scanning electron microscopy (SEM) images through sorption, precipitation, and coprecipitation. Such Fe containing complexes might impede As translocation from root to shoot and subsequently reduce As accumulation in the plant with modified biochar amendment.

Geminivirus C4: Interplaying with Receptor-like Kinases.

Geminivirus infection results in systemic symptoms in plants, but the mechanism by which the virus affects cell-to-cell signalling involved in development and resistance remains unclear. Based on recent evidence, we suggest a potential mechanism that geminivirus C4 proteins interfere with intercellular signals by interacting with receptor-like kinases on the plasma membrane.

S-acylation of a geminivirus C4 protein is essential for regulating the CLAVATA pathway in symptom determination.

Geminiviruses, such as beet severe curly top virus (BSCTV), are a group of DNA viruses that cause severe plant diseases and agricultural losses. The C4 protein is a major symptom determinant in several geminiviruses; however, its regulatory mechanism and molecular function in plant cells remain unclear. Here, we show that BSCTV C4 is S-acylated in planta, and that this post-translational lipid modification is necessary for its membrane localization and functions, especially its regulation of shoot development of host plants. Furthermore, the S-acylated form of C4 interacts with CLAVATA 1 (CLV1), an important receptor kinase in meristem maintenance, and consequentially affects the expression of WUSCHEL, a major target of CLV1. The abnormal development of siliques in Arabidopsis thaliana infected with BSCTV is also dependent on the S-acylation of C4, implying a potential role of CLAVATA signaling in this process. Collectively, our results show that S-acylation is essential for BSCTV C4 function, including the regulation of the CLAVATA pathway, during geminivirus infection.