Glycolysis regulation in tumor-associated macrophages: Its role in tumor development and cancer treatment.

Tumor-associated macrophages constitute the main cell population in the tumor microenvironment and play a crucial role in regulating the microenvironment composition. Emerging evidence has revealed that the metabolic profile determines the tumor-associated macrophage phenotype. Tumor-associated macrophage function is highly dependent on glucose metabolism, with glycolysis being the major metabolic pathway. Recent reports have demonstrated diversity in glucose flux of tumor-associated macrophages and complex substance communication with cancer cells. However, how the glucose flux in tumor-associated macrophages connects with glycolysis to influence tumor progression and the tumor microenvironment is still obscure. Moreover, while the development of single-cell sequencing technology allows a clearer and more accurate classification of tumor-associated macrophages, the metabolic profiles of tumor-associated macrophages from the perspective of single-cell omics has not been well summarized. Here, we review the current state of knowledge on glucose metabolism in tumor-associated macrophages and summarize the metabolic profiles of different tumor-associated macrophage subtypes from the perspective of single-cell omics. Additionally, we describe the current strategies targeting glycolysis in tumor-associated macrophages for cancer therapy.

Phase 1b/2 study of penpulimab (AK105), an antiprogrammed cell death-1 immunoglobulin G1 antibody, in advanced or metastatic solid tumors (AK105-204).

BACKGROUND: Penpulimab, a new-generation antiprogrammed cell death-1 immunoglobulin G1 monoclonal antibody, was engineered to optimize receptor occupancy and eliminate fragment crystallizable γ-mediated effector function. In this multicenter, phase 1b/2, multicohort study, the objective was to investigate the efficacy, safety, and immunogenicity of penpulimab in advanced solid tumors. METHODS: Patients who had unresectable, advanced solid tumors were enrolled from six centers and received 200 mg penpulimab on day 1 every 2 weeks for up to 24 months. The primary end point was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, version criteria 1.1. RESULTS: Between September 2, 2019, and January 1, 2020, 65 patients were enrolled and received penpulimab. At the time of data cutoff (May 11, 2022), the median follow-up was 12.6 months (range, 1.1-28.6 months). The ORR was 12.3 (95% confidence interval [CI], 5.5%-22.8%), with three (4.6%) complete responses and five (7.7%) partial responses. Twelve patients (18.5%) achieved stable disease, resulting in a disease control rate of 30.8% (95% CI, 19.9%-43.4%). The median duration of response was not reached (95% CI, 6.70 months to not estimable). In all cohorts, the median progression-free survival was 1.74 months (95% CI, 1.41-2.69 months), and the median overall survival was 16.59 months (95% CI, 7.82-22.18 months). Grade 3 or greater treatment-related adverse events and immune-related adverse events occurred in 9.2% and 27.7% of patients, respectively. Positive antidrug antibody responses to penpulimab were observed in one patient (1.8%). CONCLUSIONS: Penpulimab showed promising antitumor activity with an acceptable safety profile, offering a potential new treatment approach for solid tumors. These findings supported the evaluation of penpulimab's durable activity and safety, as monotherapy or in combination therapy, in specific malignancies.

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.

Bispecific Nanobody-Aptamer Conjugates for Enhanced Cancer Therapy in Solid Tumors.

Bispecific antibodies possess exceptional potential as therapeutic agents due to their capacity to bind to two different antigens simultaneously. However, challenges pertain to unsatisfactory stability, manufacturing complexity, and limited tumor penetration hinder their broad applicability. In this study, a versatile technology is presented for the rapid generation of bispecific nanobody-aptamer conjugates with efficient tumor penetration. The approach utilizes microbial transglutaminase (MTGase) and click chemistry to achieve site-specific conjugation of nanobodies and aptamers, which are termed nanotamers. The nanotamers recognize and bind to two types of molecular targets expressed on cancer cells. As a prototype, a bispecific nanotamer is developed that binds both clusters of differentiation 47 (CD47) and mesenchymal epithelial transition receptor (Met) expressed on the tumor cell membrane. This CD47-Met nanotamer demonstrates high affinity and specificity toward tumor cells expressing both targets, exhibits improved receptor functional inhibition through a strong steric hindrance effect. Moreover, its capacity for deep tumor penetration greatly enhances the impact of conventional chemotherapy on antitumor efficacy. The as-developed nanotamer synthesis approach shows promise to customize bispecific molecular probes targeting different cancer types and different therapeutic goals.

Stress response membrane protein OsSMP2 negatively regulates rice tolerance to drought.

In a gene chip analysis, rice (Oryza sativa) OsSMP2 gene expression was induced under various abiotic stresses, prompting an investigation into its role in drought resistance and abscisic acid signaling. Subsequent experiments, including qRT-PCR and ß-glucuronidase activity detection, affirmed the OsSMP2 gene's predominant induction by drought stress. Subcellular localization experiments indicated the OsSMP2 protein primarily localizes to the cell membrane system. Overexpressing OsSMP2 increased sensitivity to exogenous abscisic acid, reducing drought resistance and leading to reactive oxygen species accumulation under drought stress. Conversely, in simulated drought experiments, OsSMP2-silenced transgenic plants showed significantly longer roots compared with the wild-type Nipponbare. These results suggest that OsSMP2 overexpression negatively affects rice drought resistance, offering valuable insights into molecular mechanisms, and highlight OsSMP2 as a potential target for enhancing crop resilience to drought stress.

An Aptamer-Based Nanoflow Cytometry Method for the Molecular Detection and Classification of Ovarian Cancers through Profiling of Tumor Markers on Small Extracellular Vesicles.

Molecular profiling of protein markers on small extracellular vesicles (sEVs) is a promising strategy for the precise detection and classification of ovarian cancers. However, this strategy is challenging owing to the lack of simple and practical detection methods. In this work, using an aptamer-based nanoflow cytometry (nFCM) detection strategy, a simple and rapid method for the molecular profiling of multiple protein markers on sEVs was developed. The protein markers can be easily labeled with aptamer probes and then rapidly profiled by nFCM. Seven cancer-associated protein markers, including CA125, STIP1, CD24, EpCAM, EGFR, MUC1, and HER2, on plasma sEVs were profiled for the molecular detection and classification of ovarian cancers. Profiling these seven protein markers enabled the precise detection of ovarian cancer with a high accuracy of 94.2 %. In addition, combined with machine learning algorithms, such as linear discriminant analysis (LDA) and random forest (RF), the molecular classifications of ovarian cancer cell lines and subtypes were achieved with overall accuracies of 82.9 % and 55.4 %, respectively. Therefore, this simple, rapid, and non-invasive method exhibited considerable potential for the auxiliary diagnosis and molecular classification of ovarian cancers in clinical practice.

Dual CAR-T cells to treat cancers co-expressing NKG2D and PD1 ligands in xenograft models of peritoneal metastasis.

While the expression of either NKG2D ligands or PD-1 ligands has been reported in various types of cancers, the co-expression of the two sets of ligands in the same tumour tissues is still un-investigated. After examining 68 primary ovarian cancer samples, we observed around 80% of the co-expression in low grade serous and endometrioid ovarian cancer samples. We then constructed a dual CAR system that splits the conventional single-input of a 2nd generation CAR into two independent chimeric receptors, one composed of the NKG2D extracellular domain linked with DAP12 for T cell activation and another using the PD-1 extracellular domain linked with 4-1BB for costimulatory signal 2 input. Given the limitation of the low-affinity PD-1 receptor in recognizing cancer cells with low levels of PD-1 ligands, we also used a high-affinity scFv specific to PD-L1 in our combinatorial approach to expand the range of target cancer cells with different expression levels of PD-L1. The two types of dual CAR-T cells were generated through electroporation of non-viral piggyBac transposon plasmids and were effective in eliminating the target cancer cells. Especially, the dual CAR-T cells with anti-PD-L1 scFv were capable of eradicating established tumors in mouse models of peritoneal metastasis of colorectal cancer and ovarian cancer. Since both NKG2D ligands and PD-1 ligands have been marked as favourable cancer therapeutic targets, the new dual CAR-T cells developed in this study hold attractive application potential in treating metastatic peritoneal carcinoma.

Efficacy and safety of zimberelimab (GLS-010) monotherapy in patients with recurrent or metastatic cervical cancer: a multicenter, single-arm, phase II study.

OBJECTIVE: There is an unmet need to improve clinical outcomes for patients with recurrent/metastatic cervical cancer. Checkpoint inhibitors represent a promising treatment strategy. We evaluated the safety and anti-tumor activity of zimberelimab, an anti-programmed cell death protein-1 antibody, in patients with previously treated, recurrent, metastatic cervical cancer. METHODS: This phase II, single-arm, open-label study used a Simon two-stage minimax design. Eligible patients were women aged 18-75 years with programmed death ligand-1-positive recurrent or metastatic cervical cancer that had progressed after first- or subsequent-line chemotherapy (Eastern Cooperative Oncology Group (ECOG) performance status 0-1). Patients received intravenous zimberelimab (240 mg every 2 weeks) for 2 years until disease progression, intolerable adverse effects, or withdrawal from the study. The primary endpoint was objective response rate assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, by an independent review committee. RESULTS: A total of 105 patients were enrolled. Median age was 51 (range, 31-75) years; 63.8% had an ECOG performance status of 1. The median number of previous treatment lines was 1 (range, 1-4). Median follow-up was 16.9 (range, 16.3-18.4) months. The objective response rate was 27.6%, and the disease control rate was 55.2%. Median duration of response was not reached. Median overall survival was 16.8 months, and median progression-free survival was 3.7 months. The incidence of treatment-related adverse events of any grade was 78.1%, of which the most common were hypothyroidism (26.7%) and anemia (19.0%). CONCLUSION: Zimberelimab monotherapy demonstrated durable anti-tumor activity and an acceptable safety profile in patients with cervical cancer. CLINICAL TRIAL REGISTRATION: NCT03972722.

Pulmonary metastasectomy for recurrent metastatic ovarian cancer.

AIM: The prognosis of patients with ovarian cancer with lung metastasis is poor; data on pulmonary metastasectomy for such patients are lacking. This study aimed to determine the safety and feasibility of pulmonary resection as part of cytoreductive surgery for recurrent metastatic ovarian cancer. METHODS: Medical records of patients with ovarian cancer, who underwent pulmonary resection for lung metastasis in our hospital from April 2012 to February 2022, were retrospectively reviewed. RESULTS: Ten patients were included (median age, 53 years). Five patients had metastatic disease limited to the lungs. Additional surgeries included diaphragm resection, partial hepatectomy, para-aortic lymph node dissection, and cytoreduction. We achieved complete cytoreduction for all patients without severe complications, and the 30-day mortality was zero. After a median follow-up of 23 months, four of the patients experienced recurrence. One patient recurred 9 months after the operation and was lost to follow-up at 17 months, two died at 68 and 26 months respectively, one is alive with disease (23 months), and six are alive without recurrence, among whom two have survived for 56 and 124 months. CONCLUSIONS: Pulmonary resection for recurrent metastatic ovarian cancer seems safe and feasible, with long-term survival observed in certain patients. Pulmonary metastasectomy can be performed as part of the debulking surgery for selected patients with relapsed metastatic ovarian cancer. Both the patient lost to follow-up and the one who died at 26 months, had two lung metastatic nodules and did not receive postoperative chemotherapy, which might have led to relatively poor prognosis.

Margin-Based Modal Adaptive Learning for Visible-Infrared Person Re-Identification.

Visible-infrared person re-identification (VIPR) has great potential for intelligent transportation systems for constructing smart cities, but it is challenging to utilize due to the huge modal discrepancy between visible and infrared images. Although visible and infrared data can appear to be two domains, VIPR is not identical to domain adaptation as it can massively eliminate modal discrepancies. Because VIPR has complete identity information on both visible and infrared modalities, once the domain adaption is overemphasized, the discriminative appearance information on the visible and infrared domains would drain. For that, we propose a novel margin-based modal adaptive learning (MMAL) method for VIPR in this paper. On each domain, we apply triplet and label smoothing cross-entropy functions to learn appearance-discriminative features. Between the two domains, we design a simple yet effective marginal maximum mean discrepancy (M3D) loss function to avoid an excessive suppression of modal discrepancies to protect the features' discriminative ability on each domain. As a result, our MMAL method could learn modal-invariant yet appearance-discriminative features for improving VIPR. The experimental results show that our MMAL method acquires state-of-the-art VIPR performance, e.g., on the RegDB dataset in the visible-to-infrared retrieval mode, the rank-1 accuracy is 93.24% and the mean average precision is 83.77%.

Progressively Hybrid Transformer for Multi-Modal Vehicle Re-Identification.

Multi-modal (i.e., visible, near-infrared, and thermal-infrared) vehicle re-identification has good potential to search vehicles of interest in low illumination. However, due to the fact that different modalities have varying imaging characteristics, a proper multi-modal complementary information fusion is crucial to multi-modal vehicle re-identification. For that, this paper proposes a progressively hybrid transformer (PHT). The PHT method consists of two aspects: random hybrid augmentation (RHA) and a feature hybrid mechanism (FHM). Regarding RHA, an image random cropper and a local region hybrider are designed. The image random cropper simultaneously crops multi-modal images of random positions, random numbers, random sizes, and random aspect ratios to generate local regions. The local region hybrider fuses the cropped regions to let regions of each modal bring local structural characteristics of all modalities, mitigating modal differences at the beginning of feature learning. Regarding the FHM, a modal-specific controller and a modal information embedding are designed to effectively fuse multi-modal information at the feature level. Experimental results show the proposed method wins the state-of-the-art method by a larger 2.7% mAP on RGBNT100 and a larger 6.6% mAP on RGBN300, demonstrating that the proposed method can learn multi-modal complementary information effectively.

AP2/EREBP Pathway Plays an Important Role in Chaling Wild Rice Tolerance to Cold Stress.

Cold stress is the main factor limiting rice production and distribution. Chaling wild rice can survive in cold winters. AP2/EREBP is a known transcription factor family associated with abiotic stress. We identified the members of the AP2/EREBP transcription factor family in rice, maize, and Arabidopsis, and conducted collinearity analysis and gene family analysis. We used Affymetrix array technology to analyze the expression of AP2/EREBP family genes in Chaling wild rice and cultivated rice cultivar Pei'ai64S, which is sensitive to cold. According to the GeneChip results, the expression levels of AP2/EREBP genes in Chaling wild rice were different from those in Pei'ai64S; and the increase rate of 36 AP2/EREBP genes in Chaling wild rice was higher than that in Pei'ai64S. Meanwhile, the MYC elements in cultivated rice and Chaling wild rice for the Os01g49830, Os03g08470, and Os03g64260 genes had different promoter sequences, resulting in the high expression of these genes in Chaling wild rice under low-temperature conditions. Furthermore, we analyzed the upstream and downstream genes of the AP2/EREBP transcription factor family and studied the conservation of these genes. We found that the upstream transcription factors were more conserved, indicating that these upstream transcription factors may be more important in regulating cold stress. Meanwhile, we found the expression of AP2/EREBP pathway genes was significantly increased in recombinant inbred lines from Nipponbare crossing with Chaling wild rice, These results suggest that the AP2/EREBP signaling pathway plays an important role in Chaling wild rice tolerance to cold stress.

Ectopic Expression of a Maize Gene ZmDUF1645 in Rice Increases Grain Length and Yield, but Reduces Drought Stress Tolerance.

As the human population grows rapidly, food shortages will become an even greater problem; therefore, increasing crop yield has become a focus of rice breeding programs. The maize gene, ZmDUF1645, encoding a putative member of the DUF1645 protein family with an unknown function, was transformed into rice. Phenotypic analysis showed that enhanced ZmDUF1645 expression significantly altered various traits in transgenic rice plants, including increased grain length, width, weight, and number per panicle, resulting in a significant increase in yield, but a decrease in rice tolerance to drought stress. qRT-PCR results showed that the expression of the related genes regulating meristem activity, such as MPKA, CDKA, a novel crop grain filling gene (GIF1), and GS3, was significantly changed in the ZmDUF1645-overexpression lines. Subcellular colocalization showed that ZmDUF1645 was primarily localized on cell membrane systems. Based on these findings, we speculate that ZmDUF1645, like the OsSGL gene in the same protein family, may regulate grain size and affect yield through the cytokinin signaling pathway. This research provides further knowledge and understanding of the unknown functions of the DUF1645 protein family and may serve as a reference for biological breeding engineering to increase maize crop yield.

Penpulimab, an anti-PD1 IgG1 antibody in the treatment of advanced or metastatic upper gastrointestinal cancers.

BACKGROUND: The safety and anti-tumor activity of penpulimab in patients with advanced upper gastrointestinal (UGI) cancers were evaluated in this study. METHODS: Patients with advanced UGI cancers naive to immune checkpoint inhibitors were enrolled in two trials of penpulimab. In the Phase Ia/Ib trial in Australia, patients received penpulimab intravenous infusion of 1, 3 and 10 mg/kg every 2 weeks in dose-escalation phase and 200 mg every 2 weeks in dose-expansion phase. In the phase Ib/II trial conducted in China, patients received 200 mg penpulimab every 2 weeks. Primary endpoints were safety and tolerability for the phase Ia/Ib trial and the objective response rate for the phase Ib/II trial. The safety and efficacy of penpulimab in patients with UGI cancers in these two trials were evaluated. RESULTS: A total of 67 patients with UGI cancers from Australia and China were enrolled in these two trials and had received penpulimab with a median of 6 (1-64) doses. 44.8% of patients experienced at least one treatment-related adverse event (TRAE), and 7.5% of patients experienced a grade ≥3 TRAE. Among 60 patients evaluable for response, the confirmed objective response rates ranged between 11.1 and 26.3% across cohorts for pancreatic cancer, cholangiocarcinoma, gastric or Gastroesophageal junction carcinoma (Gastric/GEJ), and hepatocellular carcinoma. 11/13 (85.0%) responders had ongoing responses at data cutoff date. CONCLUSIONS: Penpulimab monotherapy demonstrated an acceptable safety and encouraged anti-tumor activity in patients with advanced UGI cancers. Further exploration in a large cohort of patients is warranted. TRIAL REGISTRATION: Phase Ia/Ib trial in Australia (NCT03352531) and phase Ib/II trial in China (NCT04172506).

Genome-wide association study-based identification genes influencing agronomic traits in rice (Oryza sativa L.).

Rice is one of the most important cereal crops, providing the daily dietary intake for approximately 50% of the global human population. Here, we re-sequenced 259 rice accessions, generating 1371.65 Gb of raw data. Furthermore, we performed genome-wide association studies (GWAS) on 13 agronomic traits using 2.8 million single nucleotide polymorphisms (SNPs) characterized in 259 rice accessions. Phenotypic data and best linear unbiased prediction (BLUP) values of each of the 13 traits over two years of each trait were used for the GWAS. The results showed that 816 SNP signals were significantly associated with the 13 agronomic traits. Then we detected candidate genes related to target traits within 200 kb upstream and downstream of the associated SNP loci, based on linkage disequilibrium (LD) blocks in the whole rice genome. These candidate genes were further identified through haplotype block constructions. This comprehensive study provides a timely and important genomic resource for breeding high yielding rice cultivars.

Secondary cytoreduction followed by chemotherapy versus chemotherapy alone in platinum-sensitive relapsed ovarian cancer (SOC-1): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The benefits of secondary cytoreduction for platinum-sensitive relapsed ovarian cancer are still widely debated. We aimed to assess the efficacy of secondary cytoreduction plus chemotherapy versus chemotherapy alone in this patient population. METHODS: This multicentre, open-label, randomised, controlled, phase 3 trial (SOC-1), was done in four primarily academic centres in China (two in Shanghai, one in Hangzhou, and one in Guangzhou). Eligible patients were women aged 18 years and older with platinum-sensitive relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months after the end of first-line platinum-based chemotherapy and were predicted to have potentially resectable disease according to the international model (iMODEL) score and PET-CT imaging. iMODEL score was calculated using six variables: International Federation of Gynecology and Obstetrics stage, residual disease after primary surgery, platinum-free interval, Eastern Cooperative Oncology Group performance status, serum level of cancer antigen 125 at recurrence, and presence of ascites at recurrence. An iMODEL score of 4·7 or lower predicted a potentially complete resection. As per a protocol amendment, patients with an iMODEL score of more than 4·7 could only be included if the serum level of cancer antigen 125 was more than 105 U/mL, but the principal investigators assessed the disease to be resectable by PET-CT. Eligible participants were randomly assigned (1:1) via a permuted block design (block size of six) and stratified by study centre, iMODEL score, residual disease at primary surgery, and enrolment in the Shanghai Gynecologic Oncology Group SUNNY trial, to undergo secondary cytoreductive surgery followed by intravenous chemotherapy (six 3-weekly cycles of intravenous paclitaxel [175 mg/m2] or docetaxel [75 mg/m2] combined with intravenous carboplatin [area under the curve of 5 mg/mL per min]; surgery group) or intravenous chemotherapy alone (no surgery group). Primary endpoints were progression-free survival and overall survival, analysed in all participants randomly assigned to treatment, regardless of treatment received (intention-to-treat [ITT] population). Here, we report the final analysis of progression-free survival and the prespecified interim analysis of overall survival. Safety was assessed in all participants who received their assigned treatment and had available adverse event data. This study is registered with ClinicalTrials.gov, NCT01611766, and is ongoing but closed to accrual. FINDINGS: Between July 19, 2012, and June 3, 2019, 357 patients were recruited and randomly assigned to the surgery group (182) or the no surgery group (175; ITT population). Median follow-up was 36·0 months (IQR 18·1-58·3). In the no surgery group, 11 (6%) of 175 participants had secondary cytoreduction during second-line therapy while 48 (37%) of 130 participants who had disease progression crossed-over and had surgery at a subsequent recurrence. Median progression-free survival was 17·4 months (95% CI 15·0-19·8) in the surgery group and 11·9 months (10·0-13·8) in the no surgery group (hazard ratio [HR] 0·58; 95% CI 0·45-0·74; p<0·0001). At the interim overall survival analysis, median overall survival was 58·1 months (95% CI not estimable to not estimable) in the surgery group and 53·9 months (42·2-65·5) in the no surgery group (HR 0·82, 95% CI 0·57-1·19). In the safety population, nine (5%) of 172 patients in the surgery group had grade 3-4 surgical morbidity at 30 days, and no patients in either group had died at 60 days after receiving assigned treatment. The most common grade 3-4 adverse events during chemotherapy were neutropenia (29 [17%] of 166 patients in the surgery group vs 19 [12%] of 156 patients in the no surgery group), leucopenia (14 [8%] vs eight [5%]), and anaemia (ten [6%] vs nine [6%]). Four serious adverse events occurred, all in the surgery group. No treatment-related deaths occurred in either group. INTERPRETATION: Secondary cytoreduction followed by chemotherapy was associated with significantly longer progression-free survival than was chemotherapy alone in patients with platinum-sensitive relapsed ovarian cancer, and patients should be counselled about the option of secondary cytoreduction in specialised centres. Long-term survival outcomes will be assessed using mature data on overall survival. FUNDING: Zhongshan Development Program. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Olaparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 mutation: SOLO1 China cohort.

PURPOSE: Maintenance therapy with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib provided a substantial progression-free survival (PFS) benefit compared with placebo in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (BRCAm) who were in clinical complete or partial response following platinum-based chemotherapy in the Phase III SOLO1 global study. This led to the approval of maintenance olaparib in China, USA, EU, Japan and other countries, in the newly diagnosed setting. This separate China cohort of the SOLO1 study investigated the efficacy and safety of maintenance olaparib within the Chinese population. PATIENTS AND METHODS: In this double-blind, multicentre study, patients were randomized 2:1 to receive oral olaparib tablets (300 mg twice daily) or placebo. The primary endpoint was investigator-assessed PFS (modified RECIST v1.1). RESULTS: Of the 64 randomized patients, 44 received olaparib and 20 placebo. Olaparib reduced the risk of disease progression or death by 54% compared with placebo (HR 0.46, 95% Cl 0.23-0.97; median PFS was not reached in the olaparib arm vs 9.3 months in the placebo arm). The most common AEs in the olaparib arm were nausea (63.6 vs 25.0% with placebo), anaemia (59.1 vs 15.0%) and leukopenia (54.5 vs 20.0%). Grade ≥3 AEs were experienced by 56.8% of olaparib patients and 30.0% of placebo patients. CONCLUSIONS: Results in the SOLO1 China cohort support the use of olaparib as maintenance treatment for Chinese patients with newly diagnosed advanced ovarian cancer who have a BRCAm and are in complete or partial response after platinum-based chemotherapy.

Quick selenium accumulation in the selenium-rich rice and its physiological responses in changing selenium environments.

BACKGROUND: The element selenium (Se) deficiency is thought to be a global human health problem, which could disperse by daily-supplement from Se-rich food. Increasing the accumulation of Se in rice grain is an approach matched to these nutrient demands. Nonetheless, Se is shown to be essential but also toxic to plants, with a narrow margin between deficiency and toxicity. Notably, the regulatory mechanism balancing the accumulation and tolerance of Se in Se-rich rice plants remains unknown. RESULTS: In this study, we investigated the phenotypical, physiological, and biochemical alterations of Se-rich rice in the exposure to a variety of Se applications. Results showed that the Se-rich rice was able to accumulate more abundance of Se from the root under a low Se environment comparing to the Se-free rice. Besides, excessive Se led to phytotoxic effects on Se-rich rice plants by inducing chlorosis and dwarfness, decreasing the contents of antioxidant, and exacerbating oxidative stresses. Furthermore, both phosphate transporter OsPT2 and sulfate transporters OsSultr1;2 may contribute to the uptake of selenate in rice. CONCLUSIONS: Se-rich red rice is more sensitive to exogenous application of Se, while and the most effective application of Se in roots of Se-rich rice was reached in 20 µM. Our findings present a direct way to evaluate the toxic effects of Se-rich rice in the Se contaminated field. Conclusively, some long-term field trial strategies are suggested to be included in the evaluation of risks and benefits within various field managements.

Accumulation, mobilization, and transformation of selenium in rice grain provided with foliar sodium selenite.

BACKGROUND: Selenium is an indispensable trace element for humans and its deficiency can lead to serious health complications. Nearly 70% of the area of China faces selenium deficiency. To deal with this problem, selenium-enriched rice has been increasingly incorporated into everyday diets. However, there is a lack of in-depth studies of the absorption, translocation, and transformation of selenium in the different parts of the rice plant when sprayed with sodium selenite. RESULTS: Foliar sodium selenite applied at critical growth stages can significantly improve the total and organic selenium content of plants. Application of 10 mg L-1 sodium selenite led to the most organic selenium (0.03 mg kg-1 ) in polished rice. Correlation studies of sodium selenite applied to leaves and other plant parts showed that total selenium accumulated most in glume, followed by rice bran, then polished rice, and finally embryo. The behavior of organic selenium was different. Organic selenium accumulated most in polished rice, then embryo, then rice bran, and finally glume. Moreover, 75-85% of the Se found in polished rice and embryo was organic in nature. CONCLUSIONS: We propose that 10 mg L-1 sodium selenite can be recommended as appropriate for foliar fertilization in the organic selenium biofortification of Se-free rice. © 2018 Society of Chemical Industry.

A single nucleotide mutation of IspF gene involved in the MEP pathway for isoprenoid biosynthesis causes yellow-green leaf phenotype in rice.

KEY MESSAGE: We identified IspF gene through yellow-green leaf mutant 505ys in rice. OsIspF was expressed in all tissues detected, and its encoded protein was targeted to the chloroplast. On expression levels of genes in this mutant, OsIspF itself and the genes encoding other enzymes of the MEP pathway and chlorophyll synthase were all up-regulated, however, among eight genes associated with photosynthesis, only psaA, psaN and psbA genes for three reaction center subunits of photosystem obviously changed. Isoprenoids are the most abundant natural compounds in all organisms, which originate from the basic five-carbon units isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). In plants, IPP and DMAPP are synthesized through two independent pathways, the mevalonic acid pathway in cytoplasm and the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in plastids. The MEP pathway comprises seven enzymatic steps, in which IspF is the fifth enzyme. So far, no IspF gene has been identified in monocotyledonous plants. In this study, we isolated a leaf-color mutant, 505ys, in rice (Oryza sativa). The mutant displayed yellow-green leaf phenotype, reduced level of photosynthetic pigments, and arrested development of chloroplasts. By map-based cloning of this mutant, we identified OsIspF gene (LOC_Os02g45660) showing significant similarity to IspF gene of Arabidopsis, in which a missense mutation occurred in the mutant, resulting in an amino acid change in the encoded protein. OsIspF gene was expressed in all tissues detected, and its encoded protein was targeted to the chloroplast. Further, the mutant phenotype of 505ys was complemented by transformation with the wild-type OsIspF gene. Therefore, we successfully identified an IspF gene in monocotyledonous plants. In addition, real-time quantitative RT-PCR implied that a positive regulation could exist between the OsIspF gene and the genes encoding other enzymes of the MEP pathway and chlorophyll synthase. At the same time, it also implied that the individual genes involved in the MEP pathway might differentially regulated expression levels of the genes associated with photosynthesis.