Search

Background: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. Methods: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0–2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). Results: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8–18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7–77.2%) and 96.6% (95% CI 92.2–98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6–70.8%) and 94.5% (95% CI 89.5–97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4–17.7) and 14.5 months (95% CI 11.7–20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1–not evaluable [NE]), 19.8 months (95% CI 14.5–NE), and NE (95% CI 14.5–NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35–56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48–78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. Conclusions: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. Trial registration: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020. [ABSTRACT FROM AUTHOR]

Beckett's reception in mainland China was delayed until 1965 when Waiting for Godot was first translated into Chinese. The overall critical response to the play was largely negative due to the leftist ideological influence dominating the studies of foreign literatures at the time. Only a few of Beckett's other plays have been translated besides Waiting for Godot. The reception of Beckett's fiction started in the 1980s, much later than the reception of his drama. Due to the absence of Chinese translations of his fiction, studies of it were, and still are, limited in terms of quantity. A five-volume translation of Beckett's work from French was published in 2006 in celebration of the author's one hundredth anniversary. But Beckett's English fiction still remains untranslated to this day, which has created many constraints for Beckett studies in China. However, Beckett studies since the 1990s has shown promise, with some scholars beginning to look for new approaches to his dramatic and fictional works. Overall, while Beckett studies in China tends to rely heavily on Beckett material published elsewhere, thus lacking fresh critical perspective, it has managed to survive the earlier dark times and has entered a new phase of growth since the new millennium. [ABSTRACT FROM PUBLISHER]

Simple Summary: There remain substantial gaps in our understanding of the sex-linked region (SLR) in two wild spinach progenitors, Spinacia turkestanica and S. tetrandra, although SLR in cultivated spinach is well understood. Using 63 Spinacia accessions comprising 32 S. oleracea, 19 S. turkestanica and 12 S. tetrandra, we found that S. oleracea shared a similar SLR with S. turkestanica, while the SLR was remarkably divergent between S. oleracea/S. turkestanica and S. tetrandra. Additionally, the SLR increasingly expanded via accumulating repetitive sequences and was more conserved than the pseudoautosomal region (PAR) during the evolution of S. tetrandra to S. oleracea. The results obtained in this study provide a broader understanding of the evolution of SLR in Spinacia species. The sex-linked region (SLR) plays an important role in determining the sex of a plant. The SLR of the Y chromosome, composed of a 14.1-Mb inversion and a 10-Mb Y-duplication region (YDR), was deciphered in Spinacia oleracea previously. However, our understanding of the SLR in its wild relatives, S. turkestanica and S. tetrandra, remains limited. In this study, we used 63 resequencing data from the three Spinacia species to infer the evolution of the SLR among the Spinacia species. In the SLR, all the cultivated spinach and S. turkestanica accessions were clustered into two distinct categories with both sexes, while the S. tetrandra accessions of both sexes were grouped. This suggests that S. oleracea shared a similar SLR with S. turkestanica, but not with S. tetrandra, which was further confirmed based on the population structure and principal component analysis. Furthermore, we identified 3910 fully sex-linked SNPs in S. oleracea and 92.82% of them were available in S. turkestanica, while none of the SNPs were adopted in S. tetrandra. Genome coverage in males and females supported the hypothesis that the YDR increasingly expanded during its evolution. Otherwise, we identified 13 sex-linked transposable element insertion polymorphisms within the inversion in both S. oleracea and S. turkestanica, demonstrating that the transposable element insertions might have occurred before the recombination suppression event of the inversion. The SLR was conserved compared with the pseudoautosomal region given that the genetic hitchhiking process occurred in the SLR during its evolution. Our findings will significantly advance our understanding of the characteristics and evolution of the SLR in Spinacia species. [ABSTRACT FROM AUTHOR]

Summary: Cultivated spinach (Spinacia oleracea) is a dioecious species. We report high‐quality genome sequences for its two closest wild relatives, Spinacia turkestanica and Spinacia tetrandra, which are also dioecious, and are used to study the genetics of spinach domestication.Using a combination of genomic approaches, we assembled genomes of both these species and analyzed them in comparison with the previously assembled S. oleracea genome.These species diverged c. 6.3 million years ago (Ma), while cultivated spinach split from S. turkestanica 0.8 Ma. In all three species, all six chromosomes include very large gene‐poor, repeat‐rich regions, which, in S. oleracea, are pericentromeric regions with very low recombination rates in both male and female genetic maps. We describe population genomic evidence that the similar regions in the wild species also recombine rarely. We characterized 282 structural variants (SVs) that have been selected during domestication. These regions include genes associated with leaf margin type and flowering time. We also describe evidence that the downy mildew resistance loci of cultivated spinach are derived from introgression from both wild spinach species.Collectively, this study reveals the genome architecture of spinach assemblies and highlights the importance of SVs during the domestication of cultivated spinach. [ABSTRACT FROM AUTHOR]

Simple Summary: Using 138 snap bean accessions as plant materials, we investigated their suture strings across two years. With the goal of identifying the gene(s) responsible for the formation of suture strings, we conducted a genome-wide association study. A strong association signal was found in a 266.19 kb region on Chr02. Within the region, 23 candidate genes were identified. Importantly, the sequence and gene expression of PvGUX1_1 differed significantly between sutured pods and non-sutured pods. In addition, PvGUX1_1 was also a domesticated locus that diverged from PvGUX1_2 during an early stage. The results obtained in this study can provide important information for the improvement of pod quality in snap beans. Suture strings are a particularly important pod trait that determine the quality and texture of snap beans (Phaseolus vulgaris L.). The St locus on chromosome 2 has been described as a major locus associated with suture strings. However, the gene and genetic basis underlying this locus remain unknown. Here, we investigated the suture strings of 138 snap bean accessions across two years. A total of 3.66 million single-nucleotide polymorphisms (SNPs) were obtained by deep resequencing. Based on these SNPs, we identified a strong association signal on Chr02 and a promising candidate gene, PvGUX1_1. Further analysis revealed that the 2 bp deletion in the exon of PvGUX1_1 was significantly associated with stringlessness. Comparative mapping indicated that PvGUX1_1 was a domesticated locus and diverged from PvGUX1_2 during an early stage. Our study provides important insights into the genetic mechanism of suture string formation and useful information for snap bean improvement. [ABSTRACT FROM AUTHOR]

Spinach is a significant source of vitamins, minerals, and antioxidants. These nutrients make it delicious and beneficial for human health. However, the genetic mechanism underlying the accumulation of nutrients in spinach remains unclear. In this study, we analyzed the content of chlorophyll a, chlorophyll b, oxalate, nitrate, crude fiber, soluble sugars, manganese, copper, and iron in 62 different spinach accessions. Additionally, 3,356,182 high-quality, single-nucleotide polymorphisms were found using resequencing and used in a genome-wide association study. A total of 2077 loci were discovered that significantly correlated with the concentrations of the nutritional elements. Data mining identified key genes in these intervals for four traits: chlorophyll, oxalate, soluble sugar, and Fe. Our study provides insights into the genetic architecture of nutrient variation and facilitates spinach breeding for good nutrition. [ABSTRACT FROM AUTHOR]

Superhydrophobic (SH) and superamphiphobic (SAP) coatings have been viewed as an alternative to conventional hydrophobic room temperature vulcanizing (RTV) silicone rubber coatings in anti-pollution flashover application. However, being one of the most important properties in RTV-based anti-flashover materials and devices, the hydrophobicity transfer property was rarely documented for SH and SAP coatings, which restricts their practical applications in environments with heavy contamination. Herein, we propose for the first time a superhydrophobicity transfer effect in superwetting (SW) coatings (e.g., SAP and SH coatings) containing low-surface-energy molecules (e.g., polydimethylsiloxane (PDMS)) as a migratory reagent. When the surface is stained by artificial simulated pollutants, PDMS molecules can migrate from the coating to the contamination layer, followed by a surface modification. Through this process, the surface wettability of the contaminant layer gradually evolves from superhydrophilicity to hydrophobicity, and finally to SH state. This evolution is investigated in relation to the amount and species of migratory reagents, migration time, pollution grade, and pollutant species. The superhydrophobicity transfer effect offers the coated glass insulators an outstanding anti-pollution flashover strength. This work can provide a novel and universal protocol to realize a superhydrophobicity transfer property in SW coatings, which may stimulate further investigation and applications in not only anti-pollution flashover but also other fields such as anti-fouling and anti-icing. • Superhydrophobicity transfer effect is proposed for the first time. • Superwetting coatings with superhydrophobicity transfer property are obtained. • The mechanism behind the superhydrophobicity transfer effect is proposed. • Superhydrophobicity transfer effect improves the anti-pollution flashover strength of insulator. [ABSTRACT FROM AUTHOR]

The members of the myeloblastosis (MYB) family of transcription factors (TFs) participate in a variety of biological regulatory processes in plants, such as circadian rhythm, metabolism, and flower development. However, the characterization of MYB genes across the genomes of spinach Spinacia oleracea L. has not been reported. Here, we identified 140 MYB genes in spinach and described their characteristics using bioinformatics approaches. Among the MYB genes, 54 were 1R-MYB, 80 were 2R-MYB, 5 were 3R-MYB, and 1 was 4R-MYB. Almost all MYB genes were located in the 0–30 Mb region of autosomes; however, the 20 MYB genes were enriched at both ends of the sex chromosome (chromosome 4). Based on phylogeny, conserved motifs, and the structure of genes, 2R-MYB exhibited higher conservation relative to 1R-MYB genes. Tandem duplication and collinearity of spinach MYB genes drive their evolution, enabling the functional diversification of spinach genes. Subcellular localization prediction indicated that spinach MYB genes were mainly located in the nucleus. Cis-acting element analysis confirmed that MYB genes were involved in various processes of spinach growth and development, such as circadian rhythm, cell differentiation, and reproduction through hormone synthesis. Furthermore, through the transcriptome data analysis of male and female flower organs at five different periods, ten candidate genes showed biased expression in spinach males, suggesting that these genes might be related to the development of spinach anthers. Collectively, this study provides useful information for further investigating the function of MYB TFs and novel insights into the regulation of sex determination in spinach. [ABSTRACT FROM AUTHOR]

Bolting is a symbol of the transition from vegetative to reproductive growth in plants. Late bolting can effectively prolong the commercial value of spinach and is of great importance for spinach breeding. Bolting has complex regulatory networks, and current research on spinach bolting is relatively weak, with specific regulatory pathways and genes unclear. To clarify the regulatory characteristics and key genes related to bolting in spinach, we conducted a comparative transcriptome analysis. In this study, 18 samples from three periods of bolting-tolerant spinach material 12S3 and bolting-susceptible material 12S4 were analyzed using RNA-seq on, resulting in 10,693 differentially expressed genes (DEGs). Functional enrichment and co-expression trend analysis indicated that most DEGs were enriched in the photoperiod pathway, the hormone signaling pathway, and the cutin, suberin, and wax biosynthetic pathways. According to the weighted gene co-expression network analysis (WGCNA), SpFT (SOV4g003400), SOV4g040250, and SpGASA1 (SOV6g017600) were likely to regulate bolting through the gibberellin and photoperiod pathways, and SpELF4 (SOV1g028600) and SpPAT1 (SOV4g058860) caused differences in early and late bolting among different cultivars. These results provide important insights into the genetic control of bolting in spinach and will help elucidate the molecular mechanisms of bolting in leafy vegetables. [ABSTRACT FROM AUTHOR]

Background: BAT1706 is a proposed biosimilar of bevacizumab (Avastin®). We aimed to compare the efficacy and safety of BAT1706 with that of EU‐sourced reference bevacizumab (EU‐bevacizumab) in patients with advanced nonsquamous non‐small cell lung cancer (NSCLC). Methods: Patients were randomized 1:1 to BAT1706 plus paclitaxel and carboplatin (BAT1706 arm) or EU‐bevacizumab plus paclitaxel and carboplatin (EU‐bevacizumab arm) given every 3 weeks for six cycles, followed by maintenance therapy with BAT1706 or EU‐bevacizumab. The primary endpoint was overall response rate at week 18 (ORR18). Clinical equivalence was demonstrated if the 90% confidence interval (CI) of the BAT1706:EU‐bevacizumab ORR18 risk ratio was contained within the predefined equivalence margins of 0.75–1.33 (China National Medical Products Administration requirements), or 0.73–1.36 (US Food and Drug Administration), or if the 95% CI of the ORR18 risk difference between treatments was contained within the predefined equivalence margin of −0.12 to 0.15 (EMA requirements). Results: In total, 649 randomized patients (BAT1706, n = 325; EU‐bevacizumab, n = 324) received at least one cycle of combination treatment. The ORR18 was comparable between the BAT1706 and EU‐bevacizumab arms (48.0% and 44.5%, respectively). The ORR18 risk ratio of 1.08 (90% CI: 0.94–1.24) and the ORR18 risk difference of 0.03 (95% CI: −0.04 to 0.11) were within the predefined equivalence margins, demonstrating the biosimilarity of BAT1706 and EU‐bevacizumab. The safety profile of BAT1706 was consistent with that of EU‐bevacizumab and no new safety signals were observed. Conclusion: In patients with advanced nonsquamous NSCLC, BAT1706 demonstrated clinical equivalence to EU‐bevacizumab in terms of efficacy, safety, pharmacokinetics, and immunogenicity. [ABSTRACT FROM AUTHOR]

Key message: A SLAF-BSA approach was used to locate the RPF1 locus. The three most likely candidate genes were identified which provide a basic for cloning the resistance gene at the RPF1 locus.Abstract: Spinach downy mildew is a globally devastating oomycete disease. The use of downy mildew resistance genes constitutes the most effective approach for disease management. Hence, the objective of the present study was to fine map the first-reported resistance locus RPF1. The resistance allele at this resistance locus was effective against races 1-7, 9, 11, 13, and 15 of Peronospora farinosa f. sp. spinaciae (P. effusa). The approach fine mapped RPF1 using specific-locus amplified fragment sequencing (SLAF-Seq) technology combined with bulked segregant analysis. A 1.72 Mb region localized on chromosome 3 was found to contain RPF1 based on association analysis. After screening recombinants with the SLAF markers within the region, the region was narrowed down to 0.89 Mb. Within this region, 14 R genes were identified based on the annotation information. To identify the genes involved in resistance, resequencing of two resistant inbred lines (12S2 and 12S3) and three susceptible inbred lines (12S1, 12S4, and 10S2) was performed. The three most likely candidate genes were identified via amino acid sequence analysis and conserved domain analysis between resistant and susceptible inbred lines. These included Spo12729, encoding a receptor-like protein, and Spo12784 and Spo12903, encoding a nucleotide-binding site and leucine-rich repeat domains. Additionally, based on the sequence variation in the three genes between the resistant and susceptible lines, molecular markers were developed for marker-assisted selection. The results could be valuable in cloning the RPF1 alleles and improving our understanding of the interaction between the host and pathogen. [ABSTRACT FROM AUTHOR]

Background Preeclampsia (PE), characterized by hypertension and proteinuria, is a leading cause of perinatal and maternal mortality. Considering that mutation of H19 gene is closely associated with PE, we aimed to explore the functional role of long non-coding RNA H19 (lncRNA-H19) in trophoblast cells. Methods Expression of lncRNA-H19 in placenta tissues from patients with PE and healthy pregnant women after delivery was determined by quantitative reverse transcription PCR. Then, lncRNA-H19 was abnormally expressed in JEG-3 and HTR-8 cells by stable cell transfection. Cell viability and invasion were assessed by using CCK-8 and Matrigel-coated Millicell system, respectively. Expression of key proteins associated with invasion and autophagy as well as key kinases in the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathways were measured by Western blot analysis. Number of GFP-labeled autophagosomes was counted under a confocal microscope. Results Level of lncRNA-H19 in the placenta tissues from PE patients was higher than that from healthy controls. LncRNA-H19 overexpression reduced cell viability but increased invasion of JEG-3 and HTR-8 cells. LncRNA-H19 silence showed the opposite effects. In addition, lncRNA-H19 overexpression promoted autophagy in trophoblast cells. Furthermore, phosphorylated levels of key kinases in the PI3K/AKT/mTOR pathways were enhanced by lncRNA-H19 overexpression while were reduced by lncRNA-H19 silence. Conclusion LncRNA-H19, which was up-regulated in PE, reduced cell viability but promoted invasion and autophagy in trophoblast cells, along with activation of the PI3K/AKT/mTOR pathways. Our study provides a theoretical basis for pathogenesis of PE, aiding to identification of novel therapeutic strategies for PE. [ABSTRACT FROM AUTHOR]

Background: Denosumab has been approved for the treatment of bone metastases from solid tumors. QL1206 is the first denosumab biosimilar and needs to be compared with denosumab in a phase III trial. Objective: This phase III trial aims to compare the efficacy, safety, and pharmacokinetics between QL1206 and denosumab in patients with bone metastases from solid tumors. Methods: This randomized, double-blind, phase III trial was conducted in 51 centers in China. Patients aged 18–80 years, with solid tumors and bone metastases, and an Eastern Cooperative Oncology Group performance status of 0–2 were eligible. This study was divided into a 13-week double-blind period, a 40-week open-label period, and a 20-week safety follow-up period. In the double-blind period, patients were randomly assigned (1:1) to receive three doses of QL1206 or denosumab (120 mg subcutaneously every 4 weeks, each). Randomization was stratified by tumor types, previous skeletal-related events, and current systemic anti-tumor therapy. In the open-label period, up to ten doses of QL1206 could be given in both groups. The primary endpoint was percentage change in urinary N-telopeptide/creatinine ratio (uNTX/uCr) from baseline to Week 13. Equivalence margins were ± 0.135. Secondary endpoints included percentage change in uNTX/uCr at Week 25 and 53, percentage change in serum bone-specific alkaline phosphatase at Week 13, 25, and 53, and time to on-study skeletal-related events. The safety profile was evaluated based on adverse events and immunogenicity. Results: From September 2019 to January 2021, in the full analysis set, 717 patients were randomly assigned to receive QL1206 (n = 357) or denosumab (n = 360). Median percentage changes in uNTX/uCr at Week 13 in two groups were − 75.2% and − 75.8%, respectively. Least-squares mean difference in the natural log-transformed ratio of uNTX/uCr at Week 13 to baseline between the two groups was 0.012 (90% confidence interval − 0.078 to 0.103), within the equivalence margins. There were no differences in the secondary endpoints between the two groups (all p > 0.05). Adverse events, immunogenicity, and pharmacokinetics were similar in the two groups. Conclusions: Denosumab biosimilar QL1206 had promising efficacy, tolerable safety, and pharmacokinetics equivalent to denosumab and could benefit patients with bone metastases from solid tumors. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04550949, retrospectively registered on 16 September, 2020 [ABSTRACT FROM AUTHOR]

To compare the efficacy and safety of hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy in the treatment of malignant pleural or peritoneal effusion. A randomized clinical trial was carried out in 8 cancer centers across China. Patients with malignant pleural or peritoneal effusion were randomly assigned to the study group or control group. Patients in the study group were treated with cisplatin-based hyperthermic intrathoracic chemotherapy (HITHOC) or hyperthermic intraperitoneal chemotherapy (HIPEC), while the control group was treated with conventional intrapleural or intraperitoneal chemotherapy using same chemotherapeutic regime as the study group. The objective response rate (ORR) was analyzed as primary outcome. Quality-of-life (QOL) score was recorded as secondary outcome using the questionnaire 30 (QLQ-C30) of the European Organization for Research and Treatment of Cancer (EORTC). The efficacy and safety of the two treatments were compared. Total 135 patients were recruited and randomized in this study, with 67 patients in the study group and 68 patients in the control group. The ORR in the study group (80.70%) was significantly higher than that in the control group (31.03%, p < 0.001). However, neither changes of QOL scores, nor incidence rates of adverse events were significantly different between the two groups (p = 0.076 and 0.197, respectively). Efficacy of HITHOC or HIPEC is superior to that of conventional modality for the treatment of malignant effusion with comparable side effects. [ABSTRACT FROM AUTHOR]

Downy mildew is a major threat to the economic value of spinach. The most effective approach to managing spinach downy mildew is breeding cultivars with resistance genes. The resistance allele RPF2 is effective against races 1–10 and 15 of Peronospora farinosa f. sp. Spinaciae (P. effusa) and is widely used as a resistance gene. However, the gene and the linked marker of RPF2 remain unclear, which limit its utilization. Herein, we located the RPF2 gene in a 0.61 Mb region using a BC1 population derived from Sp39 (rr) and Sp62 (RR) cultivars via kompetitive allele specific PCR (KASP) markers. Within this region, only one R gene, Spo12821, was identified based on annotation information. The amino acid sequence analysis showed that there were large differences in the length of the LRR domain between the parents. Additionally, a molecular marker, RPF2-IN12821, was developed based on the sequence variation in the Spo12821, and the evaluation in the BC1 population produced a 100% match with resistance/susceptibility. The finding of the study could be valuable for improving our understanding of the genetic basis of resistance against the downy mildew pathogen and breeding resistance lines in the future. [ABSTRACT FROM AUTHOR]

Background: CheckMate 9LA, a phase 3, randomized, open-label study in first-line advanced non-small cell lung cancer (NSCLC), showed significantly improved overall survival (OS) with nivolumab plus ipilimumab combined with 2 cycles of chemotherapy versus chemotherapy alone (4 cycles). We present results for the Asian subpopulation enrolled in Japan and China. Methods: Patients aged ≥ 18 years with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0–1 and no sensitizing EGFR/ALK mutations were randomized 1:1 to nivolumab [360 mg every 3 weeks (Q3W)] plus ipilimumab (1 mg/kg Q6W) combined with chemotherapy (Q3W for 2 cycles), or chemotherapy alone (Q3W for 4 cycles). Primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Results: Twenty-eight patients received nivolumab plus ipilimumab combined with chemotherapy and 30 received chemotherapy. At a minimum follow-up of 12.7 months, median OS was not reached with nivolumab plus ipilimumab combined with chemotherapy versus 13.3 months with chemotherapy [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14–0.80]. Median PFS was 8.4 versus 5.4 months (HR 0.47; 95% CI 0.24–0.92) and ORR was 57% versus 23%, respectively. Grade 3–4 treatment-related adverse events were observed in 57% versus 60% of patients, respectively. Conclusion: Consistent with results in the all randomized population, nivolumab plus ipilimumab combined with chemotherapy improved efficacy in the Asian subpopulation versus chemotherapy alone and had a manageable safety profile, supporting its use as first-line treatment for advanced NSCLC in Asian patients. [ABSTRACT FROM AUTHOR]

Spinacia is a genus of important leafy vegetable crops worldwide and includes cultivated Spinacia oleracea and two wild progenitors, Spinacia turkestanica and Spinacia tetrandra. However, the chloroplast genomes of the two wild progenitors remain unpublished, limiting our knowledge of chloroplast genome evolution among these three Spinacia species. Here, we reported the complete chloroplast genomes of S. oleracea, S. turkestanica, and S. tetrandra obtained via Illumina sequencing. The three chloroplast genomes exhibited a typical quadripartite structure and were 150,739, 150,747, and 150,680 bp in size, respectively. Only three variants were identified between S. oleracea and S. turkestanica, whereas 690 variants were obtained between S. oleracea and S. tetrandra, strongly demonstrating the close relationship between S. turkestanica and S. oleracea. This was further supported by phylogenetic analysis. We reported a comprehensive variant dataset including 503 SNPs and 83 Indels using 85 Spinacia accessions containing 61 S. oleracea, 16 S. turkestanica, and eight S. tetrandra accessions. Thirteen S. oleracea accessions were derived through introgression from S. turkestanica that acts as the maternal parent. Together, these results provide a valuable resource for spinach breeding programs and improve our understanding of the phylogenetic relationships within Amaranthaceae. [ABSTRACT FROM AUTHOR]

Importance: Standard first-line therapy for advanced or metastatic esophageal carcinoma is chemotherapy, but the prognosis remains poor. Camrelizumab (an anti-programmed death receptor 1 [PD-1] antibody) showed antitumor activity in previously treated advanced or metastatic esophageal squamous cell carcinoma.Objective: To evaluate the efficacy and adverse events of camrelizumab plus chemotherapy vs placebo plus chemotherapy as a first-line treatment in advanced or metastatic esophageal squamous cell carcinoma.Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (ESCORT-1st study) enrolled patients from 60 hospitals in China between December 3, 2018, and May 12, 2020 (final follow-up, October 30, 2020). A total of 751 patients were screened and 596 eligible patients with untreated advanced or metastatic esophageal squamous cell carcinoma were randomized.Interventions: Patients were randomized 1:1 to receive either camrelizumab 200 mg (n = 298) or placebo (n = 298), combined with up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were given intravenously every 3 weeks.Main Outcomes and Measures: Coprimary end points were overall survival (significance threshold, 1-sided P < .02) and progression-free survival (significance threshold, 1-sided P < .005).Results: Of the 596 patients randomized (median age, 62 years [interquartile range, 56-67 years]; 523 men [87.8%]), 1 patient in the placebo-chemotherapy group did not receive planned treatment. A total of 490 patients (82.2%) had discontinued the study treatment. The median follow-up was 10.8 months. The overall survival for the camrelizumab-chemotherapy group was a median of 15.3 months (95% CI, 12.8-17.3; 135 deaths) vs a median of 12.0 months (95% CI, 11.0-13.3; 174 deaths) for the placebo-chemotherapy group (hazard ratio [HR] for death, 0.70 [95% CI, 0.56-0.88]; 1-sided P = .001). Progression-free survival for camrelizumab plus chemotherapy was a median of 6.9 months (95% CI, 5.8-7.4; 199 progression or deaths) vs 5.6 months (95% CI, 5.5-5.7; 229 progression or deaths) for the placebo-chemotherapy group (HR for progression or death, 0.56 [95% CI, 0.46-0.68]; 1-sided P < .001). Treatment-related adverse events of grade 3 or higher occurred in 189 patients (63.4%) in the camrelizumab-chemotherapy group and 201 (67.7%) in the placebo-chemotherapy group, including treatment-related deaths among 9 patients (3.0%) and 11 patients (3.7%), respectively.Conclusions and Relevance: Among patients with advanced or metastatic esophageal squamous cell carcinoma, the addition of camrelizumab to chemotherapy, compared with placebo and chemotherapy, significantly improved overall survival and progression-free survival.Trial Registration: ClinicalTrials.gov Identifier: NCT03691090. [ABSTRACT FROM AUTHOR]

Spinach (Spinacia oleracea L.) is commonly considered a dioecious plant with heterogametic (XY) and homogametic (XX) sex chromosomes. The characteristic is also utilized for the production of spinach hybrid seeds. However, the molecular mechanisms of sex determination in spinach are still unclear because of a lack of genomic and transcriptomic information. In this study, RNA sequencing (RNA-seq) was performed in male and female inflorescences to provide insight into the molecular basis of sex determination in spinach. Comparative transcriptome analyses showed that 2278 differentially expressed genes (DEGs) were identified between male and female inflorescences. A high correlation between the RNA-Seq and qRT-PCR validation for DEGs was observed. Among these, 182 DEGs were annotated to transcription factors including the MYB family protein, bHLH family, and MADS family, suggesting these factors might play a vital role in sex determination. Moreover, 26 DEGs related to flower development, including nine ABCE class genes, were detected. Expression analyses of hormone pathways showed that brassinosteroids may be key hormones related to sex determination in spinach. Overall, this study provides a large amount of DEGs related to sexual expression and lays a foundation for unraveling the regulatory mechanism of sex determination in spinach. [ABSTRACT FROM AUTHOR]

Background: Spinach (Spinacia oleracea L.) is an important leafy vegetable crop, and leaf-related traits including leaf length, leaf width, and petiole length, are important commercial traits. However, the underlying genes remain unclear. The objective of the study was to conduct QTL mapping of leaf-related traits in spinach. Results: A BC1 population was used to construct the linkage map and for QTL mapping of leaf length, leaf width, petiole length, and the ratio of leaf length to width in 2015 and 2019. Two genetic linkage maps were constructed by specific locus amplified fragment sequencing (SLAF-seq), and kompetitive allele specific PCR (KASP) technology, respectively using BC1 population in 2015. Based on the results of 2015, the specific linkage groups (LG) detected QTLs were generated using BC1 population in 2019. A total of 13 QTLs were detected for leaf-related traits, only five QTLs being repeatedly detected in multiple years or linkage maps. Interestingly, the major QTLs of leaf length, petiole length, and the ratio of leaf length to width were highly associated with the same SNP markers (KM3102838, KM1360385 and KM2191098). A major QTL of leaf width was mapped on chromosome 1 from 41.470−42.045 Mb. And 44 genes were identified within the region. Based on the GO analysis, these genes were significantly enriched on ribonuclease, lyase activity, phosphodiester bond hydrolysis process, and cell wall component, thus it might change cell size to determine leaves shape. Conclusions: Five QTLs for leaf-related traits were repeatedly detected at least two years or linkage maps. The major QTLs of leaf length, petiole length, and the ratio of leaf length to width were mapped on the same loci. And three genes (Spo10792, Spo21018, and Spo21019) were identified as important candidate genes for leaf width. [ABSTRACT FROM AUTHOR]

Key message: The Fs gene, which controls spinach fruit spines, was fine mapped to a 0.27 Mb interval encompassing four genes on chromosome 3. There are two types of fruit of spinach (Spinacia oleracea L.), spiny and spineless, which are visually distinguishable by the spines of fruit coat. In spinach breeding, the fruit characteristic is an important agronomic trait that have impacts on "seed" treatment and mechanized sowing. However, the gene(s) controlling the fruit spiny trait have not been characterized and the genetic mechanism of this trait remained unclear. The objectives of the study were to fine map the gene controlling fruit spines and develop molecular markers for marker-assisted selection purpose. Genetic analysis of the spiny trait in segregating populations indicated that fruit spines were controlled by a single dominant gene, designated as Fs. Using a super-BSA method and recombinants analysis in a BC1 population, Fs was mapped to a 1.9-Mb interval on chromosome 3. The Fs gene was further mapped to a 0.27-Mb interval using a recombinant inbred line (RIL) population with 120 lines. From this 0.27 Mb region, four candidate genes were identified in the reference genome. The structure and expression of the four genes were compared between the spiny and spineless parents. A co-dominant marker YC-15 was found to be co-segregating with the fruit spines trait, which produced a 129-bp fragment specific to spiny trait and a 108-bp fragment for spineless fruit. This marker can predict spiny trait with a 94.8% accuracy rate when tested with 100 diverse germplasm, suggesting that this marker would be valuable for marker-assisted selection in spinach breeding. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients.Methods: ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or irinotecan (180 mg/m2 every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov, NCT03099382, and is closed to new participants.Findings: From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1-12·8) in the camrelizumab group and 6·2 months (3·6-10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8-9·7) in the camrelizumab group and 6·2 months (5·7-6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57-0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [<1%]), and diarrhoea (three [1%] vs nine [4%]). Serious treatment-related adverse events occurred in 37 (16%) of 228 patients in the camrelizumab group, and in 32 (15%) of 220 patients in the chemotherapy group. Ten treatment-related deaths occurred, seven (3%) in the camrelizumab group (three deaths from unknown causes, one enterocolitis, one hepatic function abnormal, one pneumonitis, and one myocarditis) and three (1%) in the chemotherapy group (two deaths from unknown causes, and one gastrointestinal haemorrhage).Interpretation: Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China.Funding: Jiangsu Hengrui Medicine. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-derived exosomes) can repair injured endometrial epithelial cells (EECs). Methods: HucMSC-derived exosomes and mouse primary EECs were isolated and purified. EECs were exposed to oxygen and glucose deprivation for 2 h followed by reoxygenation to mimic injury. After oxygen and glucose deprivation/reoxygenation (OGD/R), hucMSC-derived exosomes were added to the EEC culture medium. After 24 h of co-treatment, cell viability and cell death were tested by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and lactate dehydrogenase (LDH) assay, respectively. The expression of proinflammatory cytokines was tested by real-time PCR, enzyme-linked immunosorbent assay (ELISA), and Western blot to investigate the potential mechanism. Results: Compared with the control group, 5, 10, and 15 μg/mL of hucMSC-derived exosomes significantly attenuated cell viability decrease and inhibited LDH release of injured EECs, but 1 μg/mL of hucMSC-derived exosomes had no effect on either cell viability or LDH release. Real-time PCR and ELISA analysis revealed that 10 μg/mL of hucMSC-derived exosomes significantly inhibited the release of interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) and increased tumor necrosis factor alpha (TNFA) in injured EECs. In addition, 10 μg/mL of hucMSC-derived exosomes significantly inhibited toll-like receptor 4 (TLR4) and v-rel reticuloendotheliosis viral oncogene homolog A (RelA) expression in injured EECs. Conclusions: In OGD/R-induced injured EECs, hucMSC-derived exosomes efficiently improved the cell viability, reduced cell death, and exhibited anti-inflammatory properties against OGD/R. [ABSTRACT FROM AUTHOR]

The majority of previous studies of lobaplatin in small cell lung cancer (SCLC) are small phase I–II studies. The present study aimed to verify the non-inferiority (in terms of efficacy) of lobaplatin plus etoposide (EL) vs. cisplatin plus etoposide (EP) in patients with previously untreated extensive-stage SCLC (ES-SCLC). This phase III non-inferiority randomized clinical trial enrolled patients at 17 sites between September 2010 and May 2013. Patients were randomized to EL (30 mg/m2 lobaplatin on day 1 and 100 mg/m2 etoposide on days 1–3, for 21-day cycles) or EP (80 mg/m2 cisplatin on day 1 and 100 mg/m2 etoposide on days 1–3, for 21-day cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, disease control rate (DCR), toxicity and quality of life (QoL). A total of 234 patients were randomized to the EL (n=122) and EP (n=112) treatment groups. The median PFS, median OS and DCR were 5.1 vs. 5.3 months (P=0.786), 10.6 vs. 9.7 months (P=0.701) and 85.5 vs. 86.7% (P=0.848) in the EL vs. EP groups, respectively. Patients in the EL group had significantly lower frequencies of nephrotoxicity (2.5 vs. 11.7%; P=0.008), nausea (22.3 vs. 40.5%; P=0.003) and vomiting (14.1 vs. 35.1%; P<0.001) than those in the EP group. Overall, EL was not inferior to EP in terms of PFS and OS. The tolerance and QoL of the EL regimen were better than those of the EP regimen. EL is thus an alternative choice for the first-line treatment of ES-SCLC. [ABSTRACT FROM AUTHOR]

Background: Given the increasing use of immune checkpoint inhibitors (ICIs), a concomitant rise in adverse events is inevitable. In a recent Phase III trial of ICIs versus placebo, we found the staggering difference of incidence of fatal adverse events (FAEs). Hence, we should determine the risk of FAEs in ICIs.Objective: To address the risks of FAEs associated with each ICI regimen, we performed a systematic review and meta-analysis of clinical trials with the Food and Drug Administration-approved ICI regimens in patients with advanced solid tumors.Methods: Literature searching was based on PubMed before April 15, 2018. The numbers of FAEs in both study group and placebo group were collected. We assessed the risk of fatal adverse reactions associated with ICIs on Pooled Peto OR and associated 95% CI.Results: Twelve trials were identified. OR value of FADs in all ICIs was 2.32 (95% CI: 1.33, 4.05; P=0.003). The incidence of FAE in ICI in all included studies were up to 3.2%. OR value of clinical trials of prostate cancer was 3.71 (95% CI: 1.12, 12.26; P=0.03). Among the ICI cohorts, the common FAEs were gastrointestinal toxicity (n=12, 25%), pulmonary toxicity (n=10, 20%), cardiac toxicity (n=5, 10%), and hepatic toxicity (n=5, 10%).Conclusion: The cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors have a significantly higher risk of FAE (P=0.01), whereas programmed cell death protein 1 (PD-1) inhibitors were not. The most common CTLA-4-related FAE was gastrointestinal toxicity, and the most common PD-1-related FAE was pulmonary toxicity. Moreover, we have shown that ipilimumab has significant dose-dependent lethal toxicity. [ABSTRACT FROM AUTHOR]

Among all malignancies, lung cancer is the leading cause of cancer-related deaths in China. Bone metastasis is one of the most common complications and one of the most important factors affecting the prognosis of lung cancer patients, which resulting in very poor therapeutic effects. Previously, we have demonstrated that the expression levels of Dickkopf1 (DKK1), a protein involved in cell regulation and proliferation, was dramatically higher in cells that have a tendency to metastasize and invade the bone tissue (SBC-5 cells) compared with cells that do not (SBC-3 cells). Downregulation of DKK1 in SBC-5 cells inhibited cell malignancy in vitro, and the formation of bone metastasis in vivo. However, whether upregulating DKK1 would be sufficient to induce aggressive tumor behavior (proliferation, migration, invasion and metastasis) in SBC-3 cells remained to be investigated. The present study aimed to examine the role of DKK1 in SBC-3 cells, as well as to investigate the SBC-3 ability to metastasize and invade the bone tissue. The results demonstrated that upregulation of DKK1 in SBC-3 cells enhanced cell proliferation, colony formation, cell migration and invasion in vitro, as well as bone metastasis in vivo. These results indicate that DKK1 may be an important regulator in the development of small cell lung cancer (SCLC), and targeting DKK1 may be an effective method for preventing and/or treating skeletal metastases in SCLC cases. [ABSTRACT FROM AUTHOR]

Summary: Background: Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer. Methods: In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18–75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506. Findings: 400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67–1·05; median progression-free survival 4·6 months [95% CI 3·5–6·3] vs 3·4 months [2·3–3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033). Interpretation: Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer. Funding: Zhejiang Beta Pharma (China), the Chinese National Key Special Program for Innovative Drugs, the 863 Project, and Zhejiang Provincial Key Special Program. [ABSTRACT FROM AUTHOR]

Purpose: To explore the relationship between the expression of ZEB1 gene and the proliferation ability of lung adenocarcinoma cells. Methods: Immunohistochemistry, Western blot and Real-time PCR were used to detect the expression of ZEB1 gene in lung adenocarcinoma tissue and cell lines compared with adjacent noncancerous region and the human lung fibroblast cell HLF cells. The lentivirus RNA interference technique was used to knock down the expression of ZEB1 in lung adenocarcinoma A549 and H1299 cell lines. Cell cycle and cell apoptosis were measured by FCM assay . In vivo , four groups of 4-week-old nude mice were subcutaneously injected with the stably transfected (ZEB-si, scr-si) cells at a single site to investigate the effect of ZEB1-siRNA in the nude mice tumor growth. In situ apoptosis was detection by TUNEL assay. Results: ZEB-1 was highly expressed in lung adenocarcinoma tissue and cell lines compared with adjacent noncancerous region and the human lung fibroblast cell HLF cells. ZEB1-siRNA could decrease lung adenocarcinoma cell proliferation by delaying S-phase entry and induce cell apoptosis, which led to the inhibition of the tumorigenicity of A549 and H1299 cell lines. Further investigation showed that injecting the ZEB1-siRNA cells into the nude mice could significantly decrease the tumor growth. Conclusion: Knockdown of ZEB-1 expression by lentivirus-delivered siRNA may provide a novel therapeutic target for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Brain metastasis frequently occurs in cancer patients and is associated with a poor prognosis. We previously reported that S100B was highly expressed in PC14/B, a specific brain metastatic lung adenocarcinoma cell line, which suggests that it is associated with brain metastasis of lung cancer. However, the role of S100B in brain metastasis remains to be elucidated. In this study, using PC14/B cell line, we found that siRNA mediated depletion of S100B in PC14/B cells led to notable differences in cell proliferation, apoptosis, cell cycle progression, colony formation ability, cell migratory and invasive activity compared with the mock-transfected cells. Therefore, our data suggest that S100B promotes the brain metastasis of lung adenocarcinoma by promoting cell proliferation, preventing apoptosis and increasing cell migration and invasion. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: This clinical trial was conducted to evaluate the efficacy and safety of Palonosetron in preventing chemotherapy-induced vomiting (CIV) among the Chinese cancer patients.Patients and Methods: Two hundred and forty patients were scheduled to be enrolled and randomized to receive a single intravenous dose of palonosetron 0.25 mg, or granisetron 3 mg, 30 min before receiving highly emetogenic chemotherapy. The primary efficacy endpoint was the complete response (CR) rate for acute CIV (during the 0-24-h interval after chemotherapy). Secondary endpoints included the CR rates for delayed CIV (more than 24 h after chemotherapy).Results: Two hundred and eight patients were accrued and received study medication. CR rates for acute CIV were 82.69% for palonosetron and 72.12% for granisetron, which demonstrated that palonosetron was not inferior to granisetron in preventing acute CIV. Comparisons of CR rates for delayed CIV yielded no statistical difference between palonosetron and granisetron groups and did not reveal non-inferiority of palonosetron to granisetron. Adverse events were mostly mild to moderate, with quite low rates among the two groups.Conclusions: A single dose (0.25 mg) of palonosetron is not inferior to a single dose (3 mg) of granisetron in preventing CIV and possesses an acceptable safety profile in the Chinese population. [ABSTRACT FROM AUTHOR]