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PURPOSE Patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) have poor prognosis. For these patients, treatment options are limited after first-line systemic therapy. PATIENTS AND METHODS In this open-label phase III clinical study, patients with advanced or metastatic ESCC, whose tumor progressed after first-line systemic treatment, were randomly assigned (1:1) to receive intravenous tislelizumab, an anti–programmed cell death protein 1 antibody, 200 mg every 3 weeks or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). The primary end point was overall survival (OS) in all patients. The key secondary end point was OS in patients with programmed death-ligand 1 tumor area positivity (TAP) score ≥ 10%. RESULTS In total, 512 patients across 11 countries/regions were randomly assigned. At final analysis, conducted after 410 death events occurred, OS was significantly longer with tislelizumab versus chemotherapy in all patients (median, 8.6 v 6.3 months; hazard ratio [HR], 0.70 [95% CI, 0.57 to 0.85]; one-sided P = .0001), and in patients with TAP ≥ 10% (median, 10.3 months v 6.8 months; HR, 0.54 [95% CI, 0.36 to 0.79]; one-sided P = .0006). Survival benefit was consistently observed across all predefined subgroups, including those defined by baseline TAP score, region, and race. Treatment with tislelizumab was associated with higher objective response rate (20.3% v 9.8%) and a more durable antitumor response (median, 7.1 months v 4.0 months) versus chemotherapy in all patients. Fewer patients experienced ≥ grade 3 treatment-related adverse events (18.8% v 55.8%) with tislelizumab versus chemotherapy. CONCLUSION Tislelizumab significantly improved OS compared with chemotherapy as second-line therapy in patients with advanced or metastatic ESCC, with a tolerable safety profile. Patients with programmed death-ligand 1 TAP ≥ 10% also demonstrated statistically significant survival benefit with tislelizumab versus chemotherapy.

BackgroundRice blast disease is one of the most destructive diseases of rice worldwide. We previously cloned the rice blast resistance gene Pid2, which encodes a transmembrane receptor-like kinase containing an extracellular B-lectin domain and an intracellular serine/threonine kinase domain. However, little is known about Pid2-mediated signaling.ResultsHere we report the functional characterization of the U-box/ARM repeat protein OsPUB15 as one of the PID2-binding proteins. We found that OsPUB15 physically interacted with the kinase domain of PID2 (PID2K) in vitro and in vivo and the ARM repeat domain of OsPUB15 was essential for the interaction. In vitro biochemical assays indicated that PID2K possessed kinase activity and was able to phosphorylate OsPUB15. We also found that the phosphorylated form of OsPUB15 possessed E3 ligase activity. Expression pattern analyses revealed that OsPUB15 was constitutively expressed and its encoded protein OsPUB15 was localized in cytosol. Transgenic rice plants over-expressing OsPUB15 at early stage displayed cell death lesions spontaneously in association with a constitutive activation of plant basal defense responses, including excessive accumulation of hydrogen peroxide, up-regulated expression of pathogenesis-related genes and enhanced resistance to blast strains. We also observed that, along with plant growth, the cell death lesions kept spreading over the whole seedlings quickly resulting in a seedling lethal phenotype.ConclusionsThese results reveal that the E3 ligase OsPUB15 interacts directly with the receptor-like kinase PID2 and regulates plant cell death and blast disease resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-015-0442-4) contains supplementary material, which is available to authorized users.

Z␣ is a peptide motif that binds to Z-DNA with high affinity. This motif binds to alternating dC-dG sequences stabilized in the Z-conformation by means of bromination or supercoiling, but not to B-DNA. Z␣ is part of the N-terminal region of double-stranded RNA adenosine deaminase (ADAR1) , a candidate enzyme for nuclear pre-mRNA editing in mammals. Z␣ is conserved in ADAR1 from many species; in each case, there is a second similar motif, Z␤, separated from Z␣ by a more divergent linker. To investigate the structure-function relationship of Z␣, its domain structure was studied by limited proteolysis. Proteolytic profiles indicated that Z␣ is part of a domain, Zab, of 229 amino acids (residues 133-361 in human ADAR1). This domain contains both Z␣ and Z␤ as well as a tandem repeat of a 49-amino acid linker module. Prolonged proteolysis revealed a minimal core domain of 77 amino acids (positions 133-209), containing only Z␣, which is sufficient to bind lefthanded Z-DNA; however, the substrate binding is strikingly different from that of Zab. The second motif, Z␤, retains its structural integrity only in the context of Zab and does not bind Z-DNA as a separate entity. These results suggest that Z␣ and Z␤ act as a single bipartite domain. In the presence of substrate DNA, Zab becomes more resistant to proteases, suggesting that it adopts a more rigid structure when bound to its substrate, possibly with conformational changes in parts of the protein.Many protein domains that recognize DNA in both sequenceand conformation-specific manners have been characterized (for a review, see Ref. 1). These studies have resulted in an understanding of the variety of ways in which protein-DNA interactions can result in function. Identification of a peptide motif, Z␣, which binds specifically to Z-DNA, opens up a new vista and invites the investigation of the similarities and differences between domains that bind right-and left-handed DNAs. The conformation specificity of Z␣ binding has been characterized in many ways. Peptides including this motif bind to alternating dC-dG that has been stabilized in the Z-conformation using bromination or supercoiling, as shown by band shift assays, competition experiments, and BIAcore measurements (2). When linked to the nuclease domain from FokI, the resulting chimeric nuclease cuts supercoiled plasmid DNA to bracket a d(C-G) 13 in the Z-conformation (3). The protein also binds to short oligonucleotides of suitable sequence and converts them from the B-to the Z-conformation, as detected by CD and Raman spectroscopy (4, 5). The binding of Z-DNA by Z␣ occurs even in the presence of a 10 5 -fold excess of B-DNA (6). Z␣ binds poly(dC-dG), stabilized in the Z-conformation by bromination, with an equilibrium dissociation constant (K d ) in the lower nanomolar range, as shown by BIAcore measurements (2).Although many properties of Z␣ have been studied, its biological function in the context of ADAR1 remains unknown. The Z-DNA binding activity of Z␣ was first identified in proteolytic fragments of double...