Background: It’s still controversial whether triplet is better than doublet regimen in first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of new generation doublet regimen XELOX and EOX triplet regimen.Methods: EXELOX was an open-label, multicenter, randomized phase III trial that enrolled 448 previously untreated patients with AGC. Patients were randomly assigned to receive XELOX or EOX regimen. The primary endpoint was noninferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. The second endpoints included overall survival(OS), objective response rate(ORR), safety, and quality of life (QoL). This study is registered with ClinicalTrials.gov, number NCT02395640. Findings: Between Apr 10, 2015 and Aug 20,2020, 448 AGC patients were randomized to receive XELOX (n=222) or EOX (n=226). In ITT basis, the median PFS was 5.0 months (95%CI 4.5-6.0) in XELOX group and 5.5 months (95%CI 5.0-6.0) in EOX group (HR 0.989, 95%CI 0.812-1.203; Pnon-inferiority =0.0032). There was no significant difference in median OS (12.0 vs. 12.0 months, HR 1.097, p =0.384), or ORR(37.4% vs. 45.1%, p =0.291) between two groups. In patients with poor differentiated adenocarcinoma and liver metastasis, EOX arm had significant longer mOS(p=0.021) and trend of longer mPFS(p=0.073) than XELOX arm. The incidence of grade 3/4 adverse events (AEs) was 42.2% (90/213) in XELOX group and 72.5% (156/215) in EOX group (p=0.001). The Global Health/QoL score were significantly higher in XELOX group than EOX group during chemotherapy.Interpretation: This is the first noninferiority trial demonstrating that doublet is as effective as triplet regimen generally, with a better safety profile and QoL as first-line treatment for AGC patients; but triplet regimen might have effects advantage in selected subsets, providing solid evidence for guideline update and guidance for future clinical trial design.Trial Registration: This study is registered with ClinicalTrials.gov, number NCT02395640 .Funding: This study was supported by The National Key Research and Development Program of China [grant no. 2017YFC1308900]; The clinical research and cultivation project of shanghai Shenkang hospital development center [grant no. SHDC12017X01] and Sun Yat-sen University Xie Tong Chuang Xin Program [grant no. ZLYXXTCX201504].Declaration of Interest: None to declare. Ethical Approval: The trial protocol was approved by the local institutional review board and ethics committee.
Open reading frame 17 ( Bm17 ) of Bombyx mori nucleopolyhedrovirus is a highly conserved gene in lepidopteran nucleopolyhedroviruses, suggesting that it performs an important role in the virus life cycle whose function is unknown. In this report, we describe the characterization of Bm17 . Reversed transcriptive‐PCR (RT‐PCR) and Western blot analysis demonstrated that Bm17 was expressed as a late gen. Immunofluorescence analysis by confocal microscopy showed that BM17 protein was localized on cytoplasm and nucleus of infected cells. These results show that BM17 was a late protein localized in cytoplasm and nucleus.
Debates regarding the specific effects of general anesthesia on developing brains have persisted for over 30 years. A consensus has been reached that prolonged, repeated, high-dose exposure to anesthetics is associated with a higher incidence of deficits in behavior and executive function, while single exposure has a relatively minor effect on long-term neurological function. In this review, we summarize the dose-dependent neuroprotective or neurotoxic effects of gamma-aminobutyric acid type A receptor agonists, a representative group of sedatives, on developing brains or central nervous system diseases. Most preclinical research indicates that anesthetics have neurotoxic effects on the developing brain through various signal pathways. However, recent studies on low-dose anesthetics suggest that they may promote neurodevelopment during this critical period. These findings are incomprehensible for the general “dose-effect” principles of pharmacological research, which has attracted researchers' interest and led to the following questions: What is the threshold for the dual effects exerted by anesthetics such as propofol and sevoflurane on the developing brain? To what extent can their protective effects be maximized? What are the underlying mechanisms involved in these effects? Consequently, this issue has essentially become a “mathematical problem.” After summarizing the dose-dependent effects of gamma-aminobutyric acid type A receptor agonist sedatives in both the developing brain and the brains of patients with central nervous system diseases, we believe that all such anesthetics exhibit specific threshold effects unique to each drug. These effects range from neuroprotection to neurotoxicity, depending on different brain functional states. However, the exact values of the specific thresholds for different drugs in various brain states, as well as the underlying mechanisms explaining why these thresholds exist, remain unclear. Further in-depth exploration of these issues could significantly enhance the therapeutic translational value of these anesthetics.
Abstract A notable anomalous lower-tropospheric anticyclone appears over the western North Pacific (WNP) during post-El Niño summer, exerting a profound influence on the East Asia summertime climate. Here, we employ a suite of global climate model projections under symmetric CO2 ramp-up (RU) and ramp-down (RD) scenarios to reveal the asymmetric response of the WNP anticyclone (WNPAC). Our results demonstrate a progressive strengthening of the WNPAC with rising CO2 concentrations, a trend that persists as CO2 declines, followed by gradual recovery, and the anomalous anticyclone fails to return to its initial state when CO2 concentrations return to pre-industrial levels, attributed to Indo-Pacific zonal SST gradient variations. In contrast to the CO2 RU phase, the increased zonal SST gradient is witnessed in the CO2 RD phase, favoring anomalous moisture convergence over the Maritime Continent (MC). This strengthens the WNPAC through Kelvin wave-induced Ekman divergence or local Hadley circulation adjustment. The increased zonal SST gradient is associated with strengthened SST warming in the MC and accelerated decay of El Niño-related positive SST anomalies in the equatorial Central Pacific, ultimately attributed to a climatological equatorial Pacific El Niño-like warming pattern driving intricate air-sea interactions and processes. Our findings indicate that the overshoot of the WNPAC during the CO2 RD phase may exacerbate the flood and high temperature risks in densely populated East Asia.
2580 Background: Vorolanib (CM082) is a potent and selective inhibitor of VEGFR and PDGFR, which is well tolerated from 20 to 400 mg without G3/4 treatment-related AEs (TRAEs) in patients in US. Here we present a phase I dose escalation study that assessed vorolanib in Chinese patients with advanced solid tumor. Methods: Patients with advanced solid tumors were enrolled to receive escalating dose of vorolanib once daily from 50 mg to 300 mg following the 3+3 design. Primary endpoints included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Results: 19 patients were enrolled and treated, including 12 RCC. Most patients (n = 18) have received at least one prior systemic treatments, in which 10 have been treated with VEGFR TKIs. No DLT was seen, the MTD was not achieved. The most common TRAEs were leukopenia (9/19), fatigue (9/19), diarrhea (8/19), neutropenia (8/19), and hypertension (8/19). G3 or higher events were seen in 7 patients across 100 to 250 mg dose cohort. PK analysis was shown in table 1. Partial response was seen in 1 RCC patients in the 200 mg cohort, and 11 stable disease were seen in all dose cohorts. Conclusions: Vorolanib has an acceptable safety profile and showed preliminary activities in RCC. An expansion of RCC-enriched cohort is ongoing. Clinical trial information: NCT01863485.PK parameters. 50 mg (n = 4) 100 mg (n = 3) 150 mg (n = 3) 200 mg (n = 3) 250 mg (n = 4) Single dose t1/2 hr 3.95 ± 0.56 8.01 ± 1.67 5.78 ± 0.53 5.25 ± 0.40 6.20 ± 1.82 Tmax hr 4.00 2.33 ± 0.58 2.67 ± 0.58 3.67 ± 0.58 2.75 ± 0.96 Cmax ng/mL 239.82 ± 39.24 566.86 ± 253.54 727.75 ± 133.36 857.22 ± 94.49 1003.79 ± 92.73 AUC(0-48 h) hr*ng/mL 1973.24 ± 435.85 5501.26 ± 2972.74 6327.04 ± 654.03 7689.95 ± 1684.58 8435.56 ± 1515.97 AUC (0-inf) hr*ng/mL 1981.85 ± 437.81 5586.84 ± 3011.58 6352.55 ± 669.81 7706.55 ± 1688.32 8481.12 ± 1539.81 Multiple doses t1/2 hr 4.28 ± 0.75 5.03 ± 1.69 6.25 ± 0.81 4.83 ± 0.14 4.46 ± 0.78 Tmax hr 4.00 ± 1.63 2.33 ± 0.58 3.00 ± 1.00 3.00 ± 1.00 2.75 ± 0.05 Cmax ng/mL 254.19 ± 94.23 649.98 ± 147.51 923.83 ± 208.44 811.55 ± 266.45 959.62 ± 431.12 AUC (0-24 h) hr*ng/mL 2168.81 ± 874.37 5910.91 ± 1909.47 9224.53 ± 3153.11 6579.73 ± 2264.7 6968.75 ± 3265.82 AUC (0-inf) hr*ng/mL 2235.38 ± 883.95 6283.97 ± 2337.41 10068.74 ± 3487.21 6823.74 ± 2345.54 7221.1 ± 3439.7
ConspectusHepatic ischemia-reperfusion injury (HIRI) is an inevitable complication of clinical surgeries such as liver resection or transplantation, often resulting in postoperative liver dysfunction, hepatic failure in up to 13% of postresection patients, and early graft failure in 11-18% of liver transplantation patients. HIRI involves a series of biochemical events triggered by abnormal alterations in multiple biomarkers, characterized by short lifespans, dynamic changes, subcellular regional distribution, and multicollaborative regulation. However, traditional diagnosis, including serology, imaging, and liver puncture biopsy, suffers from low sensitivity, poor resolution, and hysteresis, which hinder effective monitoring of HIRI markers. Thus, to address the unique properties of HIRI markers, there is a pressing demand for developing novel detection strategies that are highly selective, transiently responsive, dynamically reversible, subcellular organelle-targeted, and capable of simultaneous multicomponent analysis.Optical probe-based fluorescence imaging is a powerful tool for real-time monitoring of biomarkers with the advantages of high sensitivity, noninvasiveness, rapid analysis, and high-fidelity acquisition of spatiotemporal information on signaling molecules compared with conventional methods. Moreover, with the growing demand for continuous monitoring of biomarkers, probes with reversible detection features are receiving more and more attention. Importantly, reversible probes can not only monitor fluctuations in marker concentrations but also distinguish between transient bursts of markers during physiological events and long-term sustained increases in pathological marker levels. This can effectively avoid false-positive test results, and in addition, reversible probes can be reutilized with green and economical features. Therefore, our team has employed various effective methods to design reversible optical probes for HIRI. We proposed reversible recognition strategies based on specific reactions or interactions to detect dynamic changes in markers. Given the biomarkers' unique signaling in subcellular organelles and the synergistic regulatory properties of multiple markers for HIRI, bifunctional reversible detection strategies are exploited, including organelle-targeted reversible and multicomponent simultaneous detection. With these strategies, we have tailored a variety of high-fidelity fluorescent probes for a series of HIRI markers, including reactive oxygen/nitrogen species (O
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