Numerical Analysis on Dynamic Response of CFRP-Wrapped RC Columns under Lateral Impact Loading.

This paper presents a numerical study examining the dynamic response and resistance mechanism of reinforced concrete (RC) columns strengthened with or without carbon-fiber-reinforced polymer (CFRP) wraps under lateral impact loading by using the software LS-DYNA. First, the information of eight column models was briefly introduced as part of the laboratory experimental program from the literature. Secondly, finite element (FE) models were established in terms of the geometries of impact tests. Then, a detailed comparison between numerical results and experimental results was made, and FE models showed a relatively high simulation accuracy. Subsequently, a series of parametric analyses were carried out with a focus on the effects of axial compression ratio, the boundary condition at the column top, the layer number of CFRP wraps, and the impact velocity and impact height on the dynamic responses of plain and strengthened columns. The results demonstrated that the CFRP retrofit mechanism was not activated during the initial Stage-I when the impact force rapidly increased to the first peak and then decreased to zero. CFRP strengthening came into play in the second stage, Stage-II, and affected the response of the shear force and moment along the column height, as well as had a great influence on the control of shear damage. The dynamic response of RC columns was more sensitive to the impact velocity than to other parameters, regardless of whether CFRP wrapping was applied. The axial compression ratio would have a different influence on the column failure mode if the impact velocity was varied. The variation in impact height and boundary condition at the column top had little influence on the damage mode of strengthened columns.

Influence of CNT Incorporation on the Carbonation of Conductive Cement Mortar.

This study analyzed the influence of carbon nanotubes (CNTs) on the carbonation conductive cementitious composites. Two powder types of CNT, multi-walled and single-wall CNTs, were employed to give the cement mortar the conductivity, and four tests including the accelerated carbonation, compressive and flexural strength, electrical resistance, and porosity tests were carried out. To intentionally accelerate the carbonation, the prismatic specimens of conductive cement composites were fabricated and stored in the controlled environmental chamber at a constant temperature of 20 ± 2 °C, constant relative humidity of 60 ± 5%, and carbon dioxide (CO2) concentration of 5% for 12 weeks. It was observed that carbonation resulted in only chemical damage so that there was no change in the electrical resistance value of conductive cementitious mortar that had undergone a carbonation attack.

Strain Transfer of Fiber Bragg Grating Sensor Externally Bonded to FRP Strip for Structural Monitoring after Reinforcement.

To date, a method of attaching a FRP (fiber-reinforced polymer) to concrete members with epoxy has been widely applied to increase the strength of the member. However, there are cases in which the adhesion of the epoxy deteriorates over time and the reinforcing effect of the FRP is gradually lost. Therefore, monitoring whether or not the reinforcing effect is properly maintained is needed in order to prevent a decrease in the structural performance of the member improved by FRP reinforcement. In this regard, this study examines FRP with OF (optical fiber) sensors to monitor the reinforcing effect of FRP in concrete structural members. In particular, this paper seeks to determine an appropriate adhesion length when FBG (fiber Bragg grating) based OF sensors are externally bonded to FRP strips with epoxy resin. To this end, a tensile test was carried out to evaluate the sensing performance according to the adhesion length. In addition, an analytical approach was performed and the result were compared with test result. The results of the experimental and analytical studies showed that the strain generated in the FRP is sufficiently transferred to the OF if the total adhesion length of it is 40 mm or more in consideration of the error in the epoxy thickness.

Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3-Knockin Mice.

In the tumor microenvironment, multiple inhibitory checkpoint receptors can suppress T-cell function, thereby enabling tumor immune evasion. Blockade of one of these checkpoint receptors, PD-1, with therapeutic antibodies has produced positive clinical responses in various cancers; however, the efficacy of this approach can be further improved. Simultaneously targeting multiple inhibitory checkpoint receptors has emerged as a promising therapeutic strategy. Here, we report the development and characterization of REGN3767, a fully human IgG4 antibody targeting LAG-3, another inhibitory receptor on T cells. REGN3767 binds human and monkey LAG-3 with high affinity and specificity and blocks the interaction of LAG-3 with its ligand, MHC class II. In an engineered T-cell/antigen-presenting cell bioassay, REGN3767 alone, or in combination with cemiplimab (REGN2810, human anti-PD-1 antibody), blocked inhibitory signaling to T cells mediated by hLAG-3/MHCII in the presence of PD-1/PD-L1. To test the in vivo activity of REGN3767 alone or in combination with cemiplimab, we generated human PD-1xLAG-3 knockin mice, in which the extracellular domains of mouse Pdcd1 and Lag3 were replaced with their human counterparts. In these humanized mice, treatment with cemiplimab and REGN3767 showed increased efficacy in a mouse tumor model and enhanced the secretion of proinflammatory cytokines by tumor-specific T cells. The favorable pharmacokinetics and toxicology of REGN3767 in nonhuman primates, together with enhancement of antitumor efficacy of anti-PD-1 antibody in preclinical tumor models, support its clinical development.

Characterization of the Anti-PD-1 Antibody REGN2810 and Its Antitumor Activity in Human PD-1 Knock-In Mice.

The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1 and PD-L2 expressed on antigen-presenting cells and cancer cells, resulting in suppression of T-cell effector function and tumor immune evasion. Clinical antibodies blocking the interaction between PD-1 and PD-L1 restore the cytotoxic function of tumor antigen-specific T cells, yielding durable objective responses in multiple cancers. This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4(S228P) high-affinity anti-PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2. REGN2810 was characterized in a series of binding, blocking, and functional cell-based assays, and preclinical in vivo studies in mice and monkeys. In cell-based assays, REGN2810 reverses PD-1-dependent attenuation of T-cell receptor signaling in engineered T cells and enhances responses of human primary T cells. To test the in vivo activity of REGN2810, which does not cross-react with murine PD-1, knock-in mice were generated to express a hybrid protein containing the extracellular domain of human PD-1, and transmembrane and intracellular domains of mouse PD-1. In these mice, REGN2810 binds the humanized PD-1 receptor and inhibits growth of MC38 murine tumors. As REGN2810 binds to cynomolgus monkey PD-1 with high affinity, pharmacokinetic and toxicologic assessment of REGN2810 was performed in cynomolgus monkeys. High doses of REGN2810 were well tolerated, without adverse immune-related effects. These preclinical studies validate REGN2810 as a potent and promising candidate for cancer immunotherapy. Mol Cancer Ther; 16(5); 861-70. ©2017 AACR.

Benzannulation of Triynes Initiated by an Alder-Ene Reaction and Subsequent Trifluoromethylthiolate Addition.

A new benzannulation reaction with accompanied trifluoromethylthiolation is described. This benzannulation can generate a range of trifluoromethylthiolated benzolactams and benzolactones from 1,3,8-triynes and a stoichiometric amount of AgSCF3 at 90 °C through an initial Alder-ene reaction, 1,4-addition of AgSCF3, and a series of bond-reorganization processes that include double bond migration, 6π-electrocyclization, and a [1,3]-H shift. For certain substrates containing a triisopropylsilyl (TIPS) group, the final [1,3]-H shift-interrupted products, were obtained.

Toxicology and pharmacokinetic study of orally administered 5-iodo-2-pyrimidinone-2'deoxyribose (IPdR) x 28 days in Fischer-344 rats: impact on the initial clinical phase I trial design of IPdR-mediated radiosensitization.

PURPOSE: A toxicology and pharmacokinetic study of orally administered (po) IPdR (5-3iodo-2-pyrimidinone-2'deoxyribose, NSC-726188) was performed in Fischer-344 rats using a once daily (qd) x 28 days dosing schedule as proposed for an initial phase I clinical trial of IPdR as a radiosensitizer. METHODS: For the toxicology assessment, 80 male and female rats (10/sex/dosage group) were randomly assigned to groups receiving either 0, 0.2, 1.0 or 2.0 g kg(-1)day(-1) of po IPdR x 28 days and one-half were observed to day 57 (recovery group). Animals were monitored for clinical signs during and following treatment with full necropsy of one-half of each dosage group at day 29 and 57. For the plasma pharmacokinetic assessment, 40 rats (10/sex/dosage group) were randomly assigned to groups receiving either 0.2 or 1.0 g kg(-1)day(-1) of po IPdR x 28 days with multiple blood samplings on days 1 and 28 and single blood sampling on days 8 and 15. RESULTS: No drug-related deaths occurred. Higher IPdR doses resulted in transient weight loss and transient decreased hemoglobins but had no effect on white cells or platelets. Complete serum chemistry evaluation showed transient mild decreases in total protein, alkaline phosphatase, and serum globulin. Necropsy evaluation at day 29 showed minimal to mild histopathologic changes in bone marrow, lymph nodes and liver; all reversed by day 59. There were no sex-dependent differences in plasma pharmacokinetics of IPdR noted and the absorption and elimination kinetics of IPdR were found to be linear over the dose range studied. CONCLUSIONS: A once-daily dosing schedule of po IPdR for 28 days with doses up to 2.0 g kg(-1)day(-1) appeared to be well tolerated in Fischer-344 rats. Drug-related weight loss and microscopic changes in bone marrow, lymph nodes and liver were observed. These changes were all reversed by day 57. IPdR disposition was linear over the dose range used. However, based on day 28 kinetics it appears that IPdR elimination is enhanced following repeated administration. These toxicology and pharmacokinetic data were used when considering the design of our initial phase I trial of po IPdR as a clinical radiosensitizer.