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Background: Multiple myeloma (MM) has become the second most hematological malignance. The patients are rarely cured and experience the recurrence or resistance. There is still an urgent need to develop potential therapeutic agents with better response. BCMA (B cell maturation antigen) and GPRC5D (G-protein-coupled receptor class 5 member D) are independently expressed in MM cells. The percentage of MM patients with single or co-expression of BCMA and GPRC5D is close to 90%, which means both are the ideal therapeutical targets. Methods/Results: Anti-GPRC5D and anti-BCMA antibodies with high binding affinity were respectively screened from hybridoma or alpaca phage library. Two antibodies were assembled to anti-CD3 antibody with low binding activity. Candidate molecule SCR-8572 was selected from dozens of triple-specific antibodies. The affinity of SCR-8572 to recombinant BCMA protein is 41.3pM. Binding EC50 to GPRC5D over-expressed cell is 2.4nM. SCR-8572 also showed very good binding activity with several MM cell lines, such as H929, RPMI-8226 and Molp-8, etc. The weak binding to CD3 can decrease the sink effect in peripheral blood. In vitro cytotoxicity of SCR-8572 against three MM cell lines with different expression levels was evaluated. It showed strong tumor-induced T cell activation but not non-specific activation, which resulted in the excellent tumor cytotoxicity. And the cytotoxicity was much stronger than that of BCMA-CD3 (Teclistamab analogue) and/or GPRC5D-CD3 (Talquetamab analogue) treatments. In the meanwhile, the cytokine release levels of IL-6 and TNFa are acceptable and similar with two TCE benchmarks. This predicted the low risk of CRS. We also conducted in vivo efficacy test in two MM Cell-derived-Xenograft mice models with PBMC reconstitution. SCR-8572 can eliminate the tumors and maintained tumor regression after drug withdrawal, while the tumor relapse occurred in Teclistamab and/or Talquetamb groups. The preliminary toxic effect of SCR-8572 was explored in cynomolgus by 10mpk followed by 30mpk intravenous injection with 21 days interval. The cynomolgus tolerated very well. Lymphocyte reduction was observed which indicated the lymphocyte redistribution. C Reaction Protein (CRP) level increased to 19-33mg/L and recovered to baseline in 7 days. IL-6 level increased to 116.3pg/ml in 24 hours after 10mpk injection and 52.5pg/ml in 2 hours after followed 30mpk injection. IFNγ, IL-2 and IL-10 levels were detected to be very low or below the limit of quantitation. Conclusion: We have developed a novel dual-targeted T cell engager for MM treatment, which showed strong tumor killing effect in in vitro and in vivo models with low CRS risk. The toleration of high dosage in cynomolgus suggested the good safety performance. Above all, the preclinical study illustrated SCR-8572 can be a promising therapeutic candidate in treatment of MM patients. Citation Format: Yayuan Fu, Shumei You, Menghao Wei, Bowei Yin, Qi Deng, Xiaokang Qin, Yun Zhang, Yanqiu Wang, Renhong Tang. A novel T cell engager targeting BCMA and GPRC5D showed promising preclinical activity with low toxic risk for multiple myeloma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1883.

Ignition delay time (IDT) measurements for ethylene (C2H4)/nitrogen dioxide (NO2)/oxygen/argon mixtures with various blending ratios of NO2/C2H4 = 0/100, 15/85 and 50/50 were performed in a shock tube. The sensitization effect of NO2 on C2H4 ignition was investigated at pressures ranging from 1.2 to 10 atm, in the temperature range 920–1780 K, and at equivalence ratios from 0.5 to 2.0. Similar to our recent studies of NO2 effects on CH4 and C2H6 ignition (Deng et al., 2016; Deng et al., 2017), the effect of NO2 addition on measured IDTs of the unsaturated hydrocarbon C2H4 also exhibits both temperature- and pressure- dependences. NO2 addition generally promotes the reactivity of ethylene and the promotion effect is more pronounced for the mixtures with high NO2 content at higher pressures (p > 4.0 atm), at lower temperatures (T 1250 K). A detailed kinetic mechanism of C2H4/NO2 was proposed by refining critical reactions through incorporating ab-initio calculations from this study and recently published rate constant data. This mechanism is capable of reproducing the new data reported in this work and literature ones as well and has thus been used to perform sensitivity and flux analyses to kinetically interpret the interaction of NO2 with C2H4.

H-atom abstraction and addition are the two most important reactions in alkene oxidation. As a complement of our synchronization work of 3-hexene chemistry (Feiyu Yang et al., Kinetics of Hydrogen Abstraction and Addition Reactions of 3-Hexene by ȮH Radicals, J. Phys. Chem. A 2017, 121, 1877–1889), high-accuracy electronic structure calculations (DLPNO CCSD(T)/CBS) and canonical variational transition state theory are used to predict the rate coefficients of the H-atom abstraction and addition reactions of 3-hexene + ĊH3/Ḣ/O system. Although ĊH3/Ḣ/O are all nonpolar radicals, Ḣ + 3-hexene system shows some unique features. Unlike the 3-hexene + ĊH3/O systems, the potential energy surface of 3-hexene + Ḣ system exhibits a unique “negative well” characteristic, suggesting the energy of the well is higher than its corresponding reactant or product. Analysis shows that the “negative well” characteristic is caused by the relative larger zero-point energies of Van der Waals complex of H + 3-hexene system. Moreover, the evolution of adiabatic ground-state energy shows wells/well-like curves at both reactant and product sides for 3-hexene + ĊH3 and O systems, but only at reactant end for 3-hexene + Ḣ system. Vibrational analysis reveals that for 3-hexene + ĊH3 and O systems, the wells/well-like curves are generated by the C = C double bond stretch motion, while it is generated by the forming H H single bond stretch motion for 3-hexene + Ḣ system. Branching ratio shows that addition and abstraction dominate at low and high temperatures and the critical temperatures are 478 K, 794 K and 735 K for 3-hexene + ĊH3, Ḣ and O systems, respectively. Rate coefficients with a conservative uncertainty of a factor of 5 are estimated based on similar algorithm of Sun and Law. In addition, analyses on the potential energy surface, minimum energy path, adiabatic ground-state energy and activation free Gibbs energy change are also performed in this work.

Dimethoxymethane (DMM, CH3OCH2OCH3), the simplest member in the class of polyoxymethylene dimethyl ethers (PODE), is regarded as a promising fuel substitute for compression ignition engines. To better understand its combustion characteristics, a comprehensive experimental and kinetic modeling study on the combustion of DMM was conducted. Ignition delay times (IDTs) of DMM/O2/Ar mixtures were measured in a shock tube at pressures from 1.0 to 10 atm, for temperatures from 1050 to 1450 K, and equivalence ratios of 0.5, 1.0 and 2.0. A predominantly ab initio derived detailed kinetic model of DMM with 121 species and 646 reactions was developed based on AramcoMech2.0 with an updated sub-mechanism of methyl formate (MF, CH3OCHO). C O bond fissions occurred in CH2 O and CH3 O moieties were demonstrated to be the dominating reaction pathways in DMM high temperature chemistry rather than the competing non-radical decomposition channels. Flux and sensitivity analyses indicated that the two C O bond fissions have a comparatively promoting effect on reactivity, while the DMM = CH3OCH2O + CH3 reaction was the dominating channel at high temperatures. The proposed model was also validated against literature experimental data, including ignition delay times, jet stirred reactor species concentrations, laminar pre-mixed flame speciation, laminar burning velocities and plug-flow reactor speciation. The good performance of the proposed model for reproducing these data revealed its ability to predict DMM combustion over a wide range of conditions. Major reaction pathways of DMM could also apply to larger PODE compounds.

Diosgenin is an important basic raw material for the production of steroid hormone drugs. It can be isolated and purified from a variety of traditional Chinese medicines or plants. Modern molecular biological studies have shown that diosgenin inhibits various tumor cells migration and invasion ability to varying degrees in vitro and in vivo. The aim of the present study was to observe the inhibitory effects of diosgenin on the invasive and metastatic capabilities of osteosarcoma cells and to determine the association between the effects of diosgenin on the epithelial-mesenchymal transition (EMT). Wound healing and Transwell assays were used to observe the inhibitory effects of diosgenin on the invasion and migration of two osteosarcoma cell lines. Immunofluorescence was used to observe changes in transforming growth factor β1 (TGF-β1) protein expression levels in the osteosarcoma cells following drug administration. EMT-associated proteins, including TGFβ1, E-cadherin and vimentin were detected by western blotting, which demonstrated that the drug may inhibit the initiation of EMT in osteosarcoma cells. Western blot analysis of the expression of all the proteins in the mitogen-activated protein kinase (MAPK) pathway demonstrated that the drug inhibited the MAPK signaling pathway. The primary mechanism of action of diosgenin was the inhibition of the phosphorylated p38 (pP38) protein. Through a combination of inhibitors of the p38MAPK signaling pathway and detection of the downstream EMT marker protein E-cadherin by quantitative PCR, pP38 was confirmed to be a target of diosgenin in the inhibition of EMT in the osteosarcoma cells via the MAPK molecular signaling pathway. Diosgenin may exhibit utility as an auxiliary drug for the clinical reduction of metastasis in patients with osteosarcoma.

Gas-phase auto-ignition delay times (IDTs) of methane/“air” (21% O2/79% Ar) mixtures were measured behind reflected shock waves, using a kinetic shock tube. Experiments were performed at fixed pressure of 1.8 MPa and equivalence ratios of 0.5 and 1.0, over the temperature range of 800–1000 K. Overall, the effect of equivalence ratio on IDT is negligible at entire temperatures measured in this study. The difference from traditional ignition regime at high temperatures, the undiluted methane/air mixtures present a four-stage ignition process at lower temperatures, namely deflagration delay, deflagration, deflagration-detonation transition, and detonation. Four popular kinetic mechanisms, UBC Mech 2.1, GRI Mech 3.0, Aramco Mech 2.0, and USC Mech 2.0, were used to simulate the new measurements. Only UBC Mech 2.1 showed satisfactory predictions in the reactivity of the undiluted methane mixtures; it was, thus, adopted to perform sensitivity analysis for identifying dominant reactions in the ignition process. The difference in channels contributing ȮH radicals causes a reduced global activation energy with decreasing temperatures.Keywords: Methane; multistage ignition; shock tube; sensitivity analysis

Astragaloside IV is the main ingredient of the medicinal herb Radix astragali, which has reported to have antitumor activity in vitro and in vivo. To determine whether the inhibitory effect of astragaloside IV on the invasion and metastasis of the cervical cancer cells is associated with epithelial‑mesenchymal transition (EMT), wound healing and Transwell assays were performed using SiHa cervical cancer cells and demonstrated that astragaloside IV inhibited invasion and migration of human SiHa cervical cancer cells in vitro. Immunocytochemical and western blot analyses indicated that astragaloside IV inhibited EMT by affecting the expression of transforming growth factor‑β1 (TGF‑β1) and E‑cadherin in the cancer cells. Two Smad‑independent pathways mediated by TGF‑β1 were identified to be associated with the effects of astragaloside IV, namely, mitogen‑activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K) signaling pathways. The data indicated that astragaloside IV has inhibitory effects on phosphorylation of P38 MAPK, PI3K, AKT and mTOR of SiHa cells of cervical cancer. Furthermore, MAPK and PI3K pathway inhibitors were administered to the cancer cells and the expression of E‑cadherin, a marker of EMT, was determined by reverse transcription‑quantitative polymerase chain reaction. The results demonstrated that MAPK and PI3K pathways were involved in the inhibitory effect of astragaloside IV on EMT. In vivo small animal imaging techniques was performed and demonstrated that astragaloside IV inhibited the metastasis of cervical cancer cells. Taken together, the findings demonstrated that astragaloside IV inhibits the invasion and migration of cervical cancer cells in vitro and in vivo.

To understand the effect of hydrogen addition on the auto-ignition of ammonia at high temperatures, ignition delay times of stoichiometric ammonia/hydrogen blends were measured in a shock tube at temperatures from 1020 to 1945 K, pressures of 1.2 and 10 atm, and hydrogen fractions from 0% to 70%. The measured ignition delay times were compared with seven available kinetic models. Chemical kinetic analyses were performed using both the Glarborg Model and Otomo Model to interpret the interactions between ammonia and hydrogen during the high temperature auto-ignition. Experimental results show that ammonia ignites slower than hydrogen, and hydrogen addition can reduce the ignition delay time nonlinearly. The numerical analysis identifies that 5% hydrogen addition does not significantly affect the reaction flux of ammonia at 20% fuel consumption, however, it makes the fuel H-atom abstraction reaction NH3 + H NH2 + H2 proceed in the reversed way at the initial stage of ignition, therefore generate active H radical for further chain branching and promote the reactivity.

Impact of water (H2O) vitiation on auto-ignition characteristics of kerosene/air mixtures was investigated behind the reflected shock waves covering pressures of 0.45–7.5 atm and temperatures of 900–1450 K. Arrhenius-type expressions were fitted for both mixtures with and without H2O using multiple linear regression method. Temperature- and pressure-dependences of ignition delay times were experimentally observed to be in-line with conventional hydrocarbons for all the test mixtures, but stronger pressure-dependence exhibited when presence of H2O. A four-component surrogate model fuel (25.7% n-tetradecane/23.0% 2-methylundecane/42.1% n-butylcyclohexane/9.2% n-butylbenzene) was proposed based on similarity criterion of function group. A surrogate mechanism was subsequently assembled by incorporating the modified rate rule of certain reaction class. The proposed kinetic model reproduces well the experimental observations at the entire conditions. Thermal and kinetic effects of H2O on the RP-3 reactivity were distinguished by factitiously inducing a weak collision H2O* and an inert H2O**. Results reveal that the kinetic-based promotion of H2O outweighs the thermal-based inhibition on the RP-3 reactivity at high pressures due to higher collision efficiency, which facilitates the reaction H2O2 (+M) ⟺ OH + OH (+M). However, the RP-3 reactivity is inhibited only by thermodynamics without kinetics at low pressures.

Proanthocyanidins are flavonoids that are widely present in the skin and seeds of various plants, with the highest content in grape seeds. Many experiments have shown that proanthocyanidins have antitumor activity both in vivo and in vitro. Autophagy and apoptosis of tumor cells induced by drugs are two of the major causes of tumor cell death. However, reports on the effect of autophagy induced by drugs in tumor cells are not consistent and suggest that autophagy can have synergistic or antagonistic effects with apoptosis. This research was aimed at investigating whether proanthocyanidins induced autophagy and apoptosis in human gastric cancer cell line MGC-803 cells and to identify the mechanism of proanthocyanidins action to further determine the effect of proanthocyanidins-induced autophagy on apoptosis. MTT assay was used to examine the proanthocyanidin cytotoxicity against human gastric cancer cell line MGC-803. Transmission electron microscopy and monodansylcadaverine (MDC) staining were used to detect autophagy. Annexin V APC/7-AAD double staining and Hoechst 33342/propidium iodide (PI) double staining were used to explore apoptosis. Western blotting was used to determine expression of proteins related to autophagy and apoptosis. Real-time quantitative PCR technology was used to determine the mRNA level of Beclin1 and BCL-2. The results showed that proanthocyanidins exhibit a significant inhibitory effect on the human gastric cancer cell line MGC-803 proliferation in vitro and simultaneously activate autophagy and apoptosis to promote cell death. Furthermore, when proanthocyanidin-induced autophagy is inhibited, apoptosis increases significantly, proanthocyanidins can be used together with autophagy inhibitors to enhance cytotoxicity.

A novel method was developed for grafting poly(acrylamide) (PAAM) on to the carbon fiber (CF) surface via reversible addition–fragmentation chain transfer (RAFT) polymerization to improve the interaction between carbon fibers and epoxy matrix in the composites system. The carbon fibers were first treated with nitric acid and γ-methacryloxypropyltrimethoxy silane (KH570). Then, the PAAM was grafting onto the carbon fiber surface via RAFT polymerization. The resulted carbon fibers functionalized with PAAM (CF-PAAM) were characterized by FTIR, XPS, and TGA, and the results revealed that CF-PAAM were synthesized successfully. The introduction of PAAM chains could make the fiber surface rougher and introduce a large numbers of –NH2 groups, which can improve the interfacial adhesion in the composites. The microbond test results showed that the interfacial shear strength (IFSS) of the composites reinforced by CF-PAAM has been enhanced about 107%. POLYM. COMPOS., 2015. © 2015 Society of Plastics Engineers

Multiwalled carbon nanotubes (MWNTs) functionalized with hyperbranched aliphatic polyamide (HAP) were prepared by polycondensation using 3-(2-aminoethylamino)propanoic acid methyl ester as monomer. The effects of HAP functionalized MWNTs (MWNT-HAP) on the properties of bismaleimide (BMI) resin were investigated. Nanocomposites based on BMI resin and different content of MWNTs were prepared. The properties of nanocomposites were characterized by TGA, DMA, flexural and impact tests. Because of the magnification of functional groups and the higher interfacial interaction between MWNT-HAP and BMI resin, the improvement of the mechanical and thermal properties of MWNT-HAP/BMI nanocomposites was more remarkable than nanocomposites containing pristine MWNTs.

Diosgenin, a plant steroid compound from Dioscorea nipponica, is an anti-inflammatory, antidiabetic, antitumor, vasodilatory compound, which also reduces blood lipid content and protects against ischemia‑induced neuronal damage. However, a limited number of studies have been performed on the antitumor effect of diosgenin on prostate cancer, the underlying mechanism of which remains to be fully elucidated. In the present study, the effect and underlying mechanism of diosgenin on DU145 human prostate cancer cells was investigated. DU145 cells were cultured in vitro with diosgenin, following which cell proliferation was detected by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and apoptosis was detected by flow cytometry. In addition, DU145 cells were observed under a transmission electron microscope to confirm autophagy. monodansylcadaverine staining and western blotting indicated the levels of autophagy in DU145 cells. To determine the mechanism underlying the effect of diosgenin on DU145 cells, western blotting was performed to evaluate the involvement of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. To investigate the association between apoptosis and autophagy, DU145 cells were cultured with diosgenin and 3‑methyladenine. Hoechst 33342/propidium iodide double staining was performed to detect apoptosis, and reverse transcription‑quantitative polymerase chain reaction was used to analyze mRNA expression levels of Beclin 1 and B‑cell lymphoma 2. Diosgenin inhibits the proliferation of DU145 cells by activating apoptosis and autophagy, and the mechanism underlying this activation may be associated with the inhibition of the PI3K/Akt/mTOR signaling pathway. In addition, the inhibition of autophagy mediated by diosgenin increases apoptosis and, thus, increases the therapeutic effect. The combination of diosgenin with an autophagy inhibitor may be an effective strategy to increase the antitumor effect of diosgenin.

In this work, polyacrylonitrile (PAN)-based carbon fibers (CF) were chemically modified with poly (glycidyl methacrylate) (PGMA) via atom transfer radical polymerization (ATRP) to improve the interaction between the CF and polymer matrix. The FT-IR, TGA, and XPS were used to determine the chemical structure of the resulting products and the quantities of PGMA chains grafted from the CF surface. The experimental results confirm that the CF surface was functionalized and glycidyl methacrylate was graft-polymerized onto the CF, and the grafting content of polymer could reach 10.2%.