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The pyrogallol autoxidation method has been widely utilized to evaluate various antioxidants in antioxidative bioactivities. However, this method is generally not appropriate for estimating the.O2− radical scavenging capacity of bioflavonoids, as it enables bioflavonoids to generate.O2− radical in oxygen‐alkaline (pH 8.2) surroundings. In the present study, an improved DMSO (dimethyl sulfoxide) system (pH 7.25, versus pH 8.2 of the pyrogallol autoxidation) was successfully developed to evaluate the.O2− radical scavenging capacity of bioflavonoids by EPR technique and using the spin trapping reagent DMPO (5,5‐dimethyl‐1‐pyrroline‐N‐oxide). The non‐protonic environment supplied by the system promotes the stabilization of the.O2−radical and therefore ensures a much more accurate measurement of.O2−radical scavenging capacity in bioflavonoids if compared to protonic solvents. The results demonstrated that the effects of scavenging.O2−radicals in natural bioflavonoids follows the order: dihydromyricetin>myricetin>quercetin>kaempferol>baicalein>chrysin, which are well associated with numbers of hydroxyl groups attached to their molecular skeletons and/or active H of their configurations. Interestingly, the higher superoxide‐anion scavenging effect measured for dihydromyricetin with respect to myricetin is possibly attributed to the fact that dihydromyricetin can be transformed into myricetin in the presence of.O2− radical, resulting from the homolysis of active H donated from C3−H bond of DMY via.O2− radicals. [ABSTRACT FROM AUTHOR]

Bispecific antibodies (BsAbs) are a sort of dual functional proteins with specific binding to two distinct targets, which have become a focus of interest in antibody engineering and drug development research and have a promising future for wide applications in cancer immunotherapy and autoimmune disease. The key of clinical application and commercial-scale manufacturing of BsAbs is the amenability to assembly and purification of desired heterodimers. Advances in genetic engineering technology had resulted in the development of diverse BsAbs. Multiple recombinant strategies have been used to solve the mispairing problem between light and heavy chains, as well as to enforce accurate dimerization of heterologous heavy chains. There are 23 platforms available to generate 62 BsAbs which can be further divided into IgG-like ones and fragment-based ones, and more than 50 molecules are undergoing clinical trials currently. BsAbs with IgG-like architecture exhibit superior advantages in structure (similar to natural antibodies), pharmacokinetics, half-life, FcR-mediated function, and biological activity. This review considers various IgG-like BsAb generation approaches, summarizes the clinical applications of promising new BsAbs, and describes the mechanism of BsAbs in tumor therapy. [ABSTRACT FROM AUTHOR]

The three-component Mannich reaction of among dimethyl malonate, aromatic primary amine, and aromatic aldehyde was made successfully in the presence of solid acidic catalyst SO42−/TiO2, with excellent catalytic activity, as compared to SO42−/γ-Al2O3 and SO42−/ZnO. To the best of our knowledge, SO42−/TiO2 prepared at varied calcination temperatures can perform different intensities of Lewis and Brønsted acidities. Because of this point, under the optimum conditions, the effect of SO42−/TiO2 (prepared at 200°C) was much more than that of SO42−/TiO2 (prepared at 300°C or 400°C) in the three-component Mannich reaction. In observing ionization activation mode of the three-component Mannich reaction, it disclosed that the plausible mechanism possibly undergoes formation of aldimines and transformation of aldimines into β-amino esters by applying solid acidic catalyst SO42−/MxOy. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence has revealed that the gut microbiota influences the effectiveness of immune checkpoint inhibitors (ICIs) in cancer patients. As a part of the human microbiome, Helicobacter pylori (H. pylori) was reported to be associated with reduced effectiveness of anti-PD1 immunotherapy in patients with non-small-cell lung cancer (NSCLC). Gastric cancer is more closely related to H. pylori, so we conducted a retrospective analysis to verify whether the association of H. pylori and effectiveness is applicable to advanced gastric cancer (AGC) patients. Material and methods: AGC patients who had evidence of H. pylori and received anti-PD-1 antibodies were enrolled in the study. The differences in the disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) between the H. pylori-positive group and the negative group were compared. Results: A total of 77 patients were included in this study; 34 patients were H. pylori positive, and the prevalence of H. pylori infection was 44.2%. Compared with the H. pylori-negative group, patients in the H. pylori-positive group had a higher risk of nonclinical response to anti-PD-1 antibody, with an OR of 2.91 (95% CI: 1.13–7.50). Patients in the H. pylori-negative group had a longer OS and PFS than those in the positive group, with an estimated median OS of 17.5 months vs. 6.2 months (HR = 2.85, 95% CI: 1.70–4.78; P = 0.021) and a median PFS of 8.4 months vs. 2.7 months (HR = 3.11, 95% CI: 1.96–5.07, P = 0.008). Multivariate analysis indicated that H. pylori infection was independently associated with PFS (HR = 1.90, 95% CI: 1.10–3.30; P = 0.022). Conclusion: Our study unveils for the first time that H. pylori infection is associated with the outcome of immunotherapy for AGC patients. Multicenter, large sample and prospective clinical studies are needed to verify the association. [ABSTRACT FROM AUTHOR]

Abstract: In recent years, glass fiber reinforcing polymers (GFRP) has emerged as an alternative to conventional steel reinforcing bars in concrete structures. The bond behavior of GFRP bars to concrete under acidic environment is important because of increasing acid rain in China nowadays. This paper presents an experimental investigation into comparison of the durability of the bond between GFRP and steel bars to concrete under acid environment. The specimens were subject to corrosion by immersion in acid solutions with different concentration. One hundred and twenty pullout specimens were used to study the effect of different environment on bond strength of GFRP and steel bars to concrete. Experimental results showed that, For GFRP bars, at the end of 75 days of conditioning duration, maximum bond strength loss of 11%, 22%, 17.2% and 14% were observed in tap water, pH=2, pH=3, and pH=4 environment, respectively. For steel bars, at the end of 75 days of conditioning duration, maximum bond strength loss of 19.6% and 12.3% were observed in pH=2 and pH=3 environment, respectively. The influence of solution concentration on bond strength of GFRP bars was determined using Arrhenius equation and time shift method (TSF). [Copyright &y& Elsevier]

Background: Rationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited. Method: Efficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: This retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0–42.0%), with a DCR of 85.0% (95% CI, 73.4–96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events. Conclusion: PARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) represent a major breakthrough for cancer treatment. However, evidence regarding the use of ICIs in pancreatic cancer (PC) remained scarce. To assess the efficacy and safety of ICIs plus chemotherapy, patients with advanced PC were retrospectively recruited and were treated with either chemotherapy alone or chemotherapy plus ICIs. Patients previously treated with any agents targeting T-cell co-stimulation or checkpoint pathways were excluded. The primary outcome was overall survival (OS). The secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). The combination group showed a significantly longer OS than the chemotherapy group [median, 18.1 vs 6.1 months, hazard ratio (HR) 0.46 (0.23–0.90), P = 0.021]. The median PFSs were 3.2 months in the combination group and 2.0 months in the chemotherapy group [HR 0.57 (0.32–0.99), P = 0.041]. The combination group and the chemotherapy group had similar ORRs (18.2% vs 19.4%, P = 0.906). All patients who achieved a partial response received a doublet chemotherapy regimen regardless of co-treatment with ICIs. Grade 3 or higher adverse events occurred in 31.8% of the patients in the combination group and in 16.9% of those receiving chemotherapy. Although the incidence of serious treatment-related adverse events was higher in the combination group than in the chemotherapy group, the difference was not significant (P = 0.183). Our findings suggest that the combination of ICIs with chemotherapy is both effective and tolerable for advanced PC. ICIs combined with a doublet chemotherapy regimen might be a preferable choice. [ABSTRACT FROM AUTHOR]

Background: Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. Methods: Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. Results: The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17–0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42–0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31–1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45–0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). Conclusions: Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC. [ABSTRACT FROM AUTHOR]

Two novel chiral Br?nsted acids 3b and 3c were prepared without involving the complexity of Suzuki coupling. Catalyst 3c bearing two additional hydroxyl groups at 3 and 3′ positions of axially chiral 1,1-binaphthalene-2,2′-diol phosphoric acid was applied in a model Mannich reaction to afford β-amino ester in high yield (92%) and enantiomeric excess (91%) at low reacting temperature of −40°C. In addition, those β-amino ester derivatives with high yields and excellent enatioselectivities were obtained in the presence of catalyst 3c under the above condition. [ABSTRACT FROM AUTHOR]

β-Amino esters (III) are synthesized with high yields and excellent enantioselectivities via Mannich reaction using an axially chiral (R)-1,1-binaphthalene-2,2′-diol phosphoric acid catalyst. [ABSTRACT FROM AUTHOR]