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Background: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. Objective: We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure–response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study. Methods: Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure–response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection. Results: In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from Cmax in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7–33 days) after Tmax and a 97% reduction from Cmax in teclistamab concentration at a median time of 69 days (32–163 days) after Tmax. Body weight, multiple myeloma type (immunoglobulin G vs non–immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure–response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles. Conclusion: Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure–response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure–response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM. Clinical Trial Registration: NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020). [ABSTRACT FROM AUTHOR]

Introduction: Patients with triple-class-exposed relapsed/refractory multiple myeloma (TCE-RRMM) have a poor prognosis and limited treatment options. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, was studied in patients with TCE-RRMM in the single-arm MajesTEC-1 study. To assess the relative effectiveness of teclistamab versus real-world physician's choice of therapy (RWPC), adjusted comparisons were performed using individual patient data from MajesTEC-1 and LocoMMotion, a prospective study of patients with TCE-RRMM. Methods: An external control arm for MajesTEC-1 was created from patients in LocoMMotion (n = 248; clinical cut-off: November 2, 2021) and compared with treated patients (n = 165) from MajesTEC-1 (teclistamab 1.5 mg/kg weekly; clinical cut-off: March 16, 2022). Inverse probability weighting was used to adjust for imbalances in baseline covariates. For binary endpoints [overall response rate (ORR), very good partial response or better (≥ VGPR) rate, complete response or better (≥ CR)], relative effect of teclistamab versus RWPC was estimated with an odds ratio and relative response rate and 95% confidence interval (CI), derived from weighted logistic regression. Weighted Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% CIs for time-to-event endpoints [duration of response (DOR), progression-free survival (PFS), and overall survival (OS)]. Results: After weighting, baseline characteristics were balanced across cohorts. In adjusted comparisons, teclistamab-treated patients were 2.3-fold, 5.2-fold and 148.3-fold, more likely to reach ORR [response-rate ratio (RR) = 2.31, 95% CI 1.77–2.85, p < 0.0001], ≥ VGPR (RR = 5.19, 95% CI 3.26–7.12, p < 0.0001) and ≥ CR (RR = 148.25, 95% CI 20.63–1065.40, p < 0.0001), respectively, versus patients receiving RWPC. Following adjustment, DOR (HR 0.32, 95% CI 0.19–0.54, p < 0.0001) and PFS (HR 0.48, 95% CI 0.35–0.65, p < 0.0001) were significantly longer with teclistamab versus RWPC. OS was numerically better with teclistamab versus RWPC [HR 0.77 (0.55–1.09), p = 0.1419]. Conclusion: Teclistamab demonstrated improved effectiveness versus RWPC, highlighting its clinical benefit as a novel and effective treatment for patients with TCE-RRMM. Trial Registration: Majest TEC-1, ClinicalTrials.gov NCT04557098; LocoMMotion, ClinicalTrials.gov NCT04035226. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy in women worldwide, and the discovery of new effective breast cancer therapies with lower toxicity is still needed. We screened a series of chalcone derivatives and found that MY11 ((E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-piperazinylphenyl) prop-2-en-1-one) had the strongest anti-breast cancer activity. MY11 inhibited the growth of MDA-MB-231 and MCF-7 breast cancer cells by arresting the cell cycle and promoting apoptosis, through regulation of the cell cycle and apoptosis-related proteins. PDTC (Pyrrolidinedithiocarbamate ammonium), a specific inhibitor of the NF-κB pathway, abolished the inhibitory effect of MY11 treatment. NF-κB has been shown to regulate PUMA-dependent apoptosis. Our in vitro studies demonstrated that MY11 promoted breast cancer cell apoptosis by activating the NF-κB/PUMA/mitochondrial apoptosis pathway (including Bcl-2, Bax, and Caspase-9). MY11 also inhibited tumor growth in an orthotopic breast cancer mouse model by inducing apoptosis through the NF-κB signaling pathway, importantly, with minimal toxicity. In addition, MY11 was found by docking analysis to bind to p65, which might enhance the stability of the p65 protein. Taken together, our findings indicate that MY11 exerts a significant anticancer effect in breast cancer and that it may be a potential candidate for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

E The severity of the patient's paresthesia at the first visit, the end of 31 electroacupuncture treatments, and the one-month follow-up period. After 3 days of EA treatment, the patient self-reported that the numbness was relatively relieved, which made him feel slightly gratified and prompted him to maintain a frequency of 3-5 clinic visits a week for EA treatment. Patients require adequate diagnosis and treatment in a timely manner, and EA may be a treatment worth trying for sensations of cold running water. [Extracted from the article]

Bortezomib-melphalan-prednisone (VMP) is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma (MM). Here, we compared outcomes between VMP regimens in the VISTA trial (9-cycle VMP schedule, including 4 cycles of twice weekly bortezomib) and the PETHEMA/GEM05 trial (less intensive 6-cycle VMP schedule with 1 cycle of twice weekly and 5 cycles of weekly bortezomib, then bortezomib-based maintenance). A total of 113 patient pairs matched by propensity score (estimated using logistic regression and incorporating eight exposure/outcome-related parameters) were included in this retrospective analysis. Median cumulative bortezomib dose was higher in PETHEMA/GEM05 than VISTA (49.6 vs 37.0 mg/m2); median dose intensity was lower (2.0 vs 5.1 mg/m2/month). Median progression-free survival (PFS) and time-to-progression (TTP) were significantly longer in PETHEMA/GEM05 than VISTA (PFS, 30.5 vs 20.0 months, p = 0.0265; TTP, 33.8 vs 24.2 months, p = 0.0049) after a median follow-up of 77.2 and 26.0 months, respectively. Median overall survival (OS) was similar (61.3 vs 61.0 months, p = 0.6528; median follow-up, 77.6 vs 60.1 months). Post-induction complete response rate was lower in PETHEMA/GEM05 than VISTA (19 vs 31 %; p = 0.03318); on-study (including maintenance) rate was similar (30 vs 31 %; p = 0.89437). This analysis suggests that the less-intensive PETHEMA/GEM05 VMP regimen plus maintenance may improve PFS and TTP, but not OS, compared with the VISTA VMP regimen.Trial Registrations: NCT00111319, NCT00443235. [ABSTRACT FROM AUTHOR]

The transport behavior of commercial R134a (1,1,1,2-tetrafuoroethane) refrigerant including its permeability, adsorption, and diffusion through rubber composites were investigated. Butadiene-acrylonitrile rubber (NBR), brominated butyl rubber (BIIR), and epichlorohydrin rubber (ECO) were used as a matrix, while silica, carbon black, mica sheet, and graphite were used as fillers in the present study. The effects of rubber structure and geometry, surface polarity, as well as loading of filler on transport behavior were studied to correlate transport parameters with the rubber structure and filler nature. The R134a permeation in rubber composites was largely dominated by diffusion rather than solubility. The polarities of rubber and filler played dominant roles in determining the solubility, whereas the structure of rubber and the shape and loading of filler exerted a stronger effect on diffusion than solubility. Nonpolar and layered graphite-filled BIIR rubber composites showed the lowest permeability to R134a. Additionally, shell-like free volume theory was applied to reasonably explain R134a transport behavior. [ABSTRACT FROM AUTHOR]

Poly(norbornene- co-styrene) copolymers were synthesized by copolymerizations of norbornene (NB) and styrene (St) with bis(β-ketoamino) copper complexes [ArNC(R)CHC(R)O]Cu (1, Ar = 2,6-dimethylphenyl, R = CH; 2, Ar = 2,6-diisopropylphenyl, R = CH; 3, Ar = 2,6-diisopropylphenyl, R = CF) in the presence of methylaluminoxane (MAO). The influences of catalyst structure, comonomer feeding ratio, n(Al)/n(Cu) molar ratio, and copolymerization temperature on catalytic activity and compositions of the copolymers were typically investigated. Determination of the reactivity ratios shows a much high reactivity for norbornene ( r(NB) = 19.52, r(St) = 0.48), which supports a coordination mechanism. The structural characterizations of the obtained poly(NB- co-St) copolymers show that styrene units are successfully incorporated into norbornene sequences, and isolated styrene or very short styrene sequences are randomly distributed on the copolymer chain. A high incorporation of styrene up to 35.6 mol% in the poly(NB- co-St) copolymer can be achieved by bis(β-ketoamino) copper catalyst 1. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The objective of this study was to prepare solid dispersions consisting of baicalein and a carrier with a low glass transition/melting point (Pluronic F68) by spray freeze drying (SFD). We compared these powders to those produced from the conventional solvent evaporation method. In the SFD process, a feeding solution was atomized above the surface of liquid nitrogen following lyophilization, which resulted in instantaneously frozen microparticles. However, solid dispersions prepared by the solvent evaporation method formed a sticky layer on the glass flask with crystalline baicalein separated out from the carrier. The powder samples were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), surface area measurement, differential scanning calorimetry, and Fourier transform infrared spectrometry. SEM and PXRD results suggested that the majority of baicalein in the SFD-processed solid dispersion was in the amorphous state, which has a higher specific surface area than pure baicalein. However, the majority of baicalein was recrystallized in the solid dispersion at the same composition prepared by the solvent evaporation method, which showed a similar dissolution rate to the physical mixture. SFD product was physically and chemically stable after being stored at 40°C with low humidity for 6 months. After enzyme hydrolysis, baicalein in the SFD product displayed a significantly shorter T and higher C than pure baicalein after oral dosing. The relative bioavailability of the SFD product versus pure baicalein determined by comparing the AUC was 233%, which demonstrated the significantly improved oral bioavailability of baicalein produced by the SFD technique. [ABSTRACT FROM AUTHOR]