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There is an unmet clinical need for effective anticoagulant therapies for the management of thromboembolic diseases that are not associated with a relevant risk of bleeding. Asundexian (BAY 2433334) is an oral, direct, small‐molecule inhibitor of activated factor XI (FXIa). Phase I data from healthy Caucasian male participants indicated predictable pharmacokinetic (PK) and pharmacodynamic (PD) profiles and no clinically relevant bleeding‐related adverse events (AEs). Reported here are data from two phase I, randomized, placebo‐controlled, single‐ and multiple‐dose escalation studies of asundexian conducted in 60 healthy men: 24 Japanese and 36 Chinese. Baseline characteristics were comparable between the treatment groups. All treatment‐emergent AEs were mild, with no serious AEs or AEs of special interest reported. Systemic exposure to asundexian increased dose proportionally after single or multiple dosing, with relatively low accumulation following multiple once‐daily dosing in both Chinese and Japanese volunteers. Asundexian induced dose‐dependent prolongation of activated partial thromboplastin time and inhibition of FXIa activity, with no effects on prothrombin time or FXI concentration in Japanese participants. There were no clinically relevant interethnic differences in PK profile across the Japanese, Chinese, and Caucasian (data from the previous phase I study) participants and no clinically relevant difference in PD response between Japanese and Caucasian participants. [ABSTRACT FROM AUTHOR]

In the past, rifampicin was well‐established as strong index CYP3A inducer in clinical drug–drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically‐based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs during drug development. CYP3A4 induction properties and the safety profile of carbamazepine were investigated in two open‐label, fixed sequence, crossover clinical pharmacology studies in healthy volunteers using midazolam as a sensitive index CYP3A4 substrate. Carbamazepine was up‐titrated from 100 mg twice daily (b.i.d.) to 200 mg b.i.d., and to a final dose of 300 mg b.i.d. for 10 consecutive days. Mean area under plasma concentration‐time curve from zero to infinity (AUC(0‐∞)) of midazolam consistently decreased by 71.8% (ratio: 0.282, 90% confidence interval (CI): 0.235–0.340) and 67.7% (ratio: 0.323, 90% CI: 0.256–0.407) in study 1 and study 2, respectively. The effect was adequately described by an internally developed PBPK model for carbamazepine which has been made freely available to the scientific community. Further, carbamazepine was safe and well‐tolerated in the investigated dosing regimen in healthy participants. The results demonstrated that the presented design is appropriate for the use of carbamazepine as alternative inducer to rifampicin in DDI studies acknowledging its CYP3A4 inductive potency and safety profile. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) that exert multiple functions are considered promising candidates to combat the bacterial drug resistance crisis. Nowadays, targeted peptide modification has been widely recognised to improve biological activity and make up for deficiencies in clinical applications such as toxicity. In this study, a helix-loop peptide was isolated and identified from the skin secretion of the Wuyi torrent frog Amolops wuyiensis, namely, ranatuerin-2-AW (R2AW) (GFMDTAKNVAKNVAATLLDKLKCKITGGC). Target modifications were made to R2AW to study the structure–activity relationships and to optimise its bioactivities. Five analogues were progressively designed via residue substitution and truncation and the antibacterial and anticancer activities were evaluated. We found that the serine-substitution and cyclic-domain-deletion products showed similar antibacterial activity to the natural peptide R2AW, implying that the disulphide bridge and Rana box were dispensable for the antibacterial activity of ranatuerin-2 peptides. Notably, the cationicity- and hydrophobicity-enhanced variant, [Lys4,19, Leu20]R2AW(1-22)-NH2, exhibited significantly optimised antibacterial and anticancer activities. Additionally, it killed bacteria by membrane disruption at a highly efficient rate. Moreover, [Lys4,19, Leu20]R2AW(1-22)-NH2 exerted potential in vivo efficacy in a methicillin-resistant Staphylococcus aureus (MRSA)-infected waxworm model. Overall, this study demonstrated some rational design ideas for optimising the dual antibacterial and anticancer activities of ranatuerin-2 peptides and it proposes [Lys4,19, Leu20]R2AW(1-22)-NH2 as an appealing candidate for therapeutic development. [ABSTRACT FROM AUTHOR]

Viral infections trigger a wide range of immune responses thought to drive tumorigenesis and malignant progression. Dissecting virus‐induced changes in the tumor immune microenvironment (TIME) is therefore crucial to identify key leukocyte populations that may represent novel targets for cancer therapy. Single‐cell sequencing approaches have now been widely applied to the analysis of various tumors, thus enabling multiomics characterization of the highly heterogeneous TIME that bulk‐sequencing cannot fully elucidate. In this review, we summarized key recent findings from sequencing studies of the immune infiltrate and antitumor response in virus‐associated cancers at single cell resolution. Additionally, we also reviewed recent developments in immunotherapy for virus‐associated cancers. We anticipate that the strategic use of single‐cell sequencing will advance our understanding of the TIME of viral cancers, leading to the development of more potent novel treatments. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is characterized as interlobular bile duct injury and fibrosis, which results from the loss of tolerance to self‐antigens. However, the exact pathologic mechanism leading to injury and fibrosis in PBC patients is not fully understood. Therefore, in this study, we examined the role of the T cell subsets in PBC patients and healthy controls (HCs). A higher number of invariant Natual killer T (iNKT) cells as well as CD3+CD56+ αGalcer‐CD1d tetramer– T cells were found in patients with PBC compared with HCs. Moreover, these 2 T subpopulations produced significantly higher levels of Interleukin (IL)‐17A in PBC patients than those in in HCs, which has also been positively correlated with the disease severity. Furthermore, the level of IL‐17A produced by these 2 subpopulations was increased after stimulation of the autoantibodies in patients with PBC. Also, the elevated IL‐17A levels promoted the PBC‐related fibrosis, thus presenting a change in frequencies and functions of these cell phenotypes in the deterioration of the duct damage‐related fibrosis. This study clarified PBC patients' distinct T subpopulations characteristics, providing evidence‐based diagnostic and therapies for these patients. The correlation between unclassical T subsets and IL‐17A may provide a novel target for the immunotherapy of PBC. [ABSTRACT FROM AUTHOR]