BeiGene (China)

Peptidic macrocycles have attracted increasing attention due to their well-defined structures and enhanced biological activities. However, efficient cyclization of residues lacking reactive side chains remains a significant challenge. Herein, we report a glycinamide-driven coumarin construction (GDCC) reaction that enables the in situ formation of coumarin scaffolds via condensation between C-terminal glycine residues and salicylaldehyde analogs under mild, metal- and catalyst-free conditions. While various salicylaldehyde derivatives afford efficient fluorescent labeling, symmetrical salicylaldehyde-based linkers uniquely promote intramolecular bis-glycine cyclization, generating intrinsically fluorescent peptide macrocycles with tunable topology and hydrophobicity. Notably, the optimal peptide 64 exhibits photophysical properties comparable or even superior to those of the coumarin gold standard, 7-(diethylamino)-4-methylcoumarin. The GDCC reaction displays broad substrate scope and excellent compatibility with both solid-phase and solution-phase peptide synthesis. Its potential in chemical biology is demonstrated by the streamlined construction of diverse fluorescent cyclic peptides, including RGD-based probes for live-cell imaging, peptide-drug conjugates for targeted doxorubicin delivery, and a panel of PD-1/PD-L1 interaction inhibitors with tunable activity.

Hybridogenesis is a rare reproductive mode found in interspecific hybrids that involves discarding one parental genome during gametogenesis and clonally transmitting the other, with the former renewed by backcrossing. It may in theory mediate species range expansion, since such hybrids can also cross and have pure-species offspring for establishing new populations and are often widespread probably due to hybrid vigor. Being inspired by a magnitude difference between estimates of individual heterozygosity, we collected genome-wide data and evaluated predictions from hybridogenesis of hybrids between the wideranging Asian spiny frog Quasipaa boulengeri and a narrow endemic, Q. robertingeri. We rejected other atypical modes of reproduction such as parthenogenesis or androgenesis and provided the first evidence consistent with a hypothesis that hybridogenesis mediated the occurrence of individuals far from the species range (~500 km). Despite contributing to early evidence of the only distinct hybridogenetic complex inferred in ten years, individual heterozygosity has likely been an often overlooked variable. The accumulating genome-wide data may serve as a resource for searching for individual heterozygosity clues of atypical reproduction of interspecific hybrid origin. The findings in spiny frogs make a case that genome-wide data provide crucial evidence for updating our knowledge on reproductive-mode evolution of taxa.

BackgroundIntestinal fibrosis-associated stricture is a frequent complication of inflammatory bowel disease (IBD), often necessitating endoscopic or surgical interventions. This study aims to investigate the pathogenesis of fibrosis in Crohn's disease (CD), a type of IBD, by analyzing single-cell RNA sequencing (scRNA-Seq) data from colon biopsies of both CD and ulcerative colitis (UC) patients.ResultsThe analysis revealed significant cellular heterogeneity, altered cell–cell interactions, and key molecular pathways in both CD and UC. CD showed a marked increase in IgA plasma cells. Ligand–receptor analysis indicated that IgA plasma cells strongly interacted with inflammation-associated fibroblasts (IAFs) in CD, predominantly through the PECAM1–CD38 axis, whereas these interactions were less pronounced in UC. Our study indicated that IL-1β was upregulated in Th17 cells in CD. MAPK signaling pathway were upregulated in Th17 cells.ConclusionsThese findings may provide new insights into the mechanisms underlying early intestinal fibrosis in CD by identifying critical cell types and molecular players. Nonetheless, these observations are exploratory and will require validation in future experiments.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12876-025-04312-0.

Background and Purpose: Sonrotoclax (BGB-11417), a second-generation B-cell lymphoma-2 (BCL-2) inhibitor currently in clinical development, requires comprehensive verification of its biotransformation and disposition profiles in safety species. Experi

Objective RATIONALE-305 (NCT03777657) demonstrated that tislelizumab plus chemotherapy statistically improved overall survival versus placebo plus chemotherapy as first-line treatment in patients with advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC). This analysis examined patient-reported outcomes (PROs) at final analysis. Methods Adults with previously untreated, unresectable, or metastatic GC/GEJC were randomized (1:1) to tislelizumab or placebo intravenously once every 3 weeks plus chemotherapy. PROs assessed health-related quality of life (HRQoL) using EORTC QLQ-C30 and EORTC QLQ-STO22. A mixed model for repeated measures was used for PRO endpoints at treatment cycles 4 and 6, and time to deterioration was analyzed. Results Tislelizumab arm had improved outcomes over placebo arm in least-squares (LS) mean change from baseline to cycle 6 for QLQ-C30 global health status/quality of life (GHS/QoL) (LS mean difference, 2.52 [95% CI: 0.29–4.74]), physical functioning (2.46 [0.49–4.43]), fatigue (–3.01 [–5.78 to −0.24]), and STO22 index score (–1.62 [–3.12 to −0.12]) as well as maintenance of upper gastrointestinal symptoms (–1.74 [–3.55–0.06]) and pain/discomfort (–1.88 [–4.03–0.27]). Patients receiving tislelizumab plus chemotherapy had a lower risk for deterioration of GHS/QoL (hazard ratio 0.77 [95% CI: 0.60–0.98]), physical functioning (0.72 [0.57–0.92]), STO22 index score (0.64 [0.45–0.92]), pain/discomfort (0.74 [0.58–0.96]), and upper gastrointestinal symptoms (0.73 [0.56–0.95]). Conclusions Advanced GC/GEJC patients treated with tislelizumab plus chemotherapy versus placebo plus chemotherapy in first-line had sustained and improved HRQoL. These results, along with previous efficacy and safety data, support tislelizumab plus chemotherapy as a first-line treatment option for GC/GEJC. Trial registration The RATIONALE-305 trial is registered on ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT03777657).ClinicalTrials.gov identifier: NCT03777657.

Tislelizumab, an anti-programmed cell death protein-1 monoclonal antibody, has demonstrated improved survival over the standard of care for multiple cancers. However, tislelizumab's effectiveness across different racial/ethnicity groups warrants further evaluation. This clinical pharmacology overview includes tislelizumab's pharmacokinetic properties, correlations with efficacy and safety, and immunogenicity, with a focus on racial impact. Non-compartmental pharmacokinetic analysis was conducted using data from Asian and White patients enrolled in BGB-A317-001 and BGB-A317-102. Population pharmacokinetic analyses used pooled data from 12 clinical studies to evaluate the impact of intrinsic/extrinsic factors on tislelizumab's pharmacokinetic properties, including race effect. Exposure-efficacy/exposure-safety relationships and immunogenicity assessments were evaluated for the phase III BGB-A317-302/-303 studies. Tislelizumab exhibited dose-proportional pharmacokinetics, and there were no clinically meaningful differences in tislelizumab's pharmacokinetic parameters at 200 mg once every 3 weeks between BGB-A317-001 (n = 12, 83% White patients) and BGB-A317-102 (n = 20, 100% Chinese patients); race was not a significant covariate. No clinically relevant exposure-efficacy/-safety relationships were observed in BGB-A317-302/-303. Incidence of anti-drug antibodies (ADAs) was similar between Asian and White patients. The presence of ADAs was not clinically relevant for tislelizumab's pharmacokinetic properties, efficacy, or safety. There were no differences in tislelizumab's pharmacokinetic or ADA characteristics between Asian and White patients with advanced cancer and no clinically relevant exposure-efficacy/-safety dependency or impact of immunogenicity on efficacy and safety. Data from the extensive clinical program of tislelizumab support the use of tislelizumab across broad patient populations with relevant tumor types.

Stereotactic body radiotherapy (SBRT) and immune checkpoint inhibitors (ICIs) could obtain a certain synergistic effect on bone and soft tissue sarcoma (BSTS). Given its low radiosensitivity, BSTS usually require an irradiation dose >65 Gy to achieve local control. Herein, we developed a non-classical SBRT technique called "onion-shaped simultaneous boost (OSB)," and reported a patient with prostatic leiomyosarcoma which received non-classical SBRT and other systemic treatments. In the case, a 49-year-old male patient was diagnosed with prostatic leiomyosarcoma in November 2018. In the radiotherapy plans, the maximum doses of the targets were more than 65 Gy, while the doses of the organs at risk (OARs) were strictly limited. After receiving radiotherapy, ICI, and other multidisciplinary modalities, the patient achieved partial response (PR). In this clinical case, we have observed that the OSB technique, which employs an increased per-fraction radiotherapy dose without the need to match the single-fraction doses typical of conventional SBRT, effectively enhances the therapeutic impact on leiomyosarcoma without an increase in radiotherapy-related side effects. By integrating the OSB technique with a multidisciplinary array of antineoplastic strategies, we can more effectively manage sarcomas in clinical practice.