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A humanized anti-MSLN×4-1BB bispecific antibody exhibits potent antitumour activity through 4-1BB signaling activation and fc function without systemic toxicity.
J Transl Med
January 2025
Department of Medical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Hefei, 230031, Anhui, China.
Background: Agonistic monoclonal antibodies targeting 4-1BB/CD137 have shown preclinical promise, but their clinical development has been limited by severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy.
Methods: A novel anti-MSLN×4-1BB bispecific antibody (bsAb) was generated via antibody engineering, and its affinity and activity were detected via enzyme-linked immunosorbent assay (ELISA), flow cytometry, and T-cell activation and luciferase reporter assays.
E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
EMBO J
January 2025
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.
The carboxyl terminus of Hsc70-interacting protein (CHIP) is pivotal for managing misfolded and aggregated proteins via chaperone networks and degradation pathways. In a preclinical rodent model of CHIP-related ataxia, we observed that CHIP mutations lead to increased levels of phosphodiesterase 9A (PDE9A), whose role in this context remains poorly understood. Here, we investigated the molecular mechanisms underlying the role of PDE9A in CHIP-related ataxia and demonstrated that CHIP binds to PDE9A, facilitating its polyubiquitination and autophagic degradation.
View Article and Find Full Text PDFSeverity of Impaired Oxygenation and Conservative Oxygenation Targets in Mechanically Ventilated Children: A Post Hoc Subgroup Analysis of the Oxy-PICU Trial of Conservative Oxygenation.
Pediatr Crit Care Med
January 2025
Paediatric Intensive Care Unit, Great Ormond Street Hospital for Children NHS Foundation Trust and NIHR Biomedical Research Centre, London, United Kingdom.
Objectives: A conservative oxygenation strategy is recommended in adult and pediatric guidelines for the management of acute respiratory distress syndrome to reduce iatrogenic lung damage. In the recently reported Oxy-PICU trial, targeting peripheral oxygen saturations (Spo2) between 88% and 92% was associated with a shorter duration of organ support and greater survival, compared with Spo2 greater than 94%, in mechanically ventilated children following unplanned admission to PICU. We investigated whether this benefit was greater in those who had severely impaired oxygenation at randomization.
View Article and Find Full Text PDFUnlabelled: SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSMs). These PTPs bind overlapping sets of ITIM/ITSM-bearing proteins, suggesting that they might have some redundant functions. By studying T cell-specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain naïve T cell differentiation to effector and central memory phenotypes, with SHP1 playing the dominant role.
View Article and Find Full Text PDFcan persist asymptomatically within tissues for extended periods. This remarkable feat is achieved through intricate host-pathogen interactions in immune cell aggregates called granulomas, wherein find favorable cellular niches to exploit while the host limits its expansion and tissue dissemination. Here, using a mouse model of persistent infection, we identify a host-protective role of eosinophils in control of Typhimurium ( Tm) infection within the mesenteric lymph nodes (MLN), the main lymphoid tissue of Tm persistence.
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