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Background: Acute graft-versus-host disease (aGvHD) is a major cause of death for patientsfollowing allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification. Methods: In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time-dependent risk factors on the development of grades II–IV aGvHD within 100days post-HSCT. Results: Using a dynamic longitudinal time-to-event model, we observed a nonmonotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11days. Multivariable analysis revealed significant time-dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades II–IV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo-HSCT are associated with an increased incidence of grades II–IV aGvHD within 100days indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for ater grades II–IV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios. Conclusion: Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time-dependent risk factors for the prediction of aGvHD. [ABSTRACT FROM AUTHOR]

The immunoreceptor-associated protein CD3ξ is known for its role in immunity and has also been implicated in neuronal development and synaptic plasticity. However, the mechanism by which CD3ξ regulates synaptic transmission remains unclear. In this study, we showed that mice lacking CD3ξ exhibited defects in spatial learning and memory as examined by the Barnes maze and object location memory tasks. Given that peripheral T cells have been shown to support cognitive functions and neural plasticity, we generated CD3ξ-/- mice in which the peripheral T cells were repopulated to a normal level by syngeneic bone marrow transplantation. Using this approach, we showed that T-cell replenishment in CD3ξ-/- mice did not restore spatial memory defects, suggesting that the cognitive deficits in CD3ξ-/- mice were most likely mediated through a T-cell-independent mechanism. In support of this idea, we showed that CD3ξ proteins were localized to glutamatergic postsynaptic sites, where they interacted with the NMDAR subunit GluN2A. Loss of CD3ξ in brain decreased GluN2A-PSD95 association and GluN2A synaptic localization. This effect was accompanied by a reduced interaction of GluN2A with the key NMDAR downstream signaling protein calcium/calmodulin-dependent protein kinase II (CaMKII). Using the glycine-induced, NMDA-dependent form of chemical long-term potentiation (LTP) in cultured cortical neurons, we showed that CD3ξ was required for activity-dependent CaMKII autophosphorylation and for the synaptic recruitment of the AMPAR subunit GluA1. Together, these results support the model that the procognitive function ofCD3ξ maybe mediated through its involvement in theNMDAR downstream signaling pathway leading to CaMKII-dependent LTP induction. [ABSTRACT FROM AUTHOR]

Platelet reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT) is heterogeneous and influenced by various patient- and transplantation-related factors, associated with poor prognoses for poor graft function (PGF) and isolated thrombocytopenia. Tailored interventions could improve the outcome of patients with PGF and post-HCT thrombocytopenia. To provide individual predictions of 180-day platelet counts from early phase data, we developed a model of long-term platelet reconstitution after allo-HCT. A large cohort (n = 1949) of adult patients undergoing their first allo-HCT was included. Real-world data from 1,048 retrospective patients were used for non-linear mixed-effects model development. Bayesian forecasting was used to predict platelet-time profiles for 518 retrospective and 383 prospective patients during internal and external model validation, respectively. Thrombocytopenia was defined as mean platelet count < 75 × 10 9 /L, derived from the last 12 platelet measurements within the first 180 days post-HCT. Thrombocytopenia affected 37% of all patients and was associated with significantly reduced overall survival (P-value < 0.0001). On days +7, +14, +21, and +28, the developed model achieved areas under the receiver-operating characteristic of ≥ 0.68, ≥ 0.75, ≥ 0.78, and 0.81 for the prediction of post-HCT thrombocytopenia, respectively, with anti-thymocyte globulin, donor relation, and total protein measurements representing prognostic markers for post-HCT platelet kinetics. A publicly accessible web-based demonstrator of the model was established (https://hsct.precisiondosing.de). In summary, the developed model predicts individual platelet counts from day +28 post-HCT adequately, utilizing internal and external datasets. The web-based demonstrator provides a basis to implement model-based predictions in clinical practice and to confirm these findings in future clinical studies., (© 2025 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)