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Central nervous system involvement in chronic graft-versus-host disease (CNS-cGVHD) is rare. This case report describes a young man who developed anti-glutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy after undergoing matched sibling donor hematopoietic stem cell transplantation. The therapeutic approach included intensive immunotherapy with methylprednisolone, immunoadsorption, Rituximab, and low-dose Daratumumab, in combination with four antiepileptic drugs and mycophenolate mofetil. This regimen led to a marked reduction in anti-GAD65 titers and an improvement in the NHS3 seizure severity score, decreasing from 8 to 3. Additionally, a review of the literature on post-transplant autoimmune encephalitis is also provided.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). However, most patients experience relapse after allo-HSCT, with a poor prognosis, and treatment options are limited. The lack of an ideal targetable antigen is a major obstacle for treating patients with relapsed AML. CD38 is known to be expressed on most AML and myeloma cells, and its lack of expression on hematopoietic stem cells (HSCs) renders it a potential therapeutic target for relapsed AML. To investigate the clinical therapeutic efficacy and safety of CD38-targeted chimeric antigen receptor T (CAR-T-38) cells, we enrolled 6 AML patients who experienced relapse post-allo-HSCT (clinicaltrials.gov: NCT04351022). Prior to CAR-T-38 treatment, the blasts in the bone marrow of these patients exhibited a median of 95% (92–99%) CD38 positivity. Four weeks after the initial infusion of CAR-T-38 cells, four of six (66.7%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi); the median CR or CRi time was 191 (range 117–261) days. The cumulative relapse rate at 6 months was 50%. The median overall survival (OS) and leukemia-free survival (LFS) times were 7.9 and 6.4 months, respectively. One case relapsed 117 days after the first CAR-T-38 cell infusion, with remission achieved after the second CAR-T-38 cell infusion. All six patients experienced clinically manageable side effects. In addition, multiparameter flow cytometry (FCM) revealed that CAR-T-38 cells eliminated CD38 positive blasts without off-target effects on monocytes and lymphocytes. Although this prospective study has a limited number of cases and a relatively short follow-up time, our preliminary data highlight the clinical utility and safety of CAR-T-38 cell therapy in treating relapsed AML post-allo-HSCT.

Background Patients with refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) harboring TP53 alterations have a dismal prognosis due to profound chemoresistance. While CD19 chimeric antigen receptor T-cell (CAR-T) therapy has shifted the treatment landscape, long-term efficacy in this high-risk subset remains limited. The dual-target CD19/22 CAR-T has been developed to enhance anti-tumor activity; however, its comparative efficacy and long-term survival relative to CD19 CAR-T in this high-risk population remain unclear and require further elucidation to inform clinical decision-making. Methods This study included 55 patients with TP53 -altered R/R B-ALL who were enrolled in clinical trials (NCT03919240, NCT03275493, and NCT03614858) and treated with either CD19 ( n  = 27) or CD19/22 ( n  = 28) CAR-T therapy. The outcomes assessed included the complete remission (CR) rate, minimal residual disease (MRD)-negative CR rate, overall survival (OS), leukemia-free survival (LFS), and cumulative incidence of relapse (CIR). Multivariable Cox regression models were used to estimate hazard ratios (HRs) for OS and LFS. Results The CR rate was high in both groups (CD19/22: 100%; CD19: 88.89%). Notably, the MRD-negative CR rate was higher with CD19/22 CAR-T therapy (75.00% vs. 29.63%, p  = 0.0011), and was confirmed as an independent favorable prognostic factor. The CD19/22 CAR-T also demonstrated markedly better long-term survival, with 3-year OS (59.55% vs. 25.49%, p  = 0.0050) and LFS (57.29% vs. 17.64%, p  = 0.0047) rates. Among the 32 patients who underwent consolidative allo-HSCT after CAR-T, the CD19/22 CAR-T group achieved superior 3-year survival (OS: 72.34% vs. 30.77%, p  = 0.0089; LFS: 76.69% vs. 23.07%, p  = 0.0041) and lower CIR (23.30% vs. 75.00%, p  = 0.0182). Multivariable analysis established CD19/22 CAR-T therapy and bridging to allo-HSCT as independent predictors of improved LFS. Conclusion CD19/22 CAR-T immunotherapy, particularly when followed by allo-HSCT, represents a promising and clinically effective treatment paradigm for R/R B-ALL with TP53 alterations. Trial registration A single-center retrospective clinical study.

The acylhydrazone unit is well represented in screening databases used to find ligands for biological targets, and numerous bioactive acylhydrazones have been reported. However, potential E/Z isomerization of the C=N bond in these compounds is rarely examined when bioactivity is assayed. Here we analysed two ortho-hydroxylated acylhydrazones discovered in a virtual drug screen for modulators of N-methyl-d-aspartate receptors and other bioactive hydroxylated acylhydrazones with structurally defined targets reported in the Protein Data Bank. We found that ionized forms of these compounds, which are populated under laboratory conditions, photoisomerize readily and the isomeric forms have markedly different bioactivity. Furthermore, we show that glutathione, a tripeptide involved with cellular redox balance, catalyses dynamic E⇄Z isomerization of acylhydrazones. The ratio of E to Z isomers in cells is determined by the relative stabilities of the isomers regardless of which isomer was applied. We conclude that E/Z isomerization may be a common feature of the bioactivity observed with acylhydrazones and should be routinely analysed.Acylhydrazones are often found in compounds across screening databases, and numerous bioactive acylhydrazones exist. This functional group can isomerize between E and Z in response to light or upon exposure to thiols. Now, E/Z isomerization is found to impact activities of bioactive acylhydrazones and should be routinely analysed.

Metformin, a widely used anti-diabetic agent, has shown significant anti-cancer properties as reported in in various cancers, including acute myeloid leukemia. However, the detailed mechanisms by which metformin influences acute myeloid leukemia remain unrevealed. Employing a synergistic approach of network pharmacology and experimental validation, this study systematically identifies and analyzes potential metformin targets and AML-related genes. These findings are then cross-referenced with biomedical databases to construct a target-gene network, providing insights into metformin's pharmacodynamics in AML treatment. Protein–Protein Interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses are utilized. Results show metformin's effectiveness in inhibiting AML cell proliferation and inducing apoptosis through the AKT/HIF1A/PDK1 signaling pathway. This research provides insights into metformin's clinical application in AML treatment.

The tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by CAR-T cells, but its correlation with therapeutic efficacy has not been systematically studied. This study focused on the effects of the TB level on both the safety and efficacy of ssCART-19 as a treatment for r/r B-ALL. Taking the 5% tumor burden as the boundary, the study participants were divided into 2 groups, high and low tumor burden groups. Under this grouping strategy, the impacts of differential r/r B-ALL TBs on the clinical therapeutic efficacy (CR rate and long-term survival) and safety profiles after ssCART-19 cell treatment were analysed. 78 patients were reported in this study. The differential B-ALL TBs significantly affected the complete remission (CR) rates of patients treated with ssCART-19, with rates of 93.94% and 75.56% in the low and high TB groups, respectively ( P  = 0.0358). The effects of TBs on long-term therapeutic efficacy were further studied based on event-free survival (EFS) and overall survival (OS) profiles; both the OS and EFS of the low TB group were better than those of the high TB group, but the differences were not statistically significant. Importantly, the time points of TB measurement did not significantly affect the OS and EFS profiles regardless of whether the TBs were measured before or after fludarabine-cyclophosphamide (FC) preconditional chemotherapy. On the other hand, the severity of CRS was significantly correlated with the TB level ( P  = 0.0080), and the incidence of sCRS was significantly related to the TB level (the sCRS incidence increased as the TB level increased, P  = 0.0224). Unexpectedly, the ssCART-19 cell expansion peaks were not significantly different ( P  = 0.2951) between the study groups. Patients with a low r/r B-ALL TB yield more net benefits from CAR-T treatment than those with a high TB in terms of safety and CR rate. These findings are critical and valuable for determining the optimal CAR-T cell treatment window for r/r B-ALL patients and will further the development of comprehensive and reasonable CAR-T cell treatment plans for r/r B-ALL patients with differential TBs. Trial registration: ClinicalTrials.gov identifier, NCT03919240.

Letermovir (LTV) prophylaxis is effective in reducing the incidence of clinically significant cytomegalovirus (CMV) infection (cs CMVi) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Since our centre began administering LTV prophylaxis in June 2022, we have observed a certain increase in the incidence of Epstein–Barr virus (EBV) reactivation after haploidentical HSCT. We retrospectively analysed 230 consecutive patients who underwent haploidentical HSCT with rabbit anti-thymocyte globulin (ATG) from October 2022 to June 2023. The LTV group included 133 patients who received LTV prophylaxis, and the control group included 97 patients who did not receive LTV prophylaxis. At 1 year after HSCT, EBV reactivation was observed in 36 patients (27%) in the LTV group and 13 patients (13%) in the control group ( p  = 0.012). All patients with EBV reactivation had EBV-DNAemia, and one patient in each group developed EBV-associated posttransplantation lymphoproliferative disorder (PTLD). The proportion of patients with low EBV-DNA loads (> 5 × 10 2 to < 1 × 10 4 copies/mL) was greater in the LTV group than in the control group (23% vs. 10%, p  = 0.01). The proportion of patients with CMV reactivation was lower in the LTV group than in the control group (35% vs. 56%, p  = 0.002). There was no significant difference between the groups in terms of neutrophil and platelet count recovery, the cumulative incidence of acute/chronic graft-versus-host disease, overall survival, cumulative relapse rate or nonrelapse mortality. Our results show that the increased incidence of EBV reactivation may be associated with LTV prophylaxis for CMV after haploidentical HSCT.

Background/Objectives: Phosphodiesterase 7 (PDE7), a member of the PDE superfamily, selectively catalyzes the hydrolysis of cyclic adenosine 3′,5′-monophosphate (cAMP), thereby regulating the intracellular levels of this second messenger and influencing various physiological functions and processes. There are two subtypes of PDE7, PDE7A and PDE7B, which are encoded by distinct genes. PDE7 inhibitors have been shown to exert therapeutic effects on neurological and respiratory diseases. However, FDA-approved drugs based on the PDE7A inhibitor are still absent, highlighting the need for novel compounds to advance PDE7A inhibitor development. Methods: To address this urgent and important issue, we conducted a comprehensive cheminformatics analysis of compounds with potential for PDE7A inhibition using a curated database to elucidate the chemical characteristics of the highly active PDE7A inhibitors. The specific substructures that significantly enhance the activity of PDE7A inhibitors, including benzenesulfonamido, acylamino, and phenoxyl, were identified by an interpretable machine learning analysis. Subsequently, a machine learning model employing the Random Forest–Morgan pattern was constructed for the qualitative and quantitative prediction of PDE7A inhibitors. Results: As a result, six compounds with potential PDE7A inhibitory activity were screened out from the SPECS compound library. These identified compounds exhibited favorable molecular properties and potent binding affinities with the target protein, holding promise as candidates for further exploration in the development of potent PDE7A inhibitors. Conclusions: The results of the present study would advance the exploration of innovative PDE7A inhibitors and provide valuable insights for future endeavors in the discovery of novel PDE inhibitors.

To date, there are very few effective drugs for liver fibrosis treatment; therefore, it is urgent to develop novel therapeutic targets and approaches. In the present research, we sought to study the protective effect of sweroside contained in Lonicera japonica or blue honeysuckle berries in a mouse model of liver fibrosis and investigate the underlying mechanism. The mouse model of liver fibrosis in was induced by intraperitoneal injections of 10% CCl 4 for 6 weeks (three times/week). At the beginning of the fourth week, sweroside was intragastrically administered once a day and at the end of the treatment, biochemical and histological studies were investigated. The expression of FXR, miR-29a and the downstream targets were analyzed as well. Moreover, the effect of sweroside on cell proliferation was observed in human hepatic stellate cells (HSCs) (LX-2), along with using the siRNA for FXR and miR-29a inhibitor to investigate the underpinning of the anti-fibrotic effect of sweroside. Sweroside successfully protected the liver fibrosis in CCl 4 -induced mouse model, accompanied by miR-29a induction. Furthermore, sweroside also induced miR-29a in HSCs, resulting in the inhibition of COL1 and TIMP1. Our data also showed that either silencing miR-29a or knockdown of FXR in LX-2 cell abolished the inhibition of COL1 and TIMP1 as well as the inhibition of cell proliferation by sweroside treatment. In conclusion, sweroside exerted its anti-fibrotic effect in vivo and in vitro by up-regulation of miR-29a and repression of COL1 and TIMP1, which was at least in part through FXR.

Large-area soil moisture (SM) data with high resolution and precision are the foundation for the research and application of hydrological and meteorological models, water resource evaluation, agricultural management, and warning of geological disasters. It is still challenging to downscale SM products in complex terrains that require fine spatial details. In this study, SM data from the Soil Moisture Active and Passive (SMAP) satellite were downscaled from 36 to 1 km in the summer and autumn of 2017 in Sichuan Province, China. Genetic-algorithm-optimized backpropagation (GABP) neural network, random forest, and convolutional neural network were applied. A fusion model between SM and longitude, latitude, elevation, slope, aspect, land-cover type, land surface temperature, normalized difference vegetation index, enhanced vegetation index, evapotranspiration, day sequence, and AM/PM was established. After downscaling, the in situ information was fused through a geographical analysis combined with a spatial interpolation to improve the quality of the downscaled SM. The comparative results show that in complex terrains, the GABP neural network better captures the soil moisture variations in both time and space domains. The GDA_Kriging method is able to merge in situ information in the downscaled SM while simultaneously maintaining the dynamic range and spatial details.