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关键词： Cardiotoxicity   Post-transplant cyclophosphamide   Graft-versus host disease   North Japan hematology study group  

摘要： IntroductionPost-transplant cyclophosphamide (PTCy)-based prophylaxis for graft-versus-host disease (GVHD) is widely used in HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). One of the major drawbacks of PTCy is the risk of rare but potentially lethal cardiotoxicity, which prompted the development of regimens with reduced doses of *** retrospectively compared the incidence of early cardiotoxicity with standard-dose of PTCy (cyclophosphamide 50 mg/kg/day for 2 days, PTCy100) versus reduced-dose (40 mg/kg/day for 2 days, PTCy80). In total, 179 patients underwent PTCy-based haplo-HCT, including PTCy100 (n = 111) and PTCy80 (n = 68).ResultsThe PTCy80 group included significantly more elderly patients, patients who received reduced-intensity conditioning, and patients with a history of HCT than the PTCy100 group. Nine eligible patients (5.0%) experienced severe cardiotoxicity. The incidence of severe cardiotoxicity did not differ significant between PTCy80 and PTCy100 (4.4% vs. 5.4%;p = 1). The incidence of fatal cardiotoxicity was lower with PTCy80, but the small size may have prevented the difference from reaching statistical *** the cyclophosphamide dose in PTCy-based GVHD prophylaxis may lower the risk of fatal cardiotoxicity without significantly altering the overall incidence of severe cardiotoxicity.

摘要： Long-acting controlled drug release formulations are highly desired for potentiating efficacy and reducing administration frequency. Here we present a kinetically controllable long-term interleukin-2 (IL-2) release platform by the fusion and boundary elimination of calcium carbonate and calcium phosphate amorphous phases. Unlike mixtures, a group of hybrid biominerals with the chemical formula Ca(CO3)(x)(PO4)(2(1-x)/3) (CaCPs, 0 < x < 1) was fabricated under high pressure (2 GPa), and the CaCPs showed crystallization-driven release behaviors to optimize the in vivo fate of IL-2. Ca(CO3)(1/2)(PO4)(1/3) dynamically remodeled immunosuppressive tumor microenvironments, preferentially activated cytotoxic and memory T cells by improving IL-2 redistribution and achieved weeks-long IL-2 retention in tumors with high tolerance and biosafety. In a melanoma model in female mice, Ca(CO3)(1/2)(PO4)(1/3) revealed superior antitumor effects to inhibit local tumor recurrence, hinder the growth of distant untreated tumors and maintain long-term T cell responses against the rechallenged metastatic tumors.

关键词： Mitragyna parvifolia   Green synthesis   Silver nanoparticles   Rheumatoid arthritis   COX-2 inhibition   Molecular targets  

摘要： Green nanotechnology offers a sustainable approach to rheumatoid arthritis (RA) therapy by enabling targeted modulation of key inflammatory markers, addressing the limitations of conventional treatments. This study explores biogenic approach to RA therapy through the one-pot green synthesis of silver nanoparticles (AgNPs) using Mitragyna parvifolia bark extract. The synthesis of AgNPs was optimized by varying parameters such as reaction temperature, time, AgNO3 concentration, extract volume, and pH. The fabricated AgNPs were thoroughly analyzed using UV-visible spectroscopy, dynamic light scattering, Fourier-transform infrared spectroscopy, Energy dispersive X-ray analysis, transmission electron microscopy, and X-ray diffraction, confirming their functional group composition, stability, nano-scale size, spherical shape and face-centered cubic structure. In vitro studies revealed that the AgNPs exhibited superior anti-inflammatory activity compared to the crude plant extract, effectively inhibiting protein denaturation and cyclooxygenase-2 (COX-2) enzyme activity. In vivo assessments using Carrageenan-induced paw edema and Complete Freund's Adjuvant-induced arthritis models revealed significant reductions in paw swelling, inflammatory cytokines (TNF-alpha and IL-6), and hematological markers of inflammation. Histopathological and radiographic analyses confirmed reduced soft tissue swelling and bone erosion in AgNP-treated groups. Network pharmacology and molecular docking studies identified key phytoconstituents of M. parvifolia targeting TNF-alpha (PDB ID: 2AZ5) and modulating key inflammatory pathway (TNF signaling pathway). The integration of green synthesis with phytomedicine presents a promising, sustainable, and biocompatible approach to RA treatment. Our findings establish M. parvifolia-derived silver nanoparticles as a promising therapeutic strategy for RA treatment, offering a targeted, sustainable, and effective alternative to conventional therapies through

摘要： OBJECTIVE: The proper tolerance of pregnancy is based on the interaction between human killer cell immunoglobulin-like receptors (KIR) on dNK cells with HLA-C molecules on extravillous trophoblasts (EVT). Due to their function and protein structur...

摘要： Background and Aims: A strong low-density lipoprotein cholesterol (LDL-C) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduces the residual risk in patients with myocardial infarction (MI). Recent data suggested...

摘要： Glioblastoma (GBM) is the most common primary brain cancer in adults and carries a median overall survival (OS) of 12-15 months. Effective therapy for recurrent GBM (rGBM) following frontline chemoradiation is a major unmet medical need. Here we report the dose escalation and exploration phases of a phase 1 trial investigating intracerebroventricular delivery of bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) epitope 806 and interleukin-13 receptor alpha 2 (IL-13R alpha 2), or CART-EGFR-IL13R alpha 2 cells, in patients with EGFR-amplified rGBM. Primary endpoints included dose-limiting toxicity, determination of the maximum tolerated dose and recommended dose for expansion, and occurrence of adverse events. Secondary endpoints included objective radiographic response, duration of response, progression-free survival and OS. A total of 18 patients received CART-EGFR-IL13R alpha 2 cells. The maximum tolerated dose was determined to be 2.5 x 107 cells. Of the 18 patients, 10 (56%) experienced grade 3 neurotoxicity;none had grade 4-5 neurotoxicity. Of 13 patients, 8 (62%) with measurable disease at the time of CAR T cell infusion experienced tumor regression, with one confirmed partial response by Modified Response Assessment in Neuro-Oncology criteria (objective radiographic response, 8%;90% confidence interval, 0-32%) and one patient with ongoing durable stable disease lasting over 16 months. Median progression-free survival was 1.9 months (90% confidence interval, 1.1-3.4 months), and median OS was not yet reached at the time of data cut-off (median follow-up time, 8.1 months). These findings indicate that intracerebroventricular delivery of bivalent CART-EGFR-IL13R alpha 2 is feasible and appears safe. CART-EGFR-IL13R alpha 2 cells are bioactive and exhibit a signal of antitumor effect in rGBM. *** registration: NCT05168423.

关键词： BoLA   bovine   MHC   MinION   nanopore sequencing  

摘要： The bovine leukocyte antigen DRB3 (BoLA-DRB3) gene, a crucial component of major histocompatibility complex class (MHC) II, influences disease susceptibility and production traits in cattle. Conventional PCR - (Sanger)-sequence-based typing (PCR-SBT) - has limitations, including time-intensive processing and phase ambiguity issues. We developed a nanopore-sequencing-based method for BoLA-DRB3 genotyping. The full-length gene (10.9 kbp) was amplified from blood samples of 109 Japanese Black cattle and sequenced using Oxford Nanopore Technologies' nanopore MinION. The method achieved high-quality metrics, with a mean coverage of 99.97%, an average sequencing depth of 2599x and a mean Q-score of 20.5. Perfect reference sequence alignment was obtained in 92.7% (101/109) of samples. Alleles of all samples showed complete concordance with the set of PCR-SBT typing results for exon 2. The entire process was completed within 3 days (6 h of hands-on time), substantially reducing the time and cost requirements compared with other methods. This nanopore sequencing method provides accurate BoLA-DRB3 genotyping while resolving phase ambiguity through full-length molecule analysis, presenting a potential new standard for bovine MHC genotyping.