坂下 英司

ABSTRACT While venetoclax‐based combinations have shown promising results in acute myeloid leukemia (AML), the remission duration is generally short, warranting strategies to further improve efficacy and overcome resistance. Here, we show that the natural quassinoid brusatol induces cell‐cycle arrest and apoptosis in multiple AML cell lines while enhancing venetoclax efficacy irrespective of inherent or acquired resistance. Mechanistically, brusatol increased p53 protein expression, leading to upregulation of its target genes/proteins, including CDKN1A (p21) and BBC3 (PUMA). Genetic deletion of TP53 attenuated brusatol‐induced apoptosis and its synergy with venetoclax, supporting p53 activation as a central mechanism underlying the anti‐leukemia response. Furthermore, the combination synergistically decreased mitochondrial membrane potential and respiratory activity, causing accumulation of reactive oxygen species in AML cells. Although brusatol and venetoclax exhibited limited effects individually, their combination markedly reduced leukemia burden and significantly prolonged survival in three independent cell line‐derived xenograft models, including venetoclax‐resistant and ‐refractory models. Notably, brusatol increased normal leukocyte and platelet counts while reducing leukemic infiltration in both bone marrow and extramedullary sites. These findings provide mechanistic insight into the synergistic effects of the brusatol‐venetoclax combination, supporting further evaluation of this therapeutic strategy in myeloid leukemias.

Only a few reports have generated induced pluripotent stem cells from patients with prion diseases, making it important to conduct translational studies using cells derived from individuals with prion protein (PRNP) mutations. In this study, we established induced pluripotent stem cells from a patient with a glycosylphosphatidylinositol-anchorless PRNP mutation (Y162X), which leads to abnormal deposits of prion protein in various organs. While no abnormal intracellular prion protein deposits were observed in the neurons differentiated from PRNP Y162X induced pluripotent stem cells, extracellular PrP aggregates secretions were significantly increased, and these cells were significantly more sensitive to oxidative stress compared to control cells. Utilizing this PRNP Y162X iPSC-derived neuron model, we discovered that edaravone reduced the sensitivity of PRNP Y162X cells to oxidative stress. Following this finding, we treated a PRNP Y162X patient with edaravone for two years, which successfully suppressed indicators of disease progression. Our study demonstrates that the pathology of the glycosylphosphatidylinositol-anchorless PRNP mutation is associated with oxidative stress and highlights the potential of induced pluripotent stem cell technology in identifying novel treatments for rare prion diseases.

Objectives Compared to conventional disease-modifying antirheumatic drugs (DMARDs), biological DMARDs demonstrate superior efficacy but come with higher costs and increased infection risks. The ability to stop and resume biological DMARD treatment while maintaining remission would significantly alleviate these barriers and anxieties. The objective of this study was to identify biomarkers that can predict an imminent relapse, hopefully enabling the timely resumption of biological DMARDs before relapse occurs. Methods Forty patients with rheumatoid arthritis who had been in remission for more than 12 months were included in the study. The patients discontinued their biological DMARD treatment and were monitored monthly for the next 24 months. Out of the 40 patients, 14 (35%) remained in remission at the end of the 24-month period, while 26 (65%) experienced relapses at different time points. Among the relapse cases, 13 patients experienced early relapse within 6 months, and another 13 patients had late relapse between 6 months and 24 months. Seventy-three cytokines in the sera collected longitudinally from the 13 patients with late relapse were measured by multiplex immunoassay. Using cytokines at two time points, immediately after withdrawal and just before relapse, volcano plot and area under the receiver operating characteristic curves (AUC) were drawn to select cytokines that distinguished imminent relapse. Univariate and multivariate logistic regression analyses were used for the imminent relapse prediction model. Results IL-6, IL-29, MMP-3, and thymic stromal lymphopoietin (TSLP) were selected as potential biomarkers for imminent relapse prediction. All four cytokines were upregulated at imminent relapse time point. Univariate and multivariate logistic regression showed that a combination model with IL-6, MMP-3, and TSLP yielded an AUC of 0.828 as top predictors of imminent relapse. Conclusions This methodology allows for the prediction of imminent relapse while patients are in remission, potentially enabling the implementation of on- and off-treatments while maintaining remission. It also helps alleviate patient anxiety regarding the high cost and infection risks associated with biological DMARDs, which are the main obstacles to benefiting from their superb efficacy.