Lack of effect of bone marrow transplantation on airway hyperresponsiveness in an asthmatic

ABSTRACTBronchial asthma has been recognized as an inflammatory disorder in this past decade. This leads to an assumption that perfect control of inflammatory cells may cure this disease. However, herein we report on an asthmatic whose airway hyperresponsiveness (AHR) did not change after bone marrow transplantation (BMT). The concentrations of acetylcholine to produce a 20% fall in forced expiratory volume in 1 s 15 days before and 98 days after BMT were 900 and 480 μg/mL, respectively. Asthma treatment with beclo-methasone dipropionate and theophylline was continued before and after BMT and a conventional supporting therapy for BMT with cyclosporine A and methylprednisolone, followed by oral administration of tacrolimus hydrate alone inhibited graft-versus-host disease. Plasma interleukin (IL)-4, IL-5 and IgE, but not interferon-γ, levels decreased after BMT. Note that the second measurement of airway sensitivity was performed under systemic administration of tacrolimus. The presented case suggests that replacement of bone marrow-derived inflammatory cells is not enough to reverse once-established AHR. Hence, AHR and airway inflammation may develop independently in some part, but both need to be present for asthma to be present in this asthmatic

Differentiation of hypertrophic chondrocytes from human iPSCs for the in vitro modeling of chondrodysplasias

iPS細胞から肥大軟骨細胞への誘導法を確立し、成長板疾患の病態再現に成功. 京都大学プレスリリース. 2021-02-26.Reprogramming children's cells to study cartilage diseases. 京都大学プレスリリース. 2021-02-26.Chondrodysplasias are hereditary diseases caused by mutations in the components of growth cartilage. Although the unfolded protein response (UPR) has been identified as a key disease mechanism in mouse models, no suitable in vitro system has been reported to analyze the pathology in humans. Here, we developed a three-dimensional culture protocol to differentiate hypertrophic chondrocytes from induced pluripotent stem cells (iPSCs) and examine the phenotype caused by MATN3 and COL10A1 mutations. Intracellular MATN3 or COL10 retention resulted in increased ER stress markers and ER size in most mutants, but activation of the UPR was dependent on the mutation. Transcriptome analysis confirmed a UPR with wide-ranging changes in bone homeostasis, extracellular matrix composition, and lipid metabolism in the MATN3 T120M mutant, which further showed altered cellular morphology in iPSC-derived growth-plate-like structures in vivo. We then applied our in vitro model to drug testing, whereby trimethylamine N-oxide led to a reduction of ER stress and intracellular MATN3

Ultrastructural Abnormalities of Bone Marrow Erythroblasts in Refractory Anemia

学位記番号:医博乙122

Central Nervous System Relapse of Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

AbstractLittle information is available regarding central nervous system (CNS) relapse of adult leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, we reviewed the data of 1226 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML) who received first allogeneic HSCT between 1994 and 2004, using the database of the Kanto Study Group for Cell Therapy (KSGCT), and analyzed the incidence, risk factors, and outcome of patients with CNS relapse. Twenty-nine patients developed CNS relapse at a median of 296 (9-1677) days after HSCT with a cumulative incidence of 2.3%. Independent significant factors associated with CNS relapse included ALL as the underlying diagnosis (relative risk [RR] = 9.55, 95% confidence interval [CI] = 1.26-72.2, P = .029), nonremission at HSCT (RR = 2.30, 95% CI = 1.03-5.15, P = .042), the history of CNS invasion before HSCT (RR = 5.62, 95% CI = 2.62-12.0, P = 9.2 × 10−6), and the prophylactic intrathecal chemotherapy after HSCT (RR = 2.57, 95% CI = 1.21-5.46, P = .014). The 3-year overall survival (OS) after CNS relapse was 18%. In 7 of 29 patients with CNS relapse, leukemia was observed only in CNS. Three of 7 patients were alive without systemic relapse, resulting in 3-year survival after CNS relapse of 46%. Although the outcome of patients with CNS relapse was generally poor, long-term disease-free survival could be achieved in some patients