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The prognosis of acute myeloid leukemia (AML) with KMT2A::MLLT3 rearrangement and MECOM overexpression and/or KRAS mutation is dismal, and the optimal treatment strategy remains unclear. However, to the best of our knowledge, a suitable model (such as a cell line or its xenograft model) for research on this subtype has not been established. We established a novel AML cell line, YCU-AML2, and its xenograft model harboring KMT2A::MLLT3 rearrangement, MECOM overexpression, and KRAS G12A mutation. YCU-AML2 xenograft mice models developed AML and mimicked the clinical phenotype of the original patient. YCU-AML2 expressed high sensitivity to MEK inhibitors, such as trametinib and selumetinib. Moreover, YCU-AML2 also exhibited high sensitivity to L-asparaginase with glutaminase activity, perhaps because of its reliance on oxidative phosphorylation via glutaminolysis as its main energy source. We believe that the YCU-AML2 cell line and its xenograft model can serve as models to explore the molecular pathogenesis of high-risk AML with KMT2A::MLLT3 rearrangement, MECOM overexpression, and/or KRAS mutation and develop new treatment strategies., Competing Interests: Declarations. Conflict of interest: All authors declare no conflict of interests., (© 2025. The Author(s), under exclusive licence to Japanese Society of Hematology.)

Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay. NPM1::CCDC28A is more localized to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. NPM1::CCDC28A cells were also sensitive to menin inhibition. Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Neuromuscular electrical stimulation (NMES) is widely used for improving muscle strength, preventing muscle atrophy, and decreasing pain. Recently, NMES has become a substitute for exercise therapy for metabolism improvement and functional capacity improvement. However, NMES has several disadvantages. First, slow-twitch muscle contractions are insufficient because the recruitment pattern of NMES does not obey Henneman's size principle. Second, when using surface electrodes, it is difficult to contract deep skeletal muscles at the application site. Third, electrical stimulation causes discomfort. Therefore, we devised a simultaneous combination of NMES and voluntary muscle contractions to overcome the weak points of NMES. A hybrid training system (HTS) that resists the motion of a volitionally contracting agonist muscle with force generated by its electrically stimulated antagonist was developed as a technique to combine the application of NMES and volitional contractions. This motion sensor makes it possible to simultaneously combine voluntary movements with NMES. Our HTS synchronizes with voluntary movements, enhancing safety and reducing discomfort. This HTS enhances the exercise effect of even simple exercise. So far, our HTS has been reported to be effective for muscle strength enhancement, prevention of muscle atrophy, improvement of physical function, pain relief, enhancement of physical fitness, and improvement of metabolic function. HTS are expected to be useful methods in environments where sufficient exercise load is not available or for individuals with low exercise tolerance.

Background: There is limited data on the impact of COVID-19 epidemic on the number of orthopaedic surgeries in Japan., Methods: We conducted a nationwide hospital survey asking for the monthly number of orthopaedic surgeries performed at each facility from January 2019 to June 2021. Those facilities that had performed at least 100 surgeries in 2019 were included for analyses. The facilities were further grouped by prefecture and by hospital characteristics. A brief health economic evaluation was also performed. Risk ratios were compared using univariate analyses with P < 0.05 considered statistically significant., Results: Questionnaire was sent to 1988 hospitals with 1671 hospitals (84%) responding. The survey data indicated a total number of orthopaedic surgeries decreased in 2020 compared to 2019 (1,061,541 vs 1,119,955 P < 0.01), and also for the first six months of 2021 compared to the same period in 2019 (530,388 vs 550,378 P < 0.01). In 2020, over 50% of all facilities in nearly all of the prefectures saw a decline in surgical procedures. The risk of incurring more than a 25% decease in the number of surgeries was significantly higher in 2020 for class I designated medical institutions compared to those that were not designated for any types of infectious diseases among the institutions with a tertiary emergency medical center in 2020 (crude risk ratio 2.9: 95% CI 1.2-7.4, p = 0.02) and in 2021 (crude risk ratio 4.7: 95% CI 1 0.9-12.1, p < 0.01). The estimated total nationwide decrease of revenue were in the range of approximately ¥29.2 to ¥116.8 billion per year for orthopaedic surgeries alone., Conclusion: There was a statistically significant decrease in the number of orthopaedic surgeries in Japan. The magnitude of the decline varied by prefectures and hospital characteristics, with the greater impact imposed on medical institutions with higher classification functions. The estimated immediate health economic impact was sizable., Competing Interests: Declaration of competing interest No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. The first author reports personal speaker fees from Johnson & Johnson K·K., Pfizer Japan, 3 M Japan, Stryker Japan, Taisho Toyama Pharmaceutical, MSD K.K., Hisamitsu Pharmaceutical, Kaken Pharmaceutical, Astellas Pharma, Smith＆Nephew, Daiichi Sankyo Company, outside the submitted work., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis., Procedure: To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML., Results: High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells., Conclusions: Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression., (© 2024 Wiley Periodicals LLC.)

Background: The clinical application of human induced pluripotent stem cell-derived cardiomyocytes (CMs) for cardiac repair commenced with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of human induced pluripotent stem cell-derived CMs into the cardiac muscle layer, which has reportedly induced electrical integration, is unclear because of concerns about poor engraftment of CMs and posttransplant arrhythmias. Thus, in this study, we prepared purified human induced pluripotent stem cell-derived cardiac spheroids (hiPSC-CSs) and investigated whether their direct injection could regenerate infarcted nonhuman primate hearts., Methods: We performed 2 separate experiments to explore the appropriate number of human induced pluripotent stem cell-derived CMs. In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks before transplantation and were designated as recipients of hiPSC-CSs containing 2×10 7 CMs or the vehicle. The animals were euthanized 12 weeks after transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6×10 7 CMs)., Results: Recipients of hiPSC-CSs containing 2×10 7 CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle (fractional shortening at 4 weeks after transplantation [mean ± SD]: 26.2±2.1%; 19.3±1.8%; P <0.05), with a low incidence of posttransplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits (fractional shortening at 12 weeks after transplantation: 22.5±1.0%; 16.6±1.1%; P <0.01, left ventricular ejection fraction at 12 weeks after transplantation: 49.0±1.4%; 36.3±2.9%; P <0.01). The incidence of posttransplant arrhythmia slightly increased in recipients of hiPSC-CSs containing 6×10 7 CMs., Conclusions: We demonstrated that direct injection of hiPSC-CSs restores the contractile functions of injured primate hearts with an acceptable risk of posttransplant arrhythmia. Although the mechanism for the functional benefits is not fully elucidated, these findings provide a strong rationale for conducting clinical trials using the equivalent CM products., Competing Interests: S.T. is an advisor to Heartseed Inc. K.F. is the cofounder and CEO of Heartseed Inc. S.T., H. Kanazawa, and K.F. own equity in Heartseed Inc.

The purpose of this study is to clarify whether a hip range of motion (ROM) measurement is useful in screening for early hip osteoarthritis with acetabular dysplasia (AD). Subjects were 58 healthy Japanese women volunteers (21.1 ± 0.7 (20 - 22)). We evaluated a total of 116 hip joints in these 58 cases. Sharp angle and centeredge angle were 44.1° ± 3.1° (37.0° - 51.5°) and 30.7°± 6.2° (19.5° - 47.0°), respectively. AD was present in 47.4%, but there were no severe cases. First, we compared the ROM of the hip joints with AD (AD group) and without AD (control group) according to the Mann-Whitney U test. Extension angles and external rotation angles in the AD group were significantly smaller than in the control group (18.9°± 6.1° VS. 22.1°± 4.2°, p= 0.01636, 26.3°± 8.9° VS. 34.1°± 8.8°, p= 0.001362, respectively). Next, we evaluated the following factors associated with AD by logistic regression analysis after adjustment for age: flexion, extension and internal and external rotation angles of the hip joint. As a result, internal rotation and external rotation were extracted as related factors. The area under the ROC curve was determined to have a moderate accuracy (0.72996). Cut off values of internal rotation and external rotation angles were 50 degrees and 35 degrees, respectively. Our findings suggest that ROM measurement of the internal and external rotation angles would be useful as a screening for AD in healthy young Japanese women without symptoms.

Abstract: Transient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in ∼20% of cases. Therefore, new biomarkers are needed to predict early death and determine therapeutic interventions. This study aimed to determine the association between clinical characteristics and cytokine levels in patients with TAM. A total of 128 patients with DS with TAM enrolled in the TAM-10 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group were included in this study. Five cytokine levels (interleukin-1b [IL-1b], IL-1 receptor agonist, IL-6, IL-8, and IL-13) were significantly higher in patients with early death than in those with nonearly death. Cumulative incidence rates (CIRs) of early death were significantly associated with high levels of the 5 cytokines. Based on unsupervised consensus clustering, patients were classified into 3 cytokine groups: hot-1 (n = 37), hot-2 (n = 42), and cold (n = 49). The CIR of early death was significantly different between the cytokine groups (hot-1/2, n = 79; cold, n = 49; hot-1/2 CIR, 16.5% [95% confidence interval (CI), 7.9-24.2]; cold CIR, 2.0% [95% CI, 0.0-5.9]; P = .013). Furthermore, cytokine groups (hot-1/2 vs cold) were independent poor prognostic factors in the multivariable analysis for early death (hazard ratio, 15.53; 95% CI, 1.434-168.3; P = .024). These results provide valuable information that cytokine level measurement was useful in predicting early death in patients with TAM and might help to determine the need for therapeutic interventions. This trial was registered at UMIN Clinical Trials Registry as #UMIN000005418., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Despite increasing availability of rapid molecular tests for the diagnosis of tuberculosis in high-burden settings, many people with tuberculosis are undiagnosed. Reliance on sputum as the primary specimen for tuberculosis diagnostics contributes to this diagnostic gap. We evaluated the diagnostic accuracy and additive yield of a novel stool quantitative PCR (qPCR) assay for the diagnosis of tuberculosis in three countries in Africa with high tuberculosis burdens., Methods: We undertook a prospective diagnostic accuracy study in Eswatini, Mozambique, and Tanzania from Sept 21, 2020, to Feb 2, 2023, to compare the diagnostic accuracy for tuberculosis of a novel stool qPCR test with the current diagnostic standard for Mycobacterium tuberculosis DNA detection from sputum and stool, Xpert-MTB/RIF Ultra (Xpert Ultra). Sputum, stool, and urine samples were provided by a cohort of participants, aged 10 years or older, diagnosed with tuberculosis. Participants with tuberculosis (cases) were enrolled within 72 h of treatment initiation for tuberculosis diagnosed clinically or following laboratory confirmation. Participants without tuberculosis (controls) consisted of household contacts of the cases who did not develop tuberculosis during a 6-month follow-up. The performance was compared with a robust composite microbiological reference standard (CMRS)., Findings: The cohort of adolescents and adults (n=408) included 268 participants with confirmed or clinical tuberculosis (cases), 147 (55%) of whom were living with HIV, and 140 participants (controls) without tuberculosis. The sensitivity of the novel stool qPCR was 93·7% (95% CI 87·4-97·4) compared with participants with detectable growth on M tuberculosis culture, and 88·1% (81·3-93·0) compared with sputum Xpert Ultra. The stool qPCR had an equivalent sensitivity as sputum Xpert Ultra (94·8%, 89·1-98·1) compared with culture. Compared with the CMRS, the sensitivity of the stool qPCR was higher than the current standard for tuberculosis diagnostics on stool, Xpert Ultra (80·4%, 73·4-86·2 vs 73·5%, 66·0-80·1; p=0·025 on paired comparison). The qPCR also identified 17-21% additional tuberculosis cases compared to sputum Xpert Ultra or sputum culture. In controls without tuberculosis, the specificity of the stool qPCR was 96·9% (92·2-99·1)., Interpretation: In this study, a novel qPCR for the diagnosis of tuberculosis from stool specimens had a higher accuracy in adolescents and adults than the current diagnostic PCR gold standard on stool, Xpert-MTB/RIF Ultra, and equivalent sensitivity to Xpert-MTB/RIF Ultra on sputum., Funding: National Institutes of Health (NIH) Allergy and Infectious Diseases, and NIH Fogarty International Center., Competing Interests: Declaration of interests CL has received funding for this work from the German Center for Infection Research (DZIF); consulting fees from Insmed; and speakers' honoraria from Insmed, Gilead, GSK, and Janssen outside of the scope of this work. AMM has received honoraria from Janssen for participation in a data and safety monitoring board outside of the scope of this work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Tuberculosis (TB) is a major cause of mortality worldwide. Children and people living with HIV (PLHIV) have an increased risk of mortality, particularly in the absence of rapid diagnosis. The main challenges of diagnosing TB in these populations are due to the unspecific and paucibacillary disease presentation and the difficulty of obtaining respiratory samples. Thus, novel diagnostic strategies, based on non-respiratory specimens could improve clinical decision making and TB outcomes in high burden TB settings. We propose a multi-country, prospective diagnostic evaluation study with a nested longitudinal cohort evaluation to assess the performance of a new stool-based qPCR, developed by researchers at Baylor College of Medicine (Houston, Texas, USA) for TB bacteriological confirmation with promising results in pilot studies., Methods: The study will take place in high TB/HIV burden countries (Mozambique, Eswatini and Uganda) where we will enroll, over a period of 30 months, 650 PLHIV (> 15) and 1295 children under 8 years of age (irrespective of HIV status) presenting pressumptive TB. At baseline, all participants will provide clinical history, complete a physical assessment, and undergo thoracic chest X-ray imaging. To obtain bacteriological confirmation, participants will provide respiratory samples (1 for adults, 2 in children) and 1 stool sample for Xpert Ultra MTB/RIF (Cepheid, Sunnyvale, CA, USA). Mycobacterium tuberculosis (M.tb) liquid culture will only be performed in respiratory samples and lateral flow lipoarabinomannan (LF-LAM) in urine following WHO recommendations. Participants will complete 2 months follow-up if they are not diagnosed with TB, and 6 months if they are. For analytical purposes, the participants in the pediatric cohort will be classified into "confirmed tuberculosis", "unconfirmed tuberculosis" and "unlikely tuberculosis". Participants of the adult cohort will be classified as "bacteriologically confirmed TB", "clinically diagnosed TB" or "not TB". We will assess accuracy of the novel qPCR test compared to bacteriological confirmation and Tb diagnosis irrespective of laboratory results. Longitudinal qPCR results will be analyzed to assess its use as treatment response monitoring., Discussion: The proposed stool-based qPCR is an innovation because both the strategy of using a non-sputum based sample and a technique specially designed to detect M.tb DNA in stool., Protocol Registration Details: ClinicalTrials.gov Identifier: NCT05047315., (© 2024. The Author(s).)

Innovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers adaptive sampling and computationally driven target enrichment technology. This enables more affordable intensive analysis of target gene regions compared to standard non-selective long-read sequencing. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified several SINE-R/VNTR/Alu (SVA) elements affecting the APC gene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which is typically discarded, can be effectively used to accurately genotype common single-nucleotide polymorphisms (SNPs) across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specific MLH1 promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis., (© 2024. The Author(s).)

In 2020, a 48-year-old male patient was admitted to our hospital due to unstable angina. In 2005, three first-generation sirolimus-eluting stents (1st-SESs) had been deployed to his right coronary artery (RCA). Over the past 10 years or so, the patient has been treated with single antiplatelet therapy using aspirin. Coronary angiography (CAG) revealed severe stenosis in the left circumflex artery (LCx) and total occlusion at the proximal portion of the stented RCA. Furthermore, fluoroscopy showed multiple 1st-SES fractures. After ad hoc percutaneous coronary intervention of the LCx, dual antiplatelet therapy (DAPT) was resumed by adding the P2Y12 inhibitor clopidogrel to aspirin. Two months later, CAG revealed complete recanalization and multiple peri-stent coronary artery aneurysms (CAAs) in the RCA. Intravascular ultrasound revealed late-acquired stent malapposition (LSM) and formation of true aneurysms. Coronary angioscopy showed the uncovered struts of the 1st-SES and mural red thrombus. DAPT was continued thereafter, and 8 months later, follow-up CAG showed no significant RCA restenosis. To date, the patient remains free from cardiovascular events. This report documents a rare case of thrombotic occlusion of a 1st-SES with LSM, CAA, and stent fractures followed by non-invasive recanalization after clopidogrel treatment 15 years after 1st-SES implantation., Learning Objective: Stent thrombosis due to stent fracture and coronary aneurysm can occur even years after first-generation sirolimus-eluting stent (1st-SES) implantation. Risk assessment using coronary imaging should be made and long-term dual antiplatelet therapy (DAPT) should be recommended in patients with a high risk of stent thrombosis after 1st-SES implantation. In cases of stent thrombosis of the 1st-SES, resuming DAPT, including P2Y12 receptor inhibitors, may be a useful non-invasive treatment option., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

CD25 is an aberrant marker expressed on the leukemic stem cell (LSC) surface and an immunotherapy target in acute myeloid leukemia (AML). However, the clinical prevalence and significance of CD25 expression in pediatric AML are unknown. High IL2RA/CD25 expression in pediatric AML showed a stem cell-like phenotype, and elevated CD25 expression was associated with lower overall survival (p < .001) and event-free survival (p < .001) in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. This finding was reproduced in AML without a core-binding factor in the Children's Oncology Group study cohort. High CD25 expression has prognostic significance in pediatric AML., (© 2023 Wiley Periodicals LLC.)

Risk classification in pediatric acute myeloid leukemia (P-AML) is crucial for personalizing treatments. Thus, we aimed to establish a risk-stratification tool for P-AML patients and eventually guide individual treatment. A total of 256 P-AML patients with accredited mRNA-seq data from the TARGET database were divided into training and internal validation datasets. A gene-expression-based prognostic score was constructed for overall survival (OS), by using univariate Cox analysis, LASSO regression analysis, Kaplan-Meier (K-M) survival, and multivariate Cox analysis. A P-AML-5G prognostic score bioinformatically derived from expression levels of 5 genes (ZNF775, RNFT1, CRNDE, COL23A1, and TTC38), clustered P-AML patients in training dataset into high-risk group (above optimal cut-off) with shorter OS, and low-risk group (below optimal cut-off) with longer OS (p < 0.0001). Meanwhile, similar results were obtained in internal validation dataset (p = 0.005), combination dataset (p < 0.001), two treatment sub-groups (p < 0.05), intermediate-risk group defined with the Children's Oncology Group (COG) (p < 0.05) and an external Japanese P-AML dataset (p = 0.005). The model was further validated in the COG study AAML1031(p = 0.001), and based on transcriptomic analysis of 943 pediatric patients and 70 normal bone marrow samples from this dataset, two genes in the model demonstrated significant differential expression between the groups [all log2(foldchange) > 3, p < 0.001]. Independent of other prognostic factors, the P-AML-5G groups presented the highest concordance-index values in training dataset, chemo-therapy only treatment subgroups of the training and internal validation datasets, and whole genome-sequencing subgroup of the combined dataset, outperforming two Children's Oncology Group (COG) risk stratification systems, 2022 European LeukemiaNet (ELN) risk classification tool and two leukemic stem cell expression-based models. The 5-gene prognostic model generated by a single assay can further refine the current COG risk stratification system that relies on numerous tests and may have the potential for the risk judgment and identification of the high-risk pediatric AML patients receiving chemo-therapy only treatment., (© 2024. The Author(s).)

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.

The patient, a 68-year-old man, presented to our emergency room with chest pain, prompting an emergency cardiac catheterization due to elevated cardiac troponin-I levels. While no obvious coronary artery stenosis was found, there was evidence of apical ballooning wall motion in the left ventricle, leading to a diagnosis of takotsubo syndrome. Three months later, he occasionally experienced chest pain at rest, prompting us to conduct another cardiac catheterization. Left ventriculography showed normal contraction. Suddenly, he experienced chest pain accompanied by ST elevation, which occurred spontaneously. Subsequently, slow-flow phenomenon was observed in the intermediate part of left anterior descending artery (LAD). We promptly administered nitroglycerin to alleviate the symptoms. Following the diagnosis of coronary microvascular dysfunction (CMD), he started calcium-channel blocker therapy and remained asymptomatic. One year later, we re-performed cardiac catheterization to further explore his condition. Acetylcholine provocation test was performed, which showed no epicardial coronary spasm. However, lactic acid elevation was observed in the coronary sinus blood sample. Additionally, a coronary physiological measurement in the LAD revealed a high index of microcirculatory resistance and low coronary flow reserve. Based on this series of clinical events, we inferred a significant contribution of CMD to the patient's condition., Learning Objective: Coronary microvascular dysfunction (CMD) is increasingly recognized as an important cardiovascular disease, leading to myocardial ischemia, which is occasionally associated with takotsubo syndrome (TTS). In this report, we present a case of spontaneous CMD associated with TTS. This case emphasizes the significance of accurate diagnosis and appropriate treatment, highlighting the importance of recognizing CMD in patients with TTS., Competing Interests: The authors declare that there is no conflict of interest., (© 2023 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

We retrospectively evaluated spinal surgeries performed using the high-definition three-dimensional exoscopic system, which became available at our institution in August 2020. Eleven patients (4 with cervical disease and 7 with lumbar disease) underwent surgery with the system. There were no surgical complications related to the system, and the results were satisfactory. The small, flexible camera of the exoscope allows the surgeon to view the surgical field from various angles, facilitating both the approach and technique. In addition, it allows the surgeon to operate in an upright position without strain on the head and neck. Although further surgical experience is needed, this system has the potential to improve the visualization of the surgical field in spinal surgery.

Background: Our purpose was to quantify the postoperative rotation deformity (RD) after osteosynthesis of unstable intertrochanteric fractures (ITFx) using 3D-CT / image processing software, and to clarify the clinical meaning of RD., Methods: Forty-six consecutive patients with unstable intertrochanteric fractures were enrolled in this study. All were fixed with Gamma 3 Trochanteric nail and RC Lag Screw ® (Stryker). We performed 3D-CT evaluations for the rotational deformity of head-neck fragments, the medial cortex support (MCS) between main fragments and bone healing at 3 months postoperatively., Results: The RD was significantly larger in the patients without the MCS (5.1 ± 4.0°, N = 9) than those with the MCS (2.4 ± 2.6°, N = 37) (P = 0.006*). Delayed healing (N=3) was observed in patients without the MCS, and the association between RD and delayed healing was significant (P = 0.003*, cut-off value 6.4°, sensitivity 100% and specificity 90.7%, AUC 0.91)., Conclusions: This study proposed a novel method of measuring postoperative RD. Lack of MCS may lead to RD and consequent delayed healing in unstable ITFx fixed with intramedullary nails.

The objective of this study was to study the dose reduction effect on occupational exposure of operators and public exposure other than operators when a backscatter shield and a rectangular collimator are used in conjunction with a handheld intraoral X-ray unit. The occupational exposure was reduced to 40% when the backscatter shield was attached to the cone-tip, to 13% when the rectangular collimator was attached and to 7.7% when the backscatter shield and rectangular collimator were used together. On the other hand, the public exposure was reduced to 20% when the rectangular collimator was attached, but the backscatter shield was not effective in reducing the public exposure. Attaching a backscatter shield is effective in reducing the occupational exposure, and a rectangular aperture is effective in reducing the occupational exposure, as well as the public exposure., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background/aim: The COVID-19 pandemic led to the rapid spread of the use of ultraviolet C (UVC) sterilizers in many public facilities. Considering the harmful effects of prolonged exposure to UVC, manufacturing of safe skin care products is an important countermeasure. In continuation of our recent study of water-soluble herbal extracts, the present study aimed at searching for anti-UVC components from fat-soluble herbal extracts., Materials and Methods: Human dermal fibroblast and melanoma cells were exposed to UVC (1.193 W/m 2 ) for 3 min. Viable cell number was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell-cycle analysis was performed using a cell sorter. UVC-protective activity was quantified by the selective index (SI), i.e., the ratio of the 50% cytotoxic concentration for unirradiated cells to the concentration that restored viability of UVC-treated cells by 50%., Results: Only lemongrass extract, among 12 fat-soluble herbal extracts, showed significant anti-UVC activity, comparable to that of lignified materials and tannins, but exceeding that of N-acetyl-L-cysteine and resveratrol. Lemongrass extract was highly cytotoxic, producing a subG 1 cell population. During prolonged incubation in culture medium, the anti-UVC activity of lemongrass extract, sodium ascorbate and vanillic acid declined with an approximate half-life of <0.7, 5.4-21.6, and 27.8-87.0 h, respectively., Conclusion: Removal of cytotoxic principle(s) from lemongrass extract is crucial to producing long-lasting UVC-protective effects., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Autoimmune lymphoproliferative syndrome (ALPS) is a disease of lymphocyte homeostasis caused by FAS-mediated apoptotic pathway dysfunction and is characterized by non-malignant lymphoproliferation with an increased number of TCRαβ+CD4-CD8- double-negative T cells (αβDNTs). Conversely, RAS-associated leukoproliferative disease (RALD), which is caused by gain-of-functional somatic variants in KRAS or NRAS, is considered a group of diseases with a similar course. Herein, we present a 7-year-old Japanese female of RALD harboring NRAS variant that aggressively progressed to juvenile myelomonocytic leukemia (JMML) with increased αβDNTs. She eventually underwent hematopoietic cell transplantation due to acute respiratory distress which was caused by pulmonary infiltration of JMML blasts. In general, αβDNTs have been remarkably increased in ALPS; however, FAS pathway gene abnormalities were not observed in this case. This case with RALD had repeated shock/pre-shock episodes as the condition progressed. This shock was thought to be caused by the presence of a high number of αβDNTs. The αβDNTs observed in this case revealed high CCR4, CCR6, and CD45RO expressions, which were similar to Th17. These increased Th17-like αβDNTs have triggered the inflammation, resulting in the pathogenesis of shock, because Th17 secretes pro-inflammatory cytokines such as interleukin (IL)-17A and granulocyte-macrophage colony-stimulating factor. The presence of IL-17A-secreting αβDNTs has been reported in systemic lupus erythematosus (SLE) and Sjögren's syndrome. The present case is complicated with SLE, suggesting the involvement of Th17-like αβDNTs in the disease pathogenesis. Examining the characteristics of αβDNTs in RALD, JMML, and ALPS may reveal the pathologies in these cases., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Locomotive syndrome (LS) is characterized by reduced mobility. Clinical decision limit (CDL) stage 3 in LS indicates physical frailty. Lumbar spinal canal stenosis (LSS) is one of the causes of LS, for which lumbar surgery is considered to improve the CDL stage. This study aimed to investigate the efficacy of lumbar surgery and independent factors for improving the CDL stage in patients with LSS., Methods: This retrospective study was conducted at the Department of Orthopaedic Surgery at our University Hospital. A total of 157 patients aged ≥ 65 years with LSS underwent lumbar surgery. The 25-Question Geriatric Locomotive Function scale (GLFS-25) was used to test for LS, and the Timed Up and Go test (TUG) was used to evaluate functional ability. Lower limb pain was evaluated using a visual analog scale. Patients with at least one improvement in the CDL stage following lumbar surgery were included in the improvement group. Differences in lower limb pain intensity between the groups were evaluated using the Wilcoxon rank-sum test. The Spearman's rank correlation coefficient was used to determine correlations between Δ lower limb pain and Δ GLFS-25. Logistic regression analysis was used to identify factors associated with improvement in LS., Results: The proportion of patients with improved CDL stage was 45.1% (improvement/non-improvement: 32/39). Δ Lower limb pain was significantly reduced in the improvement group compared with that in the non-improvement group (51.0 [36.3-71.0] vs 40.0 [4.0-53.5]; p = 0.0107). Δ GLFS-25 was significantly correlated with Δ lower limb pain (r = 0.3774, p = 0.0031). Multiple logistic regression analysis revealed that TUG and age were significantly associated with improvement in LS (odds ratio, 1.22; 95% confidence interval: 1.07-1.47)., Conclusions: Lumbar surgery effectively improved the CDL stage in patients with LSS. In addition, TUG was an independent factor associated with improvement in the CDL., (© 2023. The Author(s).)

Exon-skipping therapy is a promising treatment strategy for Duchenne muscular dystrophy (DMD), which is caused by loss-of-function mutations in the DMD gene encoding dystrophin, leading to progressive cardiomyopathy. In-frame deletion of exons 3-9 (Δ3-9), manifesting a very mild clinical phenotype, is a potential targeted reading frame for exon-skipping by targeting actin-binding domain 1 (ABD1); however, the efficacy of this approach for DMD cardiomyopathy remains uncertain. In this study, we compared three isogenic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing Δ3-9, frameshifting Δ3-7, or intact DMD. RNA sequencing revealed a resemblance in the expression patterns of mechano-transduction-related genes between Δ3-9 and wild-type samples. Furthermore, we observed similar electrophysiological properties between Δ3-9 and wild-type hiPSC-CMs; Δ3-7 hiPSC-CMs showed electrophysiological alterations with accelerated CaMKII activation. Consistently, Δ3-9 hiPSC-CMs expressed substantial internally truncated dystrophin protein, resulting in maintaining F-actin binding and desmin retention. Antisense oligonucleotides targeting exon 8 efficiently induced skipping exons 8-9 to restore functional dystrophin and electrophysiological parameters in Δ3-7 hiPSC-CMs, bringing the cell characteristics closer to those of Δ3-9 hiPSC-CMs. Collectively, exon-skipping targeting ABD1 to convert the reading frame to Δ3-9 may become a promising therapy for DMD cardiomyopathy., Competing Interests: K.F. is a co-founder and CEO of Heartseed Inc. S.T. is an advisor for Heartseed, Inc. S.T. and K.F. have owned equity in Heartseed, Inc., (© 2023 The Authors.)

Objective: Oncostatin M (OSM) is an inflammatory cytokine belonging to the interleukin-6 family member, which plays an important role in various cardiovascular diseases. We recently reported increased serum OSM levels in patients with coronary artery disease. However, the specific role in HF with ischemic heart disease (IHD) remains unclear., Methods and Results: A total of 120 patients with HF and 48 control subjects were enrolled in this study. Serum OSM levels were measured using a sandwich technique immunoassay during the compensated state. The results revealed significantly higher serum OSM levels in HF patients compared to controls. Importantly, HF patients with IHD had higher OSM levels, and those with collateral flow showed the even higher levels, indicating a potential involvement in angiogenesis. Furthermore, a positive correlation was found between serum OSM levels and levels of vascular endothelial growth factor (VEGF). In vitro experiments demonstrated that recombinant OSM upregulated VEGF production in cultured human coronary artery endothelial cells. We additionally observed that endogenous OSM levels were enhanced through exercise. Lastly, we identified the potential of SGLT2 inhibitors to enhance OSM production., Conclusions: Serum OSM levels were elevated in HF patients, particularly in those with IHD Our data indicated that endogenous OSM induces VEGF production in the heart, suggesting the activation of angiogenesis, which can be further enhanced by exercise or SGLT2 inhibitors., Competing Interests: The authors declare that there are no conflicts of interest associated with this study., (© 2023 The Authors.)

Background: Surgical site infection following spinal surgery causes prolonged delay in recovery after surgery, increases cost, and sometimes leads to additional surgical procedures. We investigated risk factors for the occurrence of surgical site infection events in terms of patient-related, surgery-related, and postoperative factors., Methods: This retrospective study included 1000 patients who underwent spinal surgery in our hospital between April 2016 and March 2019., Results: Patient-related factors were dementia, length of preoperative hospital stay (≥ 14 days), and diagnosis at the time of surgery (traumatic injury or deformity). The one surgery-related factor was multilevel surgery (≥ 9 intervertebral levels), and the one postoperative factor was time to ambulation (≥ 7 days) were statistically significant risk factors for spinal surgical site infection., Conclusion: One risk factor identified in this study that is amenable to intervention is time to ambulation. As delayed ambulation is a risk factor for postoperative surgical site infection, how medical staff can intervene in postoperative ambulation to further reduce the incidence of surgical site infection is a topic for future research.

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to treat heart diseases; however, the optimal maturity of hiPSC-CMs for effective regenerative medicine remains unclear. We aimed to investigate the benefits of long-term cultured mature hiPSC-CMs in injured rat hearts., Methods: Cardiomyocytes were differentiated from hiPSCs via monolayer culturing, and the cells were harvested on day 28 or 56 (D28-CMs or D56-CMs, respectively) after differentiation. We transplanted D28-CMs or D56-CMs into the hearts of rat myocardial infarction models and examined cell retention and engraftment via in vivo bioluminescence imaging and histological analysis. We performed transcriptomic sequencing analysis to elucidate the genetic profiles before and after hiPSC-CM transplantation., Results: Upregulated expression of mature sarcomere genes in vitro was observed in D56-CMs compared with D28-CMs. In vivo bioluminescence imaging studies revealed increased bioluminescence intensity of D56-CMs at 8 and 12 weeks post-transplantation. Histological and immunohistochemical analyses showed that D56-CMs promoted engraftment and maturation in the graft area at 12 weeks post-transplantation. Notably, D56-CMs consistently promoted microvessel formation in the graft area from 1 to 12 weeks post-transplantation. Transcriptomic sequencing analysis revealed that compared with the engrafted D28-CMs, the engrafted D56-CMs enriched genes related to blood vessel regulation at 12 weeks post-transplantation. As shown by transcriptomic and western blot analyses, the expression of a small heat shock protein, alpha-B crystallin (CRYAB), was significantly upregulated in D56-CMs compared with D28-CMs. Endothelial cell migration was inhibited by small interfering RNA-mediated knockdown of CRYAB when co-cultured with D56-CMs in vitro. Furthermore, CRYAB overexpression enhanced angiogenesis in the D28-CM grafts at 4 weeks post-transplantation., Conclusions: Long-term cultured mature hiPSC-CMs promoted engraftment, maturation and angiogenesis post-transplantation in infarcted rat hearts. CRYAB, which was highly expressed in D56-CMs, was identified as an angiogenic factor from mature hiPSC-CMs. This study revealed the benefits of long-term culture, which may enhance the therapeutic potential of hiPSC-CMs., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Lumbar spinal stenosis (LSS) can interfere with daily life and quality of life (QOL). Evaluating physical function and QOL and helping patients to improve is the focus of rehabilitation. Phase angle (PhA) assessment is widely used to measure body composition and is considered an indicator of physical function and QOL. This study investigated the relationship between PhA and physical function, physical activity, and QOL in patients with LSS. PhA, handgrip strength, walking speed, Timed Up and Go test (TUG), Life Space Assessment (LSA), Prognostic Nutritional Index (PNI), Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), and EQ-5D were assessed and statistically analyzed. The study included 133 patients with LSS. Multiple regression analysis of PhA adjusted for age, sex, and body mass index (Model 1) and for Model 1 + PNI (Model 2) showed significant correlations (P < 0.05) with handgrip strength, walking speed, TUG, and LSA. Regarding QOL, PhA was significantly correlated (P < 0.05) with lumbar function in JOABPEQ. PhA was associated with physical function and QOL in patients with LSS and might be a new clinical indicator in this population., (© 2023. Springer Nature Limited.)

The NUP98::NSD1 fusion gene is associated with extremely poor prognosis in patients with acute myeloid leukemia (AML). NUP98::NSD1 induces self-renewal and blocks differentiation of hematopoietic stem cells, leading to development of leukemia. Despite its association with poor prognosis, targeted therapy for NUP98::NSD1-positive AML is lacking, as the details of NUP98::NSD1 function are unknown. Here, we generated 32D cells (a murine interleukin-3 (IL-3)-dependent myeloid progenitor cell line) expressing mouse Nup98::Nsd1 to explore the function of NUP98::NSD1 in AML, including comprehensive gene expression analysis. We identified two properties of Nup98::Nsd1 + 32D cells in vitro. First, Nup98::Nsd1 promoted blocking of AML cell differentiation, consistent with a previous report. Second, Nup98::Nsd1 increased dependence on IL-3 for cell proliferation, due to overexpression of the alpha subunit of the IL-3 receptor (IL3-RA, also known as CD123). Consistent with our in vitro data, IL3-RA was also upregulated in samples from patients with NUP98::NSD1-positive AML. These results highlight CD123 as a potential new therapeutic target in NUP98::NSD1-positive AML., (© 2023. Japanese Society of Hematology.)

For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 10 4 /μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3-24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 10 5 /μL; p = 0.022) or low CD4/CD8 ratios (

Pediatric acute myeloid leukemia (AML) is a poor prognostic subtype of pediatric leukemia. However, the detailed characteristics of many genetic abnormalities are yet to be established in this disease. Although TP53 and RB1 are established as representative tumor suppressor genes in various cancers, alterations of these two genes, especially RB1, have not been characterized in pediatric AML. We performed next-generation sequencing in 328 pediatric AML patients from the Japanese AML-05 trial to ascertain TP53 and RB1 alterations, and their prognostic implications. We identified seven patients with TP53 alterations (2.1%) and six patients with RB1 alterations (1.8%). These alterations were found in only patients without RUNX1::RUNX1T1, CBFB::MYH11, or KMT2A rearrangements. TP53 and RB1 were frequently co-deleted with their neighboring genes PRPF8 and ELF1, respectively. Patients with TP53 alterations had significantly lower 5-year overall survival (OS; 14.3% vs. 71.4%, p < 0.001) and lower 5-year event-free survival (EFS; 0% vs. 56.3%, p < 0.001); similarly, patients with RB1 had significantly lower 5-year OS (0% vs. 71.8%, p < 0.001) and lower 5-year EFS (0% vs. 56.0%, p < 0.001) when compared to patients without these alterations. In gene expression analyses, oxidative phosphorylation, glycolysis, and protein secretion were upregulated in patients with TP53 and/or RB1 alterations. Additionally, Kaplan-Meier analysis revealed that high expressions of SLC2A5, KCNAB2, and CD300LF were related to poor OS of non-core-binding factor AML patients (p < 0.001, p = 0.001, and p = 0.021, respectively). This study will contribute to the development of risk-stratified therapy and precision medicine in pediatric AML., (© 2023 Wiley Periodicals LLC.)

Background: Massive rotator cuff tears (RCTs) are complicated by muscle atrophy, fibrosis, and intramuscular fatty degeneration, which are associated with postoperative tendon-to-bone healing failure and poor clinical outcomes. We evaluated muscle and enthesis changes in large tears with or without suprascapular nerve (SN) injury in a rat model., Methods: Sixty-two adult Sprague-Dawley rats were divided into SN injury (+) and SN injury (-) groups (n=31 each), comprising tendon (supraspinatus [SSP]/infraspinatus [ISP]) and nerve resection and tendon resection only cases, respectively. Muscle weight measurement, histological evaluation, and biomechanical testing were performed 4, 8, and 12 weeks postoperatively. Ultrastructural analysis with block face imaging was performed 8 weeks postoperatively., Results: SSP/ISP muscles in the SN injury (+) group appeared atrophic, with increased fatty tissue and decreased muscle weight, compared to those in the control and SN injury (-) groups. Immunoreactivity was only positive in the SN injury (+) group. Myofibril arrangement irregularity and mitochondrial swelling severity, along with number of fatty cells, were higher in the SN injury (+) group than in the SN injury (-) group. The bone-tendon junction enthesis was firm in the SN injury (-) group; this was atrophic and thinner in the SN injury (+) group, with decreased cell density and immature fibrocartilage. Mechanically, the tendon-bone insertion was significantly weaker in the SN injury (+) group than in the control and SN injury (+) groups., Conclusions: In clinical settings, SN injury may cause severe fatty changes and inhibition of postoperative tendon healing in large RCTs. Level of evidence: Basic research, controlled laboratory study.

A hybrid training system (HTS) combining antagonist muscle electrical stimulation and voluntary muscle contraction has been developed using eccentric antagonist muscle contractions with electrical stimulation as resistance to voluntary muscle contractions. We devised an exercise method using HTS combined with a cycle ergometer (HCE). The purpose of this study was to compare the muscle strength, muscle volume, aerobic functions and lactate metabolism of HCE and a volitional cycle ergometer (VCE). A total of 14 male participants performed exercise on a bicycle ergometer for 30 min per session, 3 times per week for 6 weeks. We divided 14 participants into an HCE group (7 participants) and a VCE group (7 participants). The workload was set at 40% of each participant's peak oxygen uptake (V.O 2 peak). Electrodes were placed over each motor point on the quadriceps and hamstrings. The V.O 2 peak and anaerobic threshold significantly increased before and after training when using HCE rather than VCE. The HCE group had significantly increased extension and flexion muscle strength at 180 degrees/s in post-training measurements over pre-training measurements. Knee flexion muscle strength at 180 degrees/s tended to increase in the HCE group compared to the VCE group. The quadricep muscle cross-sectional area was significantly increased in the HCE group compared to the VCE group. Additionally, the HCE group had significantly decreased maximal lactate, measured every 5 min during exercise at the end of study, between pre and post-training. Thus, HCE may be a more effective training method for muscle strength, muscle mass and aerobic functions at 40% of each participant's V.O 2 peak than conventional cycling exercise. HCE could be applied not only as aerobic exercise but also as resistance training.

Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae., (© 2022. The Author(s).)

The prognosis of pediatric acute myeloid leukemia (AML) has improved via stratification therapy. However, relapse or death occurs in 30%-40% of cases. Novel genetic factors for pediatric AML need to be elucidated to improve prognosis. We detected recurrent internal tandem duplication in upstream binding transcription factor (UBTF-ITD) in 1.2% (6/503) of Japanese pediatric patients with de novo AML. No UBTF-ITD was detected in 175 adult patients with AML or in 65 cell lines that included 15 AML, 39 acute lymphoblastic leukemia, five chronic myeloid leukemia, and six neuroblastoma cell lines. All UBTF-ITDs were found in exon 13 and shared a duplicated region. UBTF-ITD was more frequently detected in patients with trisomy 8, FLT3-ITD, WT1 mutation, and/or high PRDM16 expression (trisomy 8, 3/6; FLT3-ITD, 5/6; WT1 mutation, 2/6; and high PRDM16 expression, 6/6). Gene expression patterns of patients with UBTF-ITD were similar to those of patients with NUP98::NSD1 or FUS::ERG. Survival analysis of the AML-05 cohort revealed that patients with UBTF-ITD had worse outcomes than those without UBTF-ITD (3-year event-free survival, 20% vs. 55%; 3-year overall survival, 40% vs. 74%). Moreover, among the 27 patients with trisomy 8, all three patients with UBTF -ITD had a poor prognosis resulting in early events (relapse or non-complete remission) within 1 year. Our findings suggest that UBTF-ITD may be a novel and significant prognostic factor for pediatric patients with AML., (© 2022 Wiley Periodicals LLC.)

Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed that receptor activator of NF-κB ligand (RANKL)-mediated osteoclast induction is an important component of bone destruction in RA. Synovial fibroblasts are the crucial producers of RANKL in the RA synovium; novel analytical techniques, primarily, single-cell RNA sequencing, have confirmed that synovial fibroblasts include heterogeneous subsets of both pro-inflammatory and tissue-destructive cell types. The heterogeneity of immune cells in the RA synovium and the interaction of synovial fibroblasts with immune cells have recently received considerable attention. The current review focused on the latest findings regarding the crosstalk between synovial fibroblasts and immune cells, and the pivotal role played by synovial fibroblasts in joint destruction in RA.

Increased liver stiffness and insulin resistance are important therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD). A hybrid training system (HTS) has been developed which combines application of electrical stimulation and volitional contractions. We compared the effect of walking exercise (5.6 km/h) both with and without simultaneous HTS on liver stiffness and insulin resistance. In a single-blind, controlled trial, 32 subjects with NAFLD were randomized to 12 weeks of triweekly 30 minute walking exercise with either HTS (HTS group) or without HTS (control group). Transient elastography for the assessment of liver stiffness, body weight, visceral fat, the homeostasis model assessment of insulin resistance, fasting blood glucose, serum aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase were evaluated. Data were evaluated using the linear model after adjusting the baseline value. In the subjects with BMI of 27 kg/m 2 or more, the decrement of transient elastography in the HTS group was significantly larger than in the control group (mean ± standard error: Δ2.13 ± 0.64 kPa vs. Δ-0.67 ± 0.42 kPa, p=0.0009). There were no significant differences between groups in other endpoints. These results showed that simultaneously combining electrical stimulation with walking exercise could potentially improve liver stiffness in people who have NAFLD. In fact, because the exercise effect was increased by HTS without increasing the walking speed, this HTS could be especially useful for obese or overweight subjects, in whom NAFLD and joint problems often coexist. However, its effects on insulin resistance and body composition were not clear.

Background Context: Platelet-rich plasma (PRP) can accelerate bone union in spinal fusion surgery with an autogenous bone graft. However, it is unclear whether bone union can be obtained by using artificial bone and PRP together in spinal interbody fusion surgery., Purpose: This study aimed to determine whether interbody fusion can be achieved by transplanting porous hydroxyapatite/collagen(HAp/Col) which is an artificial bone material frequently used in spinal fusion surgery, together with PRP in the intervertebral disc space in rats., Study Design and Setting: A controlled laboratory study., Methods: A total of fourty 10-week old Sprague-Dawley rats were used in this study and assigned to three groups as follow: disc curettage only (control group, n=10), disc curettage + HAp/Col transplant (H group, n=10), and disc curettage + HAp/Col + PRP transplant (H+P group, n=10). The other 10 rats were sacrificed as blood donors for acquisition of PRP. Microcomputed tomography (μCT) examinations were performed to evaluate bone union, bone volume (BV), and bone mineral density (BMD) at 4, 8, and 12 weeks following surgery. Twelve weeks postoperatively, each group of three of L4-L5 spines was harvested to perform histological examination (hematoxylin & eosin stain) and the others were subjected to biomechanical testing (compression properties)., Results: The platelet count in PRP was approximately 4.1 times greater than that in whole blood (260.6±26.2 × 10 4 mg/dL and 64.3±2.9 × 10 4 mg/dL in PRP and whole blood, respectively). All the L4-L5 lumbar discs were fused in the H+P group, whereas only one case was fused in the H group and none in the control group at 12 weeks after surgery. BV was significantly higher in the H+P group than in the H group or control groups (both p<.01), although BMD was not significantly different among the three groups. Upon histological analysis, mature bone formation was observed at the transplanted space in all cases in the H+P group, whereas fibrous tissue was observed at the location in the H and control groups. Regarding biomechanical properties, the ultimate load to failure was significantly higher in the H+P group than in the H group or control group (p=.021 and .013, respectively), although stiffness was not significantly different between the three groups., Conclusion: The combination of porous HAp/Col and PRP at an appropriate concentration can promote bone union in the intervertebral disc space without using an autologous bone graft in the rat model. Bone tissue formation was histologically confirmed, and it was mechanically strong., Clinical Significance: This preclinical study showed that porous HAp/Col, when combined with PRP at an appropriate concentration, can induce bone union without autologous bone grafts. The results may eliminate the need for autologous bone collection for spinal fusion surgery in the future., Competing Interests: Declaration of competing interest No funding was received for this work and the authors have no conflict of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Pediatric acute myeloid leukemia (AML) is a heterogeneous disease with various genetic abnormalities. Recent advances in genetic analysis have enabled the identification of causative genes in > 90% of pediatric AML cases. Fusion genes such as RUNX1::RUNX1T1, CBFB::MYH11, and KMT2A::MLLT3 are frequently detected in > 70% of pediatric AML cases, whereas FLT3-internal tandem duplication, CEBPA-bZip, and NPM1 mutations are detected in approximately 5-15% of cases, respectively. Conversely, mutations in DNMT3A, TET2, and IDH, which are common in adults, are extremely rare in pediatric AML. The genetic characteristics of pediatric AML are slightly different from those of adult AML. For accurate risk stratification and treatment intensity, genome analysis should be performed in a simple, fast, and inexpensive manner and the results should be returned to patients in real time. As with acute lymphoblastic leukemia, the presence or absence of minimal residual disease is an important factor in determining the success of treatment against AML, and it is important to predict prognosis and formulate treatment strategies considering the genetic abnormalities. For the development and clinical application of new molecularly targeted therapies based on identified genetic abnormalities, it is necessary to explore when and in which combinations drugs will be most effective., (© 2023. Japanese Society of Hematology.)

The frequency of the manufacturing failure of chimeric antigen receptor (CAR)-T cell therapy in clinical practice is unknown. To clarify the current state of how likely CAR-T cell production is to succeed or fail for B-cell acute lymphoblastic leukemia (B-ALL), we analyzed cases in which the production of tisagenlecleucel was performed for patients with B-ALL at 15 facilities in Japan from October 2019 to March 2022. Total 81 patients (47 males and 34 females) were analyzed. The median age at apheresis was 13 years (1-25) with a median number of prior treatments of 4 (1-9). The numbers of patients with histories of allogeneic transplantation, inotuzumab ozogamicin, or blinatumomab treatments were 51 (63.0%), 26 (32.1%), and 37 (45.7%), respectively. The median blast percentage and CD3 + cell counts in peripheral blood were 0% (0-91.5), and 611/µl (35-4,210) at apheresis, and the median number of CD3 + cells shipped was 2.2×10 9 (0.5-8.3). While cases with a history of heavy prior treatment before apheresis were included, no manufacturing failures were observed. Continuing to monitor the status of manufacturing failures is necessary as the number of B-ALL cases treated with CAR-T cell therapy increases.

Induced pluripotent stem cell (iPSC)-based disease model is a useful tool that can represent the pathophysiology of patient organs that are inaccessible due to invasiveness. Here, we present a method to induce differentiation of Duchenne muscular dystrophy (DMD) patient-derived iPSCs into cardiomyocytes and restore dystrophin expression by exon skipping using antisense nucleic acids. This involves a 20-day multi-step culture process for differentiation to cardiomyocytes, followed by exon-skipping experiments. Additionally, RT-PCR, western blotting, and immunocytochemistry are used to confirm the restoration of dystrophin expression., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Advances in stem cell biology have facilitated cardiac regeneration, and many animal studies and several initial clinical trials have been conducted using human pluripotent stem cell-derived cardiomyocytes (PSC-CMs). Most preclinical and clinical studies have typically transplanted PSC-CMs via the following two distinct approaches: direct intramyocardial injection or epicardial delivery of engineered heart tissue. Both approaches present common disadvantages, including a mandatory thoracotomy and poor engraftment. Furthermore, a standard transplantation approach has yet to be established. In this study, we tested the feasibility of performing intracoronary administration of PSC-CMs based on a commonly used method of transplanting somatic stem cells. Six male cynomolgus monkeys underwent intracoronary administration of dispersed human PSC-CMs or PSC-CM aggregates, which are called cardiac spheroids, with multiple cell dosages. The recipient animals were sacrificed at 4 weeks post-transplantation for histological analysis. Intracoronary administration of dispersed human PSC-CMs in the cynomolgus monkeys did not lead to coronary embolism or graft survival. Although the transplanted cardiac spheroids became partially engrafted, they also induced scar formation due to cardiac ischemic injury. Cardiac engraftment and scar formation were reasonably consistent with the spheroid size or cell dosage. These findings indicate that intracoronary transplantation of PSC-CMs is an inefficient therapeutic approach., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: This study aimed to compare the effects of the standing low-frequency vibration exercise device (SLVED) and walking training on balance ability on an unstable surface in community-dwelling elderly people., Methods: Thirty-eight older adults were randomly allocated to the SLVED sessions: the intervention group (n = 19), and the walking sessions: the control group (n = 19). Each group session lasted 20 min and was performed twice a week for 12 weeks. Standing balance was assessed by the change in center-of-gravity sway of the participant standing on foam rubber with eyes open (EO) and eyes closed (EC). The primary outcome measures were the root mean square (RMS) values of the center of foot pressure in the mediolateral and anteroposterior directions and the RMS area. Secondary outcome measures were the results of the 10-m walking time test (10 MWT), five-times sit-to-stand (5T-STS) test, and timed up-and-go (TUG) test., Results: Analysis of variance showed a significant group × time interaction for the TUG test. Significant improvements were observed in Y-RMS for EO condition; RMS, X-RMS, Y-RMS, and RMS area for EC condition; and 10 MWT, 5T-STS test, and TUG test for the main effect of the time factor., Conclusion: SLVED for intervention in community-dwelling older adults showed a greater improvement than walking training in the TUG test. In addition, SLVED improved the Y-RMS for the EO condition on foam rubber; RMS, X-RMS, Y-RMS, and RMS area for the EC condition on foam rubber in standing balance; and the 10 MWT and 5T-STS test, suggesting that it has similar effects to walking training., Competing Interests: Yoshio Takano received research funding and materials from Cotoho Co., Ltd. The other authors have no conflicts of interest to declare., (©2023 Japanese Society of Physical Therapy.)

The purpose of this study is to establish a treatment with appropriate intensity for children (<16 years old at diagnosis) with de novo acute myeloid leukemia (excluding acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome) according to a risk stratification based on recurrent leukemic cytogenetic abnormalities and flow-cytometric minimal residual disease at end of initial induction chemotherapy and to validate the safety and efficacy of gemtuzumab ozogamicin (GO)-combined post-induction chemotherapy for the non-low-risk (non-LR) patients. The primary endpoint of this phase III study is three-year disease-free survival rate, which will be compared between the GO and non-GO arms of the non-LR (intermediate-risk and high-risk [HR]) patients. All HR patients will be allocated to allogeneic hematopoietic stem cell transplantation in first remission. This trial has been registered at the Japan Registry of Clinical Trials (jRCTs041210015)., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Preventing falls in patients is one of the most important concerns in acute hospitals. Balance disorder and hypnotic drugs lead to falls. The Standing Test for Imbalance and Disequilibrium (SIDE) is developed for the evaluation of static standing balance ability. There have been no reports of a comprehensive assessment of falls risk including hypnotic drugs and SIDE. The purpose of this study was to investigate the fall rate of each patient who took the hypnotic drug and the factor associated with falls., Methods: Fall rates for each hypnotic drug were calculated as follows (number of patients who fell/number of patients prescribed hypnotic drug x 100). We investigated the hypnotic drugs as follows; benzodiazepine drugs, Z-drugs, melatonin receptor agonists, and orexin receptor antagonists. Hypnotic drug fall rate was analyzed using Pearson's chi-square test. Decision tree analysis is the method we used to discover the most influential factors associated with falls., Results: This study included 2840 patients taking hypnotic drugs. Accidents involving falls were reported for 211 of inpatients taking hypnotic drugs. Z-drug recipients had the lowest fall rate among the hypnotic drugs. We analyzed to identify independent factors for falls, a decision tree algorithm was created using two divergence variables. The SIDE levels indicating balance disorder were the initial divergence variable. The rate of falls in patients at SIDE level ≦ 2a was 14.7%. On the other hand, the rate of falls in patients at SIDE level ≧ 2b was 2.9%. Gender was the variable for the second classification. In this analysis, drugs weren't identified as divergence variables for falls., Conclusion: The SIDE balance assessment was the initial divergence variable by decision tree analysis. In order to prevent falls, it seems important not only to select appropriate hypnotic drugs but also to assess patients for balance and implement preventive measures., Competing Interests: We have declared that no competing interests exist.