HLA-matched related peripheral blood stem cell and bone marrow transplantation with RIC regimens yield comparable outcomes for adult AML.

Introduction: Understanding differences in clinical outcomes between PBSCT and BMT is important, and this study compared outcomes of HLA-matched related PBSCT and BMT using reduced-intensity conditioning (RIC) in adult acute myeloid leukemia (AML) patients.

Methods: Data from 402 patients who underwent either PBSCT ( = 294) or BMT ( = 108) between 2000 and 2022 were analyzed using the Japanese nationwide registry database. The primary endpoint was overall survival (OS), and secondary endpoints included disease-free survival (DFS), non-relapse mortality (NRM), and GVHD.

Myeloablative conditioning in cord blood transplantation for acute myeloid leukemia patients is efficacious only until age 55.

Umbilical cord blood transplantation (CBT) is accepted as an effective treatment for acute myeloid leukemia (AML), and reduced-intensity conditioning (RIC), rather than myeloablative conditioning (MAC) regimens allowed elderly patients to be treated safely. However, appropriate intensities of conditioning regimens are still unclear, especially for middle-aged patients. To compare outcomes after RIC and MAC regimens, we analyzed AML patients aged 16 years or older in the Japanese registry database, who underwent single cord unit CBT between 2010-2019.

Analysis of synthetic polymer hydrogel-based generation of leukemia stem cells.

Leukemia stem cells (LSCs), capable of simultaneous self-renewal and differentiation, are resistant to chemotherapy and the cause of relapse in refractory cases of leukemia. As a method to rapidly generate LSCs has not been established, research on LSCs as therapeutic targets has been hampered. Here, we demonstrate that K562 leukemia cells acquired LSC properties with increase in stemness markers such as CD34, Oct3/4, and Nanog and metabolic alterations towards OXPHOS by culturing cells on synthetic polymer hydrogels.

In-silico simultaneous respiratory and circulatory measurement during voluntary breathing, exercise, and mental stress: A computational approach.

Voluntary breathing (VB), short-term exercise (STE), and mental stress (MS) can modulate breathing rate (BR), heart rate (HR), and blood pressure (BP), thereby affecting human physical and mental state. While existing experimental studies have explored the relationship between VB, STE, or MS and BR, HR, and BP changes, their findings remain fragmented due to individual differences and challenges in simultaneous, BR, HR, and BP measurements. We propose a computational approach for in-silico simultaneous measurements of the physiological values by comprehensive prediction of the respiratory and circulatory system responses to VB, STE, or MS.

Comparison of busulfan pharmacokinetics between four-times-daily and once-daily administration in pediatric patients: a preliminary prospective observational trial.

Therapeutic drug monitoring (TDM) of busulfan (BU) is useful for achieving the target area under the curve (AUC) because its effective plasma-concentration range is narrow. This preliminary observational study evaluated the pharmacokinetic (PK) parameters of BU administered four times daily or once daily to pediatric patients. The plasma concentrations were measured at both the test dose and first dose, and the doses on day 1 and days 2-4 were determined based on each TDM.

Real-world Outcomes of Commercial Tisagenlecleucel for Children, Adolescents, and Young Adults With Acute Lymphoblastic Leukemia in Japan.

Chimeric antigen receptor (CAR) T cells are a major new treatment option for children, adolescents, and young adults (CAYA) patients with relapsed and refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). Therefore, accumulating evidence from real-world experiences of CAR-T outcomes in various regions worldwide is important, particularly when comparing outcomes of patients with differing medical and ethnic backgrounds. More than 5 years have passed since tisagenlecleucel was approved in Japan.

FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with genetic alterations. The FMS-like tyrosine kinase 3 (FLT3) gene is frequently mutated in adult de novo AML, with two types of mutations: internal tandem duplication (ITD) and point mutations in the tyrosine kinase domain. This study aimed to investigate the impact of FLT3 inhibitors and hematopoietic cell transplantation (HCT) on survival outcomes in patients with FLT3-ITD AML in a real-world setting.

Inhibition of amyloid β aggregation and BACE1, and protective effect on SH-SY5Y cells, by p-terphenyl compounds from mushroom Thelephora aurantiotincta.

The number of patients with Alzheimer's disease (AD) is expected to increase as the population ages. The amyloid cascade hypothesis is proposed as the pathogenic mechanism of AD. We report the isolation and structural determination of three new p-terphenyl compounds, thelephantin P (1), thelephantin Q (2), and thelephantin R (3), with four known compounds (4-7), from the fruiting bodies of Thelephora aurantiotincta Corner.

Increased response to granulocyte-macrophage colony-stimulating factor in peripheral blood cells and transient manifestations mimicking juvenile myelomonocytic leukemia in a male patient with NEMO deficiency caused by a deep intronic pathogenic variant of IKBKG.

X-linked NF-κB essential modulator (NEMO) deficiency is a primary immunodeficiency characterized by combined immunodeficiency and ectodermal dysplasia. Monocytes from the patients demonstrate a severely impaired response to tissue necrosis factor or lipopolysaccharide, whereas hyper-inflammation is found in some patients. Juvenile myelomonocytic leukemia (JMML) is a pediatric malignancy caused by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and aberrant RAS signaling activation.

Mixture Theory-Based Finite Element Approach for Analyzing the Edematous Condition of Biological Soft Tissues.

In hydrated soft biological tissues experiencing edema, which is typically associated with various disorders, excessive fluid accumulates and is encapsulated by impermeable membranes. In certain cases of edema, an indentation induced by pressure persists even after the load is removed. The depth and duration of this indentation are used to assess the treatment response.

The RNA helicases DDX19A/B modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export in leukemia cells.

Selinexor, a first-in-class exportin1 (XPO1) inhibitor, is an attractive anti-tumor agent because of its unique mechanisms of action; however, its dose-dependent toxicity and lack of biomarkers preclude its wide use in clinical applications. To identify key molecules/pathways regulating selinexor sensitivity, we performed genome-wide CRISPR/Cas9 dropout screens using two B-ALL lines. We identified, for the first time, that paralogous DDX19A and DDX19B RNA helicases modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export.

Allogeneic Hematopoietic cell Transplantation Using Alemtuzumab in Asian Patients with Inborn Errors of Immunity.

Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months.

Groundwater dynamics on small carbonate islands: Insights from radiocarbon and stable isotopes in Kikai Island, Southwest Japan.

Groundwater, the world's largest freshwater resource, faces significant challenges due to the overexploitation and depletion of aquifers in the 21st century. Small island groundwater aquifers are particularly valuable, and a scientific understanding of the behavior of subsurface water systems is vital. A comprehensive study using radiocarbon, stable oxygen isotopes, stable hydrogen isotopes, and hardness analysis (ΔC, δO, δD, Ca, Mg) of groundwater was conducted in Kikai Island, a southern island in the Amami archipelago, Japan.

Dominant-negative type of IKZF1 deletion showed a favorable prognosis in adult B-cell acute lymphoblastic leukemia.

IKZF1 deletion is a recurrent genomic alteration in B-cell acute lymphoblastic leukemia (B-ALL) and is divided into dominant-negative (DN) and loss of function (LOF) deletions. The prognostic impact of each deletion has not been fully elucidated. We retrospectively analyzed 117 patients with adult B-ALL including 60 patients with BCR::ABL1-positive B-ALL and 57 patients with BCR::ABL1-negative B-ALL by the fluorescence in situ hybridization (FISH) method for IKZF1 deletion and multiplex PCR for the 4 most common IKZF1 deletions (∆4-7, ∆2-7, ∆2-8, and ∆4-8).

[Clinical characteristics and outcomes of childhood B-ALL with ZNF384 and MEF2D rearrangements].

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has many subtypes with diverse clinical and biological features and outcomes. Next generation sequencing has revealed several novel subtypes, including the ZNF384 and MEF2D rearrangements. The clinical characteristics and outcomes of the largest series of BCP-ALL cases with ZNF384 and MEF2D rearrangements in an international collaborative study are described here.

Impact of MRD on clinical outcomes of unrelated hematopoietic stem cell transplantation in patients with Ph ALL: A retrospective nationwide study.

Measurable residual disease (MRD) status before transplantation has been shown to be a strong prognostic factor in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL). However, the outcomes of unrelated hematopoietic stem cell transplantation based on the MRD status have not been fully investigated. In this retrospective study, we compared the outcomes of 715 consecutive adults with Ph ALL in complete remission who underwent unrelated cord blood transplantation (UCBT) (single-unit UCBT, n = 232 [4/6, 5/6, and 6/6 HLA match]), HLA-matched unrelated bone marrow transplantation (UBMT; n = 292 [8/8 HLA match]), or HLA-mismatched UBMT (n = 191 [7/8 HLA match]).

Design and synthesis of 4-acetoxypentanamide derivatives of spliceostatin A and their biological evaluation towards prostate cancer treatment.

We designed and synthesized novel 4-acetoxypentanamide derivatives of spliceostatin A, whose 4-acetoxypentenamide moiety is reduced (7), isomerized (8), or substituted with methyl at the α-position (9). The results of biological evaluation against AR-V7 and the docking analysis of each derivative suggest that the geometry of the 4-acetoxypentenamide moiety of spliceostatin A is important for its biological activity.

Respiratory entrainment of the locus coeruleus modulates arousal level to avoid physical risks from external vibration.

Slow rocking chairs can easily put people to sleep, while violent shaking, such as during earthquakes, may lead to rapid awakening. However, the influence of external body vibrations on arousal remains unclear. Herein, a computational model of a locus coeruleus (LC)-norepinephrine (NE) system and cardio-respiratory system were used to show that respiratory entrainment of the LC modulates arousal levels, which is an adaptation to avoid physical risks from external vibration.

Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance.

To identify molecules/pathways governing Venetoclax (VEN) sensitivity, we performed genome-wide CRISPR/Cas9 screens using a mouse AML line insensitive to VEN-induced mitochondrial apoptosis. Levels of sgRNAs targeting March5, Ube2j2 or Ube2k significantly decreased upon VEN treatment, suggesting synthetic lethal interaction. Depletion of either Ube2j2 or Ube2k sensitized AML cells to VEN only in the presence of March5, suggesting coordinate function of the E2s Ube2j2 and Ube2k with the E3 ligase March5.

HTLV-1 bZIP factor impairs DNA mismatch repair system.

Adult T-cell leukemia (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). Microsatellite instability (MSI) has been observed in ATL cells. Although MSI results from impaired mismatch repair (MMR) pathway, no null mutations in the genes encoding MMR factors are detectable in ATL cells.

Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study.

Mutation status of FLT3, NPM1, and CEBPA is used to classify the prognosis of acute myeloid leukemia, but its significance in patients with cytogenetically normal (CN) AML is unclear. We prospectively analyzed these genes in 295 patients with CN-AML and identified 76 (25.8%) FLT3-ITD, 113 (38.