BACKGROUND:Acute graft-versus-host disease (aGVHD), which is primarily driven by donor alloreactive T cells, is a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Daphnetin (DAPH) shows potent immunosuppressive activity by inhibiting T cell proliferation and function. However, its efficacy in preventing aGVHD remains unexplored. This study aimed to investigate the prophylactic effects of DAPH against aGVHD in murine allo-HCT models and to characterize the underlying mechanisms. MATERIALS AND METHODS:Multiple murine allo-HCT models were established to evaluate the effects of DAPH on aGVHD progression, the graft-versus-leukemia (GVL) effect, and donor immune/hematopoietic cell recovery. Flow cytometry was employed to determine cell proliferation, immune cell alterations, apoptosis profiles, and serum cytokine levels. RNA sequencing and quantitative proteomics analyses were conducted to explore the underlying molecular mechanisms. RESULTS:DAPH significantly mitigated murine aGVHD following allo-HCT, showing efficacy comparable to that of cyclophosphamide. Notably, DAPH administration did not compromise the GVL effect while transiently delaying the recovery of donor hematopoietic cells. Mechanistically, DAPH inhibited the expansion of multiple donor immune cells, preferentially suppressing the proliferation and functioning of donor conventional T cells. The potential molecular mechanisms underlying the prophylactic efficacy of DAPH against aGVHD after allo-HCT included suppression of the T cell receptor and Janus kinase 3 (JAK3)/signal transducer and activator of transcription 3 (STAT3) signaling pathways. CONCLUSION:These findings indicate that DAPH effectively mitigates aGVHD while maintaining the GVL effect and showing minimal influence on donor immune/hematopoietic cell reconstitution. Thus, DAPH is a promising candidate for aGVHD prophylaxis.

IntroductionLeukemia is a clonal malignant proliferative disease originating from hematopoietic stem cells. Although its treatment strategy has gradually developed from traditional chemotherapy to a multimodal treatment system including novel targeted therapy and immunotherapy, primary drug resistance in particular remains the core clinical problem leading to poor patient prognosis. This clinical dilemma indicates that the traditional genotyping system based on genomics has not been able to fully resolve the molecular heterogeneity of acute myeloid leukemia (AML), and it is urgent to establish a precise stratified model that can dynamically reflect the functional status of tumor cells in the initial stage of treatment.MethodsIn this study, Raman spectroscopy (RS) combined with machine learning algorithm was used to construct a metabolic prognosis prediction model for AML chemotherapy response. Bone marrow single cell Raman spectroscopy data of newly diagnosed AML patients were collected, and the molecular fingerprint was analyzed by principal component analysis linear discriminant analysis (PCA-LDA) and multivariate curve resolute alternating least square method (MCR-ALS).ResultsThe results showed that the PCALDA model achieved complete remission or non-remission (CR/NR) classification through 24 principal components (cumulative variance contribution of 90.1%), the accuracy of external validation was 94.8% (sensitivity 97.9%, specificity 92.0%), and the AUC reached 96.27%. Protein, lipid, nucleic acid and mixed components were decomposed by MCR-ALS, and lipid and nucleic acid metabolic pathways were enriched in NR group (P < 0.001).DiscussionStudies have shown that RS single-cell metabolic fingerprint can decode the metabolic reprogramming features associated with chemotherapy resistance in AML, providing a new marker-free and highly sensitive tool for real-time prognostic stratification and targeted intervention.

Background The objective of this real-world cohort study was to evaluate the efficacy and safety of decitabine versus conventional chemotherapy in the maintenance therapy (MT) of patients with acute myeloid leukemia (AML).Methods Data were collected from 156 consecutive patients diagnosed with AML at our center. All patients achieved complete remission (CR) after 1-2 courses of induction therapy, followed by consolidation with high-dose cytarabine (HiDAC). MT was administered using either decitabine or conventional chemotherapy, while patients who did not receive maintenance served as controls.Results MT significantly improved both relapse-free survival (RFS) and overall survival (OS) in AML patients. However, no significant difference was observed between decitabine and conventional chemotherapy. MT notably prolonged both RFS and OS in the cytogenetic intermediate-risk group, patients without FLT3-ITD mutations, and those achieving CR after one course of induction therapy. The benefits of MT were not influenced by the European Leukemia Net (ELN) risk category, measurable residual disease (MRD) status, or the number of HiDAC courses. Compared with chemotherapy, decitabine maintenance significantly improved RFS and OS in patients who received 3-4 courses of treatment. Additionally, the incidence of adverse reactions was significantly lower in the decitabine group than in the chemotherapy arm.Conclusion MT with either decitabine or chemotherapy can improve outcomes of AML patients in this real-world cohort. Decitabine maintenance exhibits better tolerability compared with chemotherapy and enhances survival in specific patient subgroups.

Existing immunodeficient pig models have demonstrated limited success in supporting robust human haematopoietic engraftment and multilineage differentiation. Here we hypothesize that the targeted deletion of integrin-associated protein (Cd47) in severe combined immunodeficient pigs, with deletions in the X-linked interleukin-2 receptor gamma chain and recombination activating gene 1, would enable long-term haematopoietic engraftment following transplantation with human haematopoietic stem/progenitor cells. In Cd47-deficient pigs, we observed high levels of human haematopoietic chimerism in the blood and spleen, with functional T and B lymphocytes, natural killer and myeloid cells, as well as robust thymopoiesis. Our findings suggest that severe combined immunodeficient pigs with Cd47 deletion represent an improved preclinical model for studying human haematopoiesis, disease mechanisms and therapies, and offer potential as a bioreactor for large-scale production of human immune cells. Targeted deletion of integrin-associated protein CD47 enhances long-term engraftment of human CD34+ cells in immunodeficient pigs lacking IL2RG and RAG2, enabling large-scale production of functional human immune cells.

Luteolin, a natural flavonoid, exerts broad immunomodulatory effects across multiple immune cell populations, positioning it as a promising candidate for treating inflammatory diseases, infections, and cancer. This review synthesizes current evidence on luteolin’s effects on T cells, natural killer (NK) cells, dendritic cells (DCs), macrophages, neutrophils, eosinophils, and basophils. Luteolin promotes the differentiation of regulatory T cells (Tregs) and suppresses pro-inflammatory T helper 17 (Th17) and Th2 responses, thereby restoring immune balance in sepsis, allergies, and autoimmunity. In macrophages, it skews polarization toward the anti-inflammatory M2 phenotype via the signal transducer and activator of transcription 3 (STAT3)/STAT6 and peroxisome proliferator-activated receptor γ (PPARγ) pathways, while inhibiting nuclear factor-κB (NF-κB) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation. Neutrophil functions are dampened by reduced oxidative stress, adhesion molecule expression, and induction of apoptosis. Luteolin may enhance NK-cell cytotoxicity and DC-mediated antigen presentation while curbing eosinophil and basophil activation in allergic disorders. Despite preclinical successes, future research should prioritize mechanistic insights, structural optimization, and clinical translation to unlock luteolin’s full therapeutic potential.

OBJECTIVES:Hematological malignancies (HMs) pose a severe threat to human health and contribute substantially to the disease burden in mainland China and Taiwan. Therefore, understanding their burden is crucial for informed decision-making and the effective allocation of healthcare resources. METHODS:This study utilized the latest data from the Global Burden of Disease 2021 study to describe the epidemiological indices of HMs in mainland China and Taiwan from 1990 to 2021. The future disease burden was projected for the next decade using the Bayesian age-period cohort (BAPC) model. RESULTS:Between 1990 and 2021, mainland China experienced an increase in the prevalence and incidence of leukemia and lymphoma, while the mortality and disability-adjusted life years (DALYs) for these diseases declined. Conversely, Taiwan witnessed an overall increase in the prevalence, incidence, mortality, and DALYs of leukemia over the same period. Additionally, multiple myeloma (MM), myelodysplastic/myeloproliferative neoplasms, and other hematopoietic neoplasms have shown significant increases in prevalence, incidence, mortality, and DALYs in China. While the disease burden of myeloid leukemia decreased in mainland China, that of lymphoid neoplasms (including leukemia, lymphoma, and MM) increased, which was not observed in Taiwan. Predictions from the BAPC model suggest that the incidence of several lymphoid neoplasms and MM is expected to increase in mainland China and Taiwan. CONCLUSIONS:Taiwan continues to face greater challenges in managing HMs compared to mainland China. MM imposes a significant burden on the Chinese population. The findings of this study provide valuable epidemiological insights for optimizing the allocation of medical resources.

Objective:To investigate the molecular characteristics of low-risk acute myeloid leukemia(AML)at recurrence,and analyze the factors affecting retreatment efficacy and prognosis.Methods:A retrospective analysis was conducted on the clinical and laboratory data of 31 patients with newly diagnosed low-risk AML who relapsed during consolidation treatment or follow-up after treatment in our hospital from April 2017 to January 2023.Gene mutations before and after relapse were compared,retreatment efficacy following relapse was evaluated,and univariate and multivariate analyses were performed to identify factors influencing treatment efficacy and prognosis.Results:Gene sequencing results after relapse showed that the most common newly acquired mutation was FLT3-ITD,while RAS mutation detected at initial diagnosis were predisposed to loss of expression during relapse.The median overall survival(OS)after relapse for the entire cohort was 349(170-528)days,with non-hematopoietic stem cell transplantation(HSCT)group and HSCT group demonstrating median survival times of 210(106-314)days and not reached,respectively(P=0.001).Multivariate analysis revealed that age ≥60 years was a significant risk factor for achieving remission after retreatment in initially diagnosed low-risk AML patients who experienced relapse(OR=18.222,95％CI:1.188-279.597,P=0.037).Additionally,DNMT3A mutation was identified as an independent risk factor for OS(HR=13.165,95％CI:2.018-85.877,P=0.007),while HSCT post-relapse demonstrated significant survival benefits(HR=0.133,95％CI:0.025-0.698,P=0.017)and served as an independent protective factor for OS.Conclusion:Relapsed low-risk AML is often associated with loss of RAS and novel mutations in FLT3-ITD.Age ≥ 60 years and DNMT3A mutations were identified as independent adverse factors for achieving subsequent remission and post-relapse survival,respectively,while HSCT significantly improved patient outcomes.

Fms-like tyrosine kinase 3 (FLT3) mutation is one of the most prevalent molecular abnormalities in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (FLT3-ITD) mutation being the major mutated form. AML patients with FLT3-ITD mutations have unfavorable outcomes with chemotherapy alone, while FLT3 inhibitors significantly improve patient prognoses. Recent studies have indicated that FLT3 mutated receptor has different intracellular localization of the protein, which can be specifically targeted. This review summarizes the different intracellular localization of FLT3 protein, and the influence of different positions on downstream signals. When the FLT3 receptor is located on the cell membrane, it mainly activates the downstream RAS/MAPK signaling pathway. However, the FLT3 protein located in the endoplasmic reticulum (ER) mainly activates the STAT5 signaling pathway. The wild-type FLT3 receptor is mainly located on the cell membrane, and the FLT3-ITD receptor is mainly located in the endoplasmic reticulum. We also discuss the biological mechanisms driving differential FLT3 receptors localization and potential drugs that could alter FLT3 receptors localization for therapeutic purposes. Understanding these mechanisms provides insights into FLT3 receptor biology and may guide the development of novel treatment strategies for patients with FLT3-mutated AML.

The heterogeneity in internal tandem duplications (ITDs) of FMS-like tyrosine kinase 3 (FLT3) results in diverse clinical outcomes for acute myeloid leukemia (AML) patients with FLT3-ITD mutations. This study retrospectively analyzed 124 FLT3-ITD-positive AML patients, aiming to evaluate How ITDs with exogenous sequences affect the response to induction therapy and long-term prognosis. Among them, 45.97

BACKGROUND:Acute graft-versus-host disease (aGVHD), which is mainly mediated by allogeneic T cells, is a decisive factor in the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). Prophylaxis for aGVHD in clinical patients is unsatisfactory, and there is still a huge unmet need for novel approaches. Icariin (ICA) shows potent anti-inflammatory activity and suppresses T cell-mediated immune responses. Thus, ICA is a potential drug for the prevention of aGVHD. However, there is no data assessing the impact of ICA on aGVHD after allo-HCT. PURPOSE:This study aimed to investigate the protective effect of ICA against aGVHD and its mechanisms. Moreover, the impact of ICA on the graft-versus-leukemia (GVL) effect and engraftment of donor hematopoietic and immune cells were assessed. METHODS:Different murine models of allo-HCT were developed to study the influence of the ICA on GVHD and GVL effect. Flow cytometry was used to analyze the growth of leukemia cells, alterations in different immune cells, and apoptosis. Cell proliferation was determined using a CCK-8 assay. RNA sequencing and quantitative proteomic analysis were performed to elucidate the underlying mechanisms, which were further verified by polymerase chain reaction or functional experiments. RESULTS:Different concentrations of ICA exhibited opposite effects: low-concentration ICA promoted, while high concentrations suppressed the proliferation and function of T cells. A high dose of ICA administration during days +3 to +5 post-allo-HCT can alleviate murine aGVHD but does not affect the course of chronic GVHD (cGVHD), the GVL effect against both acute myeloid and lymphoblastic leukemia, or the recovery of donor hematological and immune cells. ICA extensively represses the expansion, function, and infiltration of donor alloreactive T cells, while preserving regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Quantitative proteomic analysis showed that downregulation of integrin-linked kinase (ILK) and lymphocyte cytosolic protein 2 (LCP2) expression was possibly associated with ICA-mediated aGVHD protective effects. Furthermore, an inhibitor of ILK, which can alleviate murine aGVHD administered early after allo-HCT. CONCLUSION:These findings suggest that the bioactivities of ICA are associated with its concentration and that ICA can effectively mitigate aGVHD without losing GVL activity or engraftment of donor hematopoietic and immune cells. Thus, ICA may be a promising drug for preventing aGVHD in clinical settings.

Acute myeloid leukemia (AML) is a malignant hematological tumor disease. Chromosomal abnormality is an independent prognostic factor in AML. AML with t(8:21) (q22; q22)/AML1-ETO (AE) is an independent disease group. In this research, a new method based on Raman spectroscopy is reported for label-free single-cell identification and analysis of AE fusion genes in clinical AML patients. Raman spectroscopy reflects the intrinsic vibration information of molecules in a label-free and non-destructive manner, and the fingerprint Raman spectrum of cells characterizes intracellular molecular types and relative concentration information, so as to realize the identification and molecular metabolism analysis of different kinds of cells. We collected the Raman spectra of bone marrow cells from clinically diagnosed AML M2 patients with and without the AE fusion gene. Through comparison of the average spectra and identification analysis based on multivariate statistical methods such as principal component analysis and linear discriminant analysis, the distinction between AE positive and negative sample cells in M2 AML patients was successfully achieved, and the single-cell identification accuracy was more than 90%. At the same time, the Raman spectra of the two types of cells were analyzed by the multivariate curve resolution alternating least squares decomposition method. It was found that the presence of the AE fusion gene may lead to the metabolic changes of lipid and nucleic acid in AML cells, which was consistent with the results of genomic and metabolomic multi-omics studies. The above results indicate that single-cell Raman spectroscopy has the potential for early identification of AE-positive AML.

INTRODUCTION:Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) has an unfavorable prognosis. Recently, using newly emerging inhibitors of FLT3 has led to improved outcomes of patients with FLT3-ITD mutations. However, drug resistance and relapse continue to be significant challenges in the treatment of patients with FLT3-ITD mutations. This study aimed to evaluate the antileukemic effects of shikonin (SHK) and its mechanisms of action against AML cells with FLT3-ITD mutations in vitro and in vivo. METHODS:The CCK-8 assay was used to analyze cell viability, and flow cytometry was used to detect cell apoptosis and differentiation. Western blotting and real-time polymerase chain reaction were used to examine the expression of certain proteins and genes. Leukemia mouse model was created to evaluate the antileukemia effect of SHK against FLT3-ITD mutated leukemia in vivo. RESULTS:After screening a series of leukemia cell lines, those with FLT3-ITD mutations were found to be more sensitive to SHK in terms of proliferation inhibition and apoptosis induction than those without FLT3-ITD mutation. SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules. Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells. Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations. Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice. CONCLUSION:The findings of this study indicate that SHK may be a promising drug for the treatment of FLT3-ITD mutated AML.

As an increasingly well-known derivative of coumarin, daphnetin (7,8-dithydroxycoumarin) has demonstrated various pharmacological activities, including anti-inflammation, anti-cancer, anti-autoimmune diseases, antibacterial, organ protection, and neuroprotection properties. Various studies have been conducted to explore the action mechanisms and synthetic methods of daphnetin, given its therapeutic potential in clinical. Despite these initial insights, the precise mechanisms underlying the pharmacological activities of daphnetin remain largely unknown. In order to address this knowledge gap, we explore the molecular effects from the perspectives of signaling pathways, NOD-like receptor protein 3 (NLRP3) inflammasome and inflammatory factors; and try to find out how these mechanisms can be utilized to inform new combined therapeutic strategies.

Purpose To assess the accuracy of Raman spectroscopy in distinguishing between patients with leukemia and healthy individuals. Method PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases were searched for relevant articles published from inception of the respective database to November 1, 2023. The pooled sensitivity (SEN), specificity (SPE), diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR), were calculated along with their corresponding 95 % confidence intervals (CI). A summary comprehensive receiver operating characteristic curve (SROC) was constructed and the area under the curve (AUC) was calculated. The degree of heterogeneity was tested and analyzed. Results Fifteen groups of original studies from 13 articles were included. The pooled SEN and SPE were 0.93 (95 % CI, [0.92 –0.93]) and 0.91(95 % CI, [0.90–0.92]), respectively. The DOR was 613.01 (95 %CI, [270.79–1387.75]), and the AUC was 0.99. The Deeks’ funnel plot asymmetry test indicated no significant publication bias among the included studies (bias coefficient, 40.80; P = 0.13 < 0.10). The meta-regression analysis findings indicated that the observed heterogeneity could be attributed to variations in sample categories and Raman spectroscopy techniques. Conclusion We confirmed that Raman spectroscopy has good accuracy in differentiating patients with leukemia from healthy individuals, and may become a means of leukemia screening in clinical practice. In the case of analysis based on live cells using surface-enhanced Raman spectroscopy (SERS) improved diagnostic efficacy was observed.

Aging is an extremely intricate and progressive phenomenon that is implicated in many physiological and pathological conditions. Icariin (ICA) is the main active ingredient of Epimedium and has exhibited multiple bioactivities, such as anti-tumor, neuroprotective, antioxidant, anti-inflammatory, and anti-aging properties. ICA could extend healthspan in both invertebrate and vertebrate models. In this review, the roles of ICA in protection from declined reproductive function, neurodegeneration, osteoporosis, aging intestinal microecology, and senescence of cardiovascular system will be summarized. Furthermore, the underlying mechanisms of ICA-mediated anti-aging effects will be introduced. Finally, we will discuss some key aspects that constrain the usage of ICA in clinical practice and the corresponding strategies to solve these issues.

Acute myeloid leukemia (AML) is a heterogeneously malignant disorder resulting in poor prognosis. Ubiquitination, a major post-translational modification (PTM), plays an essential role in regulating various cellular processes and determining cell fate. Despite these initial insights, the precise role of ubiquitination in AML pathogenesis and treatment remains largely unknown. In order to address this knowledge gap, we explore the relationship between ubiquitination and AML from the perspectives of signal transduction, cell differentiation, and cell cycle control; and try to find out how this relationship can be utilized to inform new therapeutic strategies for AML patients.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the standard and curative treatment strategy for patients with hematologic malignancies. Recently, decitabine-included regimens have been investigated by several studies including ours, which may prevent relapse of primary malignant diseases. Methods: This study was to retrospectively evaluate a 7-day decitabine-included regimen with reduced dose of idarubicin for patients with hematologic malignancies who underwent allo-HSCT. Results: A total of 84 patients were enrolled, including 24 cases in 7-day and 60 cases in 5-day decitabine groups, respectively. Patients conditioned with 7-day decitabine regimen showed accelerated neutrophil (12.05 ± 1.97 vs. 13.86 ± 3.15; u = 9.309, p < 0.001) and platelet (16.32 ± 6.27 vs. 21.37 ± 8.57; u = 8.887, p < 0.001) engraftment compared with those treated with 5-day decitabine regimen. Patients in the 7-day decitabine group showed a significantly lower incidence rate of total (50.00% [12/24] versus 78.33% [47/60]; χ2 = 6.583, p = 0.010) and grade III or above (4.17% [1/24] vs. 31.67% [19/60]; χ2 = 7.147, p = 0.008) oral mucositis compared to those in the 5-day decitabine group. However, the occurrence of other major complications post-allo-HSCT and outcomes of patients in these two groups were comparable. Conclusion: These results demonstrate that this 7-day decitabine-contained new conditioning regimen seems to be feasible and safe for patients with myeloid neoplasms who receive allo-HSCT, and a large-scale prospective study is needed to confirm the findings of this study.

To analyze the effectiveness of decitabine combined with low-dose Ara‑C, aclarubicin, and rhG-CSF (DCAG) as a salvage therapy in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). This single-centered retrospective study included patients with relapsed/refractory AML between January 2013 and June 2020. The response rate and survival were calculated, and their correlations with clinical characteristics were estimated. Thirty-seven patients were enrolled. The overall response rate (ORR) was 56.8

Acute myeloid leukemia (AML) is a malignant clonal blood disease of hematopoietic stem cells with poor prognosis. Traditional diagnosis of AML depends on the morphology, immunology, cytogenetics, and molecular biology (MICM) classification. As a rapid, label-free and non-destructive detection method, Raman spectroscopy can characterize the molecular information in the biochemical process at the molecular level through peak position, intensity and other information. In this paper, we collected leukemic blast cells from 19 AML patients. Firstly, it was proved that with the help of multivariate analysis methods such as principal component analysis-linear discriminant analysis (PCA-LDA) and multivariate curve resolution-alternating least squares (MCR-ALS), Raman spectroscopy could effectively distinguish AML cells from normal leukocytes, and the accuracy rate was up to 96.71%. The results showed that compared with normal leukocytes, multiple components of information decomposed by the AML spectrum represented abnormal alterations in proteins, nucleic acids, lipids and carbohydrates in leukemia cells. Secondly, the same procedure was used to further detect different types of AML and found that Raman spectroscopy could distinguish AML cells with FMS-like tyrosine kinase 3-Internal Tandem Duplications (FLT3-ITD) mutations or not, and there were differences in spectral characteristics corresponding to nucleic acids and proteins (amino acids). The above results revealed that Raman spectroscopy has great potential for clinical diagnosis and mechanistic study of AML.

急性髓系白血病(AML)是一种常见的血液系统恶性疾病, 而RUNX1-RUNX1T1融合基因阳性AML是最常见的亚型之一[1,2], 它具有独特的形态学和免疫表型, 属于核心结合因子阳性白血病的一种[3]。虽然美国国家综合癌症网络指南将此类AML归为低危组[4], 仅用化疗, 尤其是大剂量阿糖胞苷为基础的巩固治疗方案, 长期存活率可达60%, 但疾病复发仍然是治疗失败的最重要的原因, 发生率高达30%～40%[5,6,7]。在本研究中, 我们旨在通过分析我中心RUNX1-RUNX1T1阳性AML患者的临床特征、实验室结果及预后, 评价基于二代测序技术检测下的RUNX-RUNX1阳性AML预后的影响因素, 以期更好地协助诊治, 指导临床决策。