Long Su

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. 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. 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. 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.

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.

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.

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% (57/124) had ITDs with exogenous sequences, classified as the insertion group. The remaining 54.03% (67/124) had only repetitions of the original FLT3 sequence, classified as the duplication group. Comparisons between these two groups revealed that the rates of composite complete remission (CRc) (59.09% vs. 81.03%, P = 0.017) and negative measurable residual disease (MRD) identified by multiparameter flow cytometry (MFC) (25.00% vs. 48.28%, P = 0.018) were significantly lower in the insertion group than those in the duplication group after the first cycle of induction therapy. Moreover, survival analysis conducted on 68 patients who received at least two cycles of consolidation therapy revealed that patients in the insertion group had significantly lower relapse-free survival (RFS) (2-year RFS: 50.70% ± 10.40% vs. 71.40% ± 8.90%, P = 0.033) and overall survival (OS) (2-year OS: 52.90% ± 10.20% vs. 79.00% ± 7.90%, P = 0.017) compared with those in the duplication group. Cox regression analysis identified ITD types, DNMT3A co-mutations, MFC-MRD after the second cycle (C2) of chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the first CR (CR1) as independent factors affecting RFS and OS. Furthermore, nomograms were employed to predict RFS and OS, and a new prognostic re-stratification model based on ITD types for FLT3-ITD-positive AML was proposed. Graphical Abstract

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.

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.

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.

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.

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.