Search Results (4,476)

Background: Acute myeloid leukemia with extramedullary disease (EMD-AML) represents a distinct clinical entity associated with diagnostic and therapeutic challenges, and its prognostic significance remains uncertain. Methods: A retrospective study of 617 adults with newly diagnosed AML (2005–2018) was conducted, analyzing 246 patients with EMD-AML and 371 without EMD involvement. The clinical characteristics and treatment outcomes were analyzed. Propensity score matching (PSM) was applied to adjust for baseline confounders. Results: Patients with isolated EMD-AML and those with concurrent bone marrow involvement had comparable clinical outcomes. NPM1 mutations (48% vs. 25%, p = 0.0002) and t(8;21) translocation (23.2% vs. 3.7%, p < 0.001) were enriched in the EMD-AML cohort. After PSM, EMD-AML patients achieved a higher overall response rate compared with non-EMD-AML (88.1% vs. 72.0%, p = 0.0002) but experienced significantly higher relapse rates (35.7% vs. 15.5%, p < 0.0001). Despite the achievement of a higher response rate, EMD-AML was associated with shorter median overall survival (OS) (14.2 vs. 64.1 months, p < 0.0001) and event-free survival (EFS) (9.5 vs. 55.9 months, p < 0.0001). In a multivariable analysis, EMD-AML remained independently associated with worse OS and EFS (OS HR 1.79, p = 0.01; EFS HR 1.95, p = 0.001). Allogeneic hematopoietic stem cell transplantation did not confer a survival advantage in EMD-AML patients. Conclusions: EMD-AML, whether isolated or concurrent with bone marrow disease, represents a high-risk entity characterized by poor long-term outcomes despite strong initial response rates. Obtaining tissue biopsies for molecular profiling may help improve risk stratification, identify targetable mutations and guide individualized treatment. Full article

Background and Clinical Significance: Chromothripsis represents a catastrophic genomic event in plasma cell myeloma (PCM) associated with poor prognosis. We report a case of newly diagnosed PCM with complex cytogenetic abnormalities indicative of genomic instability. Case Presentation: A 67-year-old man presented with acute dyspnea and was found to have severe acute kidney injury, anemia, hypercalcemia, and IgG lambda monoclonal gammopathy. Bone marrow biopsy revealed plasma cell infiltration. Comprehensive FISH analysis demonstrated a complex pattern with gain of 1q, monosomy 13, and multiple numeric and structural abnormalities affecting chromosomes 5, 9, and 15, suggestive of a chromothripsis-like pattern. Despite requiring hemodialysis, the patient achieved complete renal recovery and >99% reduction in serum-free light chains after one cycle of CyBorD plus daratumumab, which was continued for four cycles. Follow-up bone marrow evaluation at three months confirmed complete histologic, flow cytometric, and cytogenetic remission, allowing for preparation for autologous stem cell transplantation. Conclusions: This case demonstrates that exceptional clinical responses can be achieved in high-risk disease with contemporary quadruplet regimens. While the long-term durability of such responses in genomically unstable cases remains uncertain, this case highlights the importance of comprehensive cytogenetic characterization to identify and monitor genomic instability in PCM. Full article

Background/Objectives: VEXAS (Vacuoles, E1-Enzyme, X-linked, Autoinflammatory, and Somatic) syndrome is a recently described adult-onset autoinflammatory disorder. It is characterized by somatic mutations in the UBA1 gene, systemic inflammation, macrocytic anemia, cytopenias, and bone marrow vacuolization and frequently overlaps with Sweet’s syndrome, relapsing polychondritis, and myelodysplastic syndrome (MDS). Because treatment options are evolving, we reviewed the current and latest evidence of clinical features and therapeutic methods. Methods: A comprehensive literature review was conducted using PubMed and MEDLINE for studies published between 1 January 2020 and 1 July 2025. Search terms included “VEXAS” and “treatment.” Eligible publications comprised clinical trials, multicenter and observational studies, and case reports containing therapeutic data. Findings were analyzed narratively with emphasis on treatment response, steroid-sparing effects, survival outcomes, and molecular responses. Results: Glucocorticoids remain the first-line therapy for acute management; however, this comes with near-universal steroid dependence. DMARDs and TNF-α inhibitors showed limited benefits. IL-6 inhibitors and JAK inhibitors showed improvement in overall response, with JAK inhibitors demonstrating a superior effect. Ruxolitinib showed a higher complete response rate and transfusion independence compared to other JAK inhibitors. Hypomethylating agents, particularly azacitidine, improved hematologic responses in patients with co-existing MDS and reduced UBA1 variant allele burden. Allogeneic hematopoietic stem cell transplantation may be the only current curative method, though with notable transplant-related mortality. Conclusions: JAK inhibitors and hypomethylating agents offer promising disease-modifying potential, while transplant may provide curative intent in selected patients. Ongoing clinical trials are taking place to dictate the treatment direction of VEXAS syndrome. Full article

Type 2 diabetes mellitus (T2DM) affects approximately 10–25% of patients undergoing orthopedic procedures and is associated with impaired tissue healing, increased complication rates, and reduced responsiveness to orthobiologic therapies, including platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and mesenchymal stem cell (MSC) preparations. The underlying mechanisms include advanced glycation end-product accumulation, NF-κB-driven chronic inflammation, Nrf2 pathway impairment, mitochondrial dysfunction, and epigenetic diabetic memory, collectively compromising both orthobiologic product quality and the tissue microenvironment. Emerging, predominantly mechanistic evidence suggests that targeted nutritional interventions, including bioactive compounds targeting mitochondrial biogenesis pathways, anti-inflammatory dietary patterns, and specific micronutrients, may modulate these pathological processes and potentially improve orthobiologic outcomes. This narrative review synthesizes evidence from diabetic pathophysiology, orthobiologic outcomes research, and nutritional science to propose a conceptual clinical framework for regenerative medicine optimization in T2DM patients. Critical knowledge gaps are identified, and a research agenda is proposed. The proposed framework, based primarily on mechanistic and preclinical evidence, should be interpreted as a foundation for research prioritization and hypothesis generation rather than as a clinical protocol. Rigorous randomized trials directly evaluating nutritional optimization in orthobiologic therapy for diabetic patients are required before evidence-based recommendations can be established. Full article

Fanconi anemia (FA) is a rare inherited disorder classically defined by defective DNA interstrand crosslink repair, leading to bone marrow failure and cancer predisposition. Increasing evidence indicates that FA pathophysiology extends beyond genomic instability to include mitochondrial dysfunction, oxidative stress, and impaired antioxidant responses. Across multiple cellular models and patient-derived samples, FA cells display altered mitochondrial bioenergetics, increased reactive oxygen species (ROS) production, and defective activation of redox-adaptive pathways, contributing to cumulative damage to DNA, lipids, and proteins. These alterations are particularly relevant in hematopoietic stem and progenitor cells, where metabolic stress and redox imbalance amplify stem cell exhaustion. Current data support a bidirectional interplay in which mitochondrial dysfunction and oxidative stress act mainly as secondary but amplifying factors of the primary DNA repair defect, establishing pathogenic feedback loops. Preclinical studies suggest that modulation of redox balance and mitochondrial function may improve cellular homeostasis, and early clinical investigations of antioxidant strategies indicate acceptable safety and measurable effects on oxidative biomarkers. However, clinical evidence remains limited and heterogeneous, with uncertain impact on long-term disease progression. Moreover, most mechanistic insights derive from in vitro or patient-derived models, while animal models and longitudinal clinical studies remain insufficient. Overall, a more integrated and translational framework is needed to clarify causality, validate biomarkers, and define the therapeutic potential of targeting metabolic and redox pathways in FA. Full article

Trained immunity refers to the enduring functional reprogramming of innate immune cells after particular stimuli, driven by epigenetic and metabolic alterations that augment non-specific responses upon subsequent exposure. Neutrophils and monocytes/macrophages, as essential innate effectors, are crucial for the induction and control of trained immunity, which is the primary emphasis of this review. Neutrophils, the predominant circulating leukocytes, were historically considered incapable of memory owing to their brief lifespan. Emerging evidence indicates that trained immunity functions at the bone marrow progenitor level, influencing granulopoiesis to produce neutrophils with lasting functional modifications. This research offers new insights into neutrophil functions in infection, cancer, and inflammation. Monocytes and macrophages, characterized by phenotypic plasticity and tissue residence, function as conventional models of trained immunity. They experience direct peripheral reprogramming or emerge as primed descendants of trained bone marrow precursors, performing pro-inflammatory or reparative roles in malignancies, infections, and ischemia lesions. This study comprehensively outlines the regulatory mechanisms of trained immunity in these cells, clarifies their functions in various clinical situations, and examines therapeutic applications. Comprehending these pathways is crucial for elucidating the cellular foundation of innate immunological memory, uncovering its multiple functions in disease, and guiding innovative therapeutics aimed at granulopoiesis and monocyte-macrophage polarization. Full article

The most common complication of active brucellosis in humans is osteoarticular injury. In the bone marrow microenvironment, mesenchymal stem cells (MSCs) can differentiate into either adipocytes or osteoblasts, and this balance is tightly regulated because an increase in adipogenesis may negatively affect bone formation and favor bone loss. The differentiation of MSCs into adipocytes or osteoblasts is tightly regulated by mechanisms that promote cell fate toward one lineage while repressing the other. Our study demonstrated that Brucella abortus infects MSCs but does not affect the deposition of organic and mineral matrix during osteoblast differentiation. However, the infection upregulates Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) expression in osteoblasts, which may contribute to osteoclast activation and bone resorption. Conversely, B. abortus infection significantly influences adipocyte differentiation by modulating lipolysis, lipogenesis, and interactions between lipid droplets and mitochondria. This leads to increased cellular cholesterol levels and reduced intracellular triglycerides, accompanied by glycerol release. These changes result in more differentiated adipocytes and larger lipid droplets. Consequently, we observed increased IL-6 secretion and a higher leptin/adiponectin ratio. Importantly, these effects were independent of a functional type IV secretion system (T4SS), as purified Brucella DNA fully reproduced the adipogenic phenotype. Moreover, inhibition of TLR9—the primary sensor of bacterial DNA—significantly reduced the DNA-induced adipogenic response, demonstrating that adipocyte modulation is at least in part mediated through TLR9 signaling. In summary, B. abortus promotes MSC differentiation toward an inflammatory adipocyte phenotype. It involves a TLR-9-mediated DNA detection. It may contribute to osteoarticular injury and infection-associated bone resorption. Full article

The bone marrow tumor microenvironment (TME) is critical for acute myeloid leukemia (AML) progression, immune evasion, and treatment resistance. SRC, a non-receptor tyrosine kinase involved in multiple oncogenic pathways, has not been systematically characterized in AML in relation to prognosis and immune regulation. We integrated bulk transcriptomic and single-cell RNA-sequencing datasets from TCGA, BeatAML, and GEO. Immune-related targets were identified using xCell-based immune scoring and weighted gene co-expression network analysis (WGCNA), followed by protein–protein interaction analysis and multi-algorithm machine-learning screening. We then evaluated SRC expression patterns, prognostic associations, immune microenvironment features, predicted drug sensitivity, single-cell differentiation dynamics, intercellular communication, and in silico virtual knockout perturbation (scTenifoldKnk). SRC emerged as the most robust hub gene after integration of WGCNA, PPI analysis, machine-learning feature selection, and survival screening. SRC was significantly upregulated in AML compared with normal controls and was independently associated with poor overall survival (HR = 1.231, p = 0.037). High SRC expression was linked to adverse ELN/FAB features, increased immune checkpoint expression, enrichment of inflammatory and immunoregulatory pathways, and a higher proportion of primitive leukemia-associated cell states. Single-cell analyses further suggested that SRC was enriched in CD34⁺ progenitor compartments, associated with altered cell–cell communication, and accompanied by distinct mutation and pathway profiles. Drug-response prediction and in silico network perturbation analysis further supported the potential biological and translational relevance of SRC-centered programs. SRC is a prognostically relevant and immune-associated hub linked to AML microenvironment remodeling, and may serve as a candidate biomarker and potential therapeutic target that warrants further experimental validation. Full article

Background: Chimerism analysis is a key tool for monitoring donor-cell engraftment and the risk of relapse and graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). The advantage of lineage-specific chimerism assessment, and its dynamics in patients receiving post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis, remains unclear. Objective: This review summarizes the current state of the art on chimerism analysis in patients with myeloid neoplasms undergoing allo-HCT with PTCy, with emphasis on lineage-specific testing and modern methodologies. Methods: A structured literature review was conducted to assess chimerism dynamics in whole blood (WB), bone marrow, and peripheral blood (PB) subpopulations, including T-cells, CD34⁺, myeloid, B, and NK (natural killer) cells, and their association with clinical outcomes following PTCy. Results: Lineage-specific PB chimerism, particularly in T-cells, myeloid lineage and CD34⁺ cells, is more sensitive than WB chimerism for predicting relapse. Declining donor myeloid chimerism or persistent myeloid mixed donor chimerism (MDC) may precede hematologic relapse and provide an early signal of graft instability or ineffective graft-versus-leukemia activity. T-cell MDC has been associated with an increased risk of relapse and a lower risk of GVHD, although persistent T-cell MDC in some patients may instead indicate immune tolerance. Declining CD34⁺ donor chimerism correlates with a higher risk of relapse and inferior survival outcomes and may therefore complement measurable residual disease testing. Data regarding B-cell and NK-cell chimerism remain inconsistent, likely influenced by delayed immune reconstitution. Compared to anti-thymocyte globulin, PTCy may promote higher donor T-cell chimerism, though findings across studies are variable. Next-generation sequencing (NGS) enables more sensitive detection of microchimerism and relapse prediction. Conclusions: Chimerism analysis, particularly when lineage-specific and NGS-based, offers valuable prognostic insight in allo-HCT with PTCy. Further prospective studies are needed to standardize testing and guide personalized post-HCT strategies. Full article

Background: Acute myeloid leukemia (AML) with monocytic differentiation poses significant clinical challenges, including high relapse rates and chemotherapy resistance. Current morphological assessment is limited by inter-observer variability, low sensitivity, and inefficiency, especially for detecting low-level residual disease. This creates an urgent need for automated, objective tools to improve diagnostic consistency and monitoring. Artificial intelligence, particularly deep learning, offers potential for extracting high-dimensional cytomorphological features to address these gaps. Methods: A retrospective cohort of 184 bone marrow smear slides from patients with monocytic leukemia was used. The core biomarker was the immature monocyte percentage (IMMP), defined as monoblasts plus promonocytes among nucleated cells, with a 2.0% clinical cutoff. An EfficientNet-based convolutional neural network was developed via transfer learning and trained to classify four cell types: monoblasts, promonocytes, monocytes, and other cells. Results: The model achieved robust cell-level classification, with F1 scores of 0.82 for monoblasts and 0.34 for promonocytes. At the slide level, using an optimized IMMP threshold of 0.045, it accurately assessed persistent leukemic cell burden with 78.9% Accuracy, 81.1% Recall, and 76.9% Specificity. Model-predicted IMMP values showed strong correlation with expert-derived values (Pearson r = 0.827), demonstrating reliable quantitative agreement. Conclusions: This deep learning model provides an automated, objective tool for quantifying immature monocytes, addressing key limitations in morphological assessment of monocytic AML. The IMMP metric shows promise for monitoring treatment response, predicting relapse, and potentially identifying patients at risk of venetoclax-based therapy resistance. While promising, prospective multicenter validation is needed to translate these findings into routine clinical practice. Full article

Background/Objectives: Serum protein electrophoresis (SPE) is a widely used laboratory test for the detection and monitoring of monoclonal gammopathies, including multiple myeloma (MM). Although SPE is usually recommended in the presence of specific clinical or laboratory abnormalities, monoclonal gammopathies may occasionally develop rapidly and without typical symptoms. This case report aims to emphasize the diagnostic value of SPE in identifying an unexpected and fast-evolving monoclonal gammopathy. Methods: We report the clinical and laboratory eight-month follow-up of a 58-year-old male who initially underwent SPE for unrelated clinical conditions. Serial SPE analyses were performed using capillary zone electrophoresis. When abnormalities emerged, immunotyping and serum free light chain (FLC) assays were conducted. The diagnostic workup was completed with bone marrow aspiration, flow cytometry, and imaging studies according to current international diagnostic criteria. Results: The initial SPE (November 2023) showed a normal protein profile. After eight months, follow-up SPE revealed a prominent monoclonal spike in the gamma region (2.9 g/dL), associated with increased total serum proteins (91 g/L; range 64–82 g/L), elevated IgA levels (20.0 g/L; range 0.4–3.5 g/L), and a markedly abnormal κ/λ FLC ratio (54.00; range 0.31–1.56). Bone marrow analysis demonstrated >18% plasma cell infiltration, confirming the diagnosis of IgA-κ MM. The patient underwent standard therapy followed by autologous stem cell transplantation, achieving disease remission. Conclusions: This case highlights that clinically relevant monoclonal gammopathies may arise rapidly in the absence of classical diagnostic features. Routine SPE represents a cost-effective and accessible screening tool that can identify subtle protein abnormalities, prompting the timely use of more specific and invasive diagnostic procedures for aggressive plasma cell disorders. Full article

Background/Objectives: Bone-targeted drug delivery systems hold great promise for treating skeletal diseases, yet the optimal strategy for functionalizing lipid nanoparticles (LNPs) with bone-homing ligands remains insufficiently explored. Herein, we compared two alendronate sodium (Alen) modification approaches (pre-conjugation and post-conjugation) for constructing bone-targeted LNPs capable of delivering mRNA to skeletal tissues. Methods: LNPs were fabricated via microfluidic mixing, and the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-alendronate conjugate (DSPE-PEG-Alen) required for the pre-conjugation method was synthesized. The bone-targeting ability of LNPs prepared by the two Alen modification strategies was evaluated using an in vitro hydroxyapatite (HAP) binding assay. Furthermore, the physicochemical properties, bone-targeting performance, mRNA delivery efficiency, and biosafety of the LNPs prepared by the post-conjugation method were assessed through cellular uptake, in vivo imaging, and other methods. Results: Hydroxyapatite binding assays revealed that the post-conjugation strategy afforded significantly superior bone affinity compared to the pre-conjugation approach. In addition, ex vivo bone fragment binding experiments further confirmed that the bone-targeting LNPs prepared by the post-conjugation method exhibited stronger bone-binding capability compared to unmodified LNPs. The optimized Alen-LNPs demonstrated efficient cellular uptake and functional mRNA translation in bone marrow mesenchymal stem cells with negligible cytotoxicity. In vivo studies in mice confirmed the preferential accumulation of Alen-LNPs in bone tissues, with successful green fluorescent protein (GFP) mRNA translation detected in bone tissue sections. Histopathological analysis confirmed the biosafety of the formulation. Conclusions: This study establishes the post-conjugation strategy as the superior approach for Alen functionalization of LNPs, providing a robust and reproducible platform for bone-targeted mRNA therapeutics. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent joint inflammation and systemic immune dysregulation. While bone marrow activation has been linked to RA pathogenesis, direct access to bone marrow tissue for progenitor analysis remains limited by ethical and technical constraints. Analysis of progenitor cells in peripheral blood can serve as a surrogate reflecting bone marrow activation. In this study, we analysed peripheral blood cells from 12 RA patients and 9 healthy controls using high-dimensional spectral flow cytometry with a nine-marker panel (CD45, CD31, CD235, CD133, CD34, CD105, CD271, CD90, PDPN). Flow Self-Organizing Map (FlowSOM) clustering identified 20 distinct cell populations. Additionally, a complementary flow cytometry panel was used to assess CD31 expression on immune subsets in peripheral mononuclear cells (PBMCs) from 9 RA and 9 healthy donors of this cohort. RA patients showed increased CD45⁺CD31⁻ immune cells, but not their putative progenitors. Conversely, putative CD45⁺CD31^int progenitors and CD45⁺CD31^int mature cells were reduced, along with CD31 expression on T cells. Levels of CD235a⁺ putative erythroid precursors and CD45⁺CD31⁺ progenitors were significantly increased in RA patients. Three putative stromal cell populations were detected in circulation. Together, these findings reveal expanded erythroid precursor populations and reduced CD31 expression on T cells in RA. Our data underscore broad systemic alterations in cellular homeostasis in RA patients. In conclusion, our results suggest that the loss of CD31 expression on immune cell precursors plays a role in age-associated immune remodelling and immune activation in RA and provides the rationale for further studies on erythroblast differentiation and the functional role of erythroblasts in chronic inflammation. Full article

Titanium and its alloys are widely used for orthopedic implants, but their intrinsic bioinertness may hinder osseointegration. In this study, titanium dioxide nanotube (TNT) arrays were fabricated on Ti-6Al-4V scaffolds via anodization, and their effects on the adhesion behavior of human bone marrow mesenchymal stem cells (hBMSCs) were investigated. Surface characterization showed that anodization successfully generated ordered TNT layers, increased surface roughness, enhanced protein adsorption, and induced an apparent superhydrophilic wetting response. Compared to the untreated scaffold and TNT50, the small-diameter TNT10 surface significantly promoted hBMSC adhesion and proliferation. Microscope imaging further revealed enhanced cell spreading, F-actin organization, and vinculin expression on TNT surfaces, with the most prominent focal adhesion-related staining observed in TNT10. Quantitative proteomic analysis showed that TNT10 was associated with coordinated remodeling of adhesion- and cytoskeleton-related molecular programs, including focal adhesion, cell–substrate junction, and regulation of the actin cytoskeleton. In contrast, TNT50, despite supporting obvious cytoskeletal remodeling, was more compatible with a dynamic, higher-turnover adhesion state. Overall, these findings suggest that small-diameter TNTs provide a more favorable interfacial microenvironment for stable early hBMSC adhesion on porous titanium scaffolds. Full article