Search Results (334)

Acute myeloid leukemia (AML) is a genetically and biologically heterogeneous hematologic neoplasm that arises from the clonal transformation of hematopoietic progenitor cells. AML cells undergo extensive metabolic reprogramming to sustain proliferation, survival, and adaptation to therapeutic stress. Among these alterations, cholesterol metabolism has emerged as a critical determinant of leukemic cell fitness. AML cells enhance cholesterol biosynthesis, uptake, trafficking, and storage, generating a dynamic network that supports membrane organization, mitochondrial function, oncogenic signaling, and resistance to therapy. Beyond these tumor-intrinsic roles, accumulating evidence indicates that cholesterol and its metabolites actively shape communication between leukemic and immune cells, influencing immune checkpoint expression, inflammatory signaling, and antitumor immune responses within the bone marrow microenvironment. This narrative review examines the mechanisms underlying cholesterol reprogramming in AML and discusses how alterations in cholesterol homeostasis integrate metabolic adaptation with immune regulation. Particular emphasis is placed on the interplay between cholesterol metabolism, leukemic stem cell persistence, therapeutic resistance, and immune dysfunction. Emerging therapeutic strategies targeting cholesterol-related pathways are also considered. Collectively, these findings position cholesterol metabolism as a central interface between tumor-intrinsic biology and immune crosstalk, highlighting its potential as a therapeutic vulnerability in AML. Full article

Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal proliferation and survival of neoplastic plasma cells (PCs) within the bone marrow (BM), where disease progression is critically supported by interactions with the BM tumor microenvironment (TME). Despite significant advances in therapeutic strategies, MM remains incurable, underscoring the need for improved preclinical models to better understand the disease biology and therapeutic response. This review summarizes current and emerging MM treatment approaches and critically examines the development of models designed to more accurately recapitulate interactions between MM-PCs and the surrounding BM niche. We describe established and emerging modeling platforms, with emphasis on advanced three-dimensional (3D) culture systems and highlight their unique contributions to the preclinical assessment of both existing and novel therapies. The advantages of 3D models, including in vitro and in silico systems, over traditional two-dimensional (2D) models are discussed, alongside a comparative evaluation of scaffold-free and scaffold-based approaches. In addition, the benefits and recent advances in the customization of BM niche simulation using microfluidic technologies and organ-on-a-chip platforms are reviewed. The application of 3D models in MM research is increasingly enabling the study of disease pathogenesis, progression, drug resistance and precision-medicine approaches (informed by biomarker discovery). Although standardized preclinical approaches for evaluating MM therapeutics are currently lacking, the growing imperative to reduce reliance on preclinical animal models highlights the importance of alternate systems. Consequently, the development and adoption of physiologically relevant models that accurately recapitulate MM-PC interactions with the BM TME will be critical for advancing future therapeutic strategies in MM. Full article

Owing to clonal integration and morphological plasticity, clonal plants generally exhibit higher fitness in nutrient-heterogeneous environments. Indocalamus latifolius (Keng) McClure is a clonal plant with considerable economic value in China. However, the mechanisms of clonal integration and morphological plasticity in I. latifolius under phosphorus (P) heterogeneous conditions remain unclear. To clarify the mechanisms, a pot experiment was performed with I. latifolius clonal fragments consisting of mother ramet, rhizome, and daughter ramet. The experiment used a two-factor design with the following six treatments: P addition regime (uniform P addition, localized P addition to mother ramets, and localized P addition to daughter ramets) and rhizome status (connection vs. severance). Biomass allocation, root morphological plasticity, and the allocation pattern of P and non-structural carbohydrates were determined. The results showed that localized P addition increased the biomass of ramets growing in high-P patches and the total biomass of the clonal system compared with uniform P addition. Under three P supply regimes, rhizome connection significantly improved the biomass and P accumulation of daughter ramets relative to rhizome severance. In heterogeneous P environments, rhizome connection facilitated the proliferation of finer root and raised the soluble sugar concentrations in belowground tissues of ramets located in low-P patches compared with rhizome severance. In conclusion, resource allocation within the I. latifolius clonal system is prioritized toward daughter ramets and ramets in high-P patches. Clonal integration can promote compensatory root growth and morphological modification in ramets located in low-P patches. Localized P addition to mother ramets combined with the maintenance of rhizome connectivity between mother and daughter ramets is more conducive to the overall growth of the clonal system. Full article

Drug resistance remains a significant barrier to achieving durable treatment responses. Traditionally, resistance has been attributed to genetic alterations and clonal selection. However, accumulating evidence suggests that early adaptation to therapy is often mediated by non-genetic state transitions. In this review, we propose a conceptual framework in which resistance emerges through therapy-driven molecular evolution in bladder cancer, characterized by three interconnected axes: non-genetic plasticity, metabolic reorganization, and tumor microenvironment remodeling. Using the Gemcitabine-Resistant Cell (GRC) model as a temporal reference system, we describe a stepwise transition from drug-sensitive states dominated by proliferation to survival-optimized resistant states through a growth–survival trade-off. Early adaptive phases are marked by the attenuation of cell-cycle and glycolytic programs, increased epigenetic flexibility, and metabolic rewiring involving mitochondrial and lipid-associated pathways. Later phases involve the reinforcement of resistance through extracellular matrix remodeling, developmental and stress-response signaling, and immunometabolic interactions within the tumor microenvironment, including adenosine- and lipid-associated mediators. Projecting the GRC score onto a clinical bladder cancer cohort further suggests that these evolutionary patterns may also be reflected in patient tumors. Overall, this framework supports a temporally structured view of chemoresistance and highlights opportunities to therapeutically target transitional adaptive states before resistance becomes stabilized. Full article

Cutaneous pseudolymphomas are benign reactive lymphoid proliferations that often mimic cutaneous lymphomas both clinically and histologically. A diverse array of inflammatory, infectious, and drug-induced dermatoses can closely resemble cutaneous T-cell lymphomas (CTCLs), particularly mycosis fungoides (MFs), posing significant diagnostic challenges. These mimickers may show histopathological features such as epidermotropism, dense lymphocytic infiltrates, or even clonality, making accurate differentiation crucial to avoid overtreatment. This review endeavors to comprehensively discuss the clinicopathologic features of the various inflammatory and infectious dermatoses that may simulate CTCL, drawing on illustrative examples across disease categories. By highlighting important comparative features and emphasizing the importance of clinicopathologic correlation, this review outlines practical strategies for distinguishing true lymphoma from its inflammatory mimics. Full article

Adipogenesis is a critical factor in causing obesity, which is a global health problem associated with metabolic disorders, such as insulin resistance and cardiovascular diseases. Natural compounds with anti-adipogenic activity may represent potential approaches for modulating adipocyte function. However, despite increasing interest in natural products, the anti-adipogenic potential of acridone alkaloids, particularly prenylated derivatives, remains largely unexplored. This study examined the effects of N-methylatalaphylline (NMA), a prenylated acridone alkaloid, on adipocyte differentiation, lipid accumulation, and glucose uptake. NMA exhibited anti-adipogenesis, particularly toward preadipocytes, and significantly reduced lipid accumulation in murine 3T3-L1 and human PCS-210-010 adipocytes at nontoxic doses (1.5–6 µM). At 3–6 µM, NMA downregulated adipogenic regulators, including PPARγ, C/EBPα, and SREBP1, along with adipogenic effectors, such as FABP4, adiponectin, LPL, PLIN1, and FAS. Mechanistic studies indicated that NMA treatment was associated with reduced phosphorylation of AKT, ERK, and p38, accompanied by cell cycle arrest and inhibition of mitotic clonal expansion. Meanwhile, activation of AMPK-ACC signaling, which may contribute to suppression of adipogenesis and reduced glucose uptake, was observed in differentiated 3T3-L1 cells after treatment with 6 µM NMA for 48 h. Additionally, molecular docking and molecular dynamics simulations suggested potential interaction between NMA and ERK1, supported by hydrogen bonding and hydrophobic contacts. Overall, these findings suggest that NMA exerts anti-adipogenic effects in vitro by modulating adipocyte proliferation, differentiation, and lipid metabolism. These findings highlight NMA as a promising acridone alkaloid scaffold for anti-adiposity applications, warranting further in vivo validation. Full article

Clonal hematopoiesis refers to the clonal expansion of hematopoietic stem and progenitor cells, driven by somatic mutations. Major mutated genes in clonal hematopoiesis include genes involved in epigenetic regulation including DNA methylation and/or chromatin modification (e.g., DNMT3A, TET2, and ASXL1), tumor suppressors (e.g., TP53), signal transduction (e.g., JAK2), and RNA splicing (e.g., SF3B1 and SRSF2). Clonal hematopoiesis includes clonal hematopoiesis of indeterminate potential (CHIP), clonal cytopenia of unknown significance (CCUS), and myelodysplastic syndromes/neoplasms (MDS). CHIP occurs when the frequency of the variant allele equals or exceeds 2% (4% for X-linked genes in males) in the absence of cytopenias. CHIP is common among older persons and is associated with an increased risk of hematologic cancer. CHIP is also associated with an increased risk of atherosclerotic disease including acute myocardial infarction, stroke, cardiac failure, and abdominal aneurysm. Increasing evidence suggests that CHIP is associated with venous thromboembolic disease. Somatic mutations lead to proliferation of hematopoietic progenitor cells and their progeny, resulting in excessive activation of granulocytes and monocytes. It could be postulated that chronic inflammation caused by clonal expansion of myeloid cells carrying mutations in DNMT3A, TET2, and ASXL1 (“DTA”) genes may constitute an independent risk factor in clot formation and endothelial-cell damage. DTA mutations correlate with elevated proinflammatory cytokines such as IL-1β and IL-6 and enhanced activation of inflammasomes. Moreover, JAK2 mutations may have a direct role in the activation of platelets and coagulation. In vivo murine studies have demonstrated that activation of the JAK-STAT signaling pathway promotes neutrophil extracellular trap (NET) formation, contributing to a prothrombotic state. Insights from related clonal disorders such as paroxysmal nocturnal hemoglobinuria and the VEXAS syndrome support the concept that mutation-driven innate immune activation can directly perturb hemostatic balance. This review aims to summarize the association between clonal expansion of hematopoietic cells and thrombotic disease, and highlight how somatic mutations in hematopoietic cells may contribute to vascular disease and thrombogenesis. Full article

Background/Objectives: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the clonal proliferation of Langerhans-like dendritic cells and constitutive activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. Nearly 80% of ERK pathway activation can be attributed to B-Raf proto-oncogene, serine/threonine kinase (BRAF V600E), and mitogen-activated protein kinase kinase 1 (MAP2K1) variants, with BRAF V600E specifically detected in approximately 50% of pediatric LCH cases and associated with a higher risk of severe disease and treatment failure. The use of the HistioTrak clinical assay to detect the presence of BRAF V600E mutations in peripheral blood mononuclear cells (PBMCs) has emerged as a useful diagnostic tool and biomarker. Methods: This study is a single-center retrospective study that explores the favorable outcomes of treatment with trametinib on a small number of patients with LCH. We retrospectively analyzed the records of 11 children with LCH treated with trametinib at diagnosis as front-line therapy (n = 6), due to progressive disease (n = 3) or intolerance (n = 1) to chemotherapy, or at relapse (n = 1). Results: HistioTrak identified the presence of BRAF V600E PBMCs in five patients. In this small single-center retrospective cohort, trametinib was associated with favorable short-term outcomes in all patients, and serial HistioTrak testing appeared feasible in selected patients. Conclusions: Prospective studies are needed before routine diagnostic or monitoring use can be recommended. Full article

To overcome the seasonal constraints of explant availability and facilitate genetic improvement in Catalpa ovata, this study established a dual-pathway in vitro regeneration system (encompassing adventitious shoot organogenesis and somatic embryogenesis) using mature zygotic embryos. We systematically evaluated the synergistic effects of maternal genotypes, plant growth regulators (PGRs), basal media, and the histone deacetylase inhibitor Trichostatin A (TSA). Genotype screening revealed significant divergence in regenerative potential, with the half-sib family 32F17 exhibiting superior responsiveness (84.7% callus induction). A high cytokinin-to-auxin ratio (ZA3 medium) optimally drove direct shoot organogenesis. For adventitious shoot proliferation, the addition of TDZ significantly improved the multiplication coefficient (up to 2.99 on ZB4 medium), although a physiological trade-off with shoot elongation was observed. In parallel, the application of 10 µM TSA significantly enhanced somatic embryogenesis from embryogenic calli, effectively alleviating the inhibitory constraints of exogenous PGRs. For rhizogenesis, the DKW basal medium proved superior to half-strength MS, with the ZE3 treatment (0.1 mg·L⁻¹ NAA + 0.1 mg·L⁻¹ IBA) yielding the highest rooting frequency (69.6%) and robust root architecture. Notably, while somatic embryo conversion remained recalcitrant, plantlets derived exclusively from the adventitious shoot organogenesis pathway were successfully acclimatized ex vitro. These transplanted plantlets exhibited consistently high survival rates (83.1–84.4%) across all tested genotypes, effectively overcoming the initial genotype-dependent recalcitrance. Collectively, this optimized protocol provides a reliable technical platform for the large-scale clonal propagation and biotechnological breeding of C. ovata. Full article

Multiple myeloma is a hematological malignancy characterized by clonal proliferation of plasma cells, usually confined to the bone marrow. Extramedullary disease (EMD) occurs in 7–18% of patients during the disease course and is associated with poor prognosis. Among extramedullary sites, testicular involvement is extremely rare, with an incidence of less than 2%. We present a rare case of testicular plasmacytoma as the first manifestation of systemic multiple myeloma, highlighting its imaging features and clinical implications. Full article

The walnut cultivar ‘Yunxin No. 14’ is an early fruiting, high-yielding, and widely adaptable fruit tree with compact growth and superior nuts. Establishing a successful tissue culture system for this cultivar is crucial for its rapid clonal propagation and as a foundation for future genetic transformation. Using young fruits as explants, 3% NaClO sterilization for 20 min effectively controlled contamination and browning. Somatic embryos induced from zygotic embryos cultured on DKW medium with 30 g·L⁻¹ sucrose showed high proliferation and minimal browning. After a 4-day dehydration treatment using saturated NH₄NO₃, mature somatic embryos germinated rapidly on differentiation medium (DKW containing 1 mg·L⁻¹ 6-BA and 0.1 mg·L⁻¹ IBA), reaching 90.0% germination. Optimal shoot multiplication was achieved on DKW medium supplemented with 2 mg·L⁻¹ 6-BA and 0.3 mg·L⁻¹ IBA, yielding a proliferation rate of 91.1% and a proliferation index of 3.1. For rooting, shoots (~3 cm) treated with Clonex^® rooting gel were transferred to a low-cost, sugar-free vermiculite medium with gaseous CO₂ as the sole carbon source. Root initiation occurred within two weeks at a rate of 54.2%, significantly shortening the rooting phase. Rooted plantlets were acclimatized in a peat:perlite:vermiculite (2:2:1, v/v/v) mixture under high humidity for two weeks before outdoor transfer, achieving an 88.6% survival rate. This study provides a reliable protocol for the micropropagation of ‘Yunxin No. 14’ and a valuable reference for other difficult-to-root woody species. Full article

Ulluco (Ullucus tuberosus Caldas) is an Andean tuber crop of high nutritional and genetic importance. However, its vegetative propagation promotes the accumulation of pathogens and limits the availability of uniform, high-quality planting material. In this study, an efficient and reproducible in vitro micropropagation protocol was established for an ulluco genotype from the Amazonas region of Peru. Nodal segments were cultured on MS (Murashige and Skoog) medium supplemented with 6-benzylaminopurine (BAP) or kinetin (KIN) at increasing concentrations (0.0–2.0 mg L⁻¹). For rooting, in vitro-derived shoots were transferred to MS medium supplemented with indole-3-butyric acid (IBA) or 1-naphthaleneacetic acid (NAA) at the same concentration range (0.0–2.0 mg L⁻¹). The explants exhibited a high basal morphogenetic capacity; however, the addition of cytokinins significantly enhanced the response. KIN at 2.0 mg L⁻¹ achieved 100% regeneration, whereas BAP at 0.2 mg L⁻¹ maximized shoot proliferation, producing 2.07 shoots per explant. Shoot elongation was greater with KIN at 1.0 mg L⁻¹, reaching 39.15 mm. In the rooting phase, the response varied depending on the type and concentration of auxin. NAA at 0.1 mg L⁻¹ resulted in 100% rooting and produced the greatest root length (41.93 mm), whereas IBA at 0.1 mg L⁻¹ maximized the number of roots (4.67), although roots were shorter. Rooted plantlets exhibited 100% survival after eight weeks of acclimatization. This protocol provides an effective system for the rapid production of vigorous and uniform clonal plants and represents a useful tool for the propagation, conservation, and future biotechnological improvement of ulluco. Full article

Blood platelets are derived from megakaryocytes with functions extending beyond hemostasis to inflammation, immunity, and cancer. Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders driven by somatic mutations affecting JAK-STAT signaling, leading to excessive myeloid proliferation. Thrombosis affects approximately one-fifth of patients at diagnosis and remains elevated throughout the disease course, while the paradoxical coexistence of bleeding further complicates clinical management. In addition, MPNs may progress to advanced disease stages, including bone marrow fibrosis and transformation to acute myeloid leukemia, leading to ineffective hematopoiesis, worsening symptom burden, and poor clinical outcomes. This review outlines how peripherally circulating platelets provide a unique window into MPN pathophysiology, with emphasis on their functional and molecular abnormalities. We summarize current understanding of platelet-mediated hemostatic imbalance across MPN subtypes. We discuss the potential of platelet transcriptomics and proteomics to reveal disease-specific signatures. We further highlight emerging platelet-associated candidates with potential utility as dynamic biomarkers for both the pathological marrow niche and thrombotic and bleeding risk. Together, these insights underscore the potential of platelet-based approaches to complement existing diagnostic and prognostic strategies in MPNs. Full article

Non-coding RNAs (ncRNAs) are conserved in the genome of cells across the three domains of life. They comprise a diverse group that are particularly prominent in metazoans where they provide a crucial interface between genes and proteins, participating in key cellular processes at different levels: from control of DNA transcription to modulation of messenger RNA stability to modification of protein activity. The interactions of ncRNAs with one another as well as with other RNAs, DNA and proteins form the basis of a genome-wide regulatory network (GRN). Because of the mutual influence of its components on each other, the GRN is a dynamic system. Further, the GRN imposes constraints on which genes are expressed and when, leading to specific gene-expression patterns or transcriptomes. The configurations of the activities of all gene loci represent self-stabilizing cell states, referred to as “attractor” states, each of which corresponds to a distinct cell type. The cancer cell is also an attractor state that arises from a change in the topography of the epigenetic landscape caused by dysregulation of the GRN. It is proposed that the transition to a neoplastic attractor state is caused by ncRNA alterations, while subsequent somatic mutations of oncogenes and tumor suppressor genes drive cell proliferation and clonal expansion. Full article

Background: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells and a rapidly evolving treatment landscape. Bispecific antibodies targeting B-cell maturation antigens (BCMA) have emerged as promising therapeutic options for relapsed and/or refractory multiple myeloma (RRMM). Methods: This retrospective study evaluated the efficacy and safety of teclistamab, a BCMA-directed bispecific antibody, in patients with RRMM with renal impairment (RI) at baseline compared to those without. Conducted across seven academic centers, the study included 195 patients with RRMM, of whom 34 had baseline RI. Results: Performance status, previous lines of treatment, and prior BCMA exposure were identified as significant predictors of progression-free survival. Notably, patients with RI demonstrated overall response rates and toxicity profiles comparable to those without RI, although they required more packed red blood cell transfusions. No statistically significant differences were observed in adverse events, including cytokine release syndrome and infections. Conclusions: Overall, the findings support the efficacy and safety of teclistamab in patients with RRMM and RI, highlighting the need for prospective clinical trials to optimize the treatment strategies for this population. Full article