Search Results (639)

The major subtypes of leukemia show sex differences. This review summarizes current knowledge and identifies gaps regarding sex differences across acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphoblastic leukemia in epidemiology, mortality and survival rates, risk factors, and epigenetic, metabolomic, and sex-specific patterns. Males have higher incidence and mortality rates of leukemia compared to females, emphasizing the importance of biological sex. Underreporting of sex differences in leukemia is highlighted, suggesting that sex is often overlooked as a research variable. A significant clinical observation is that women demonstrate higher overall survival rates but experience more severe treatment-related toxicity. Clinically, women tend to survive longer but experience more severe side effects. In contrast, a significant clinical observation in pediatric leukemia contradicts this enigma, suggesting that sex differences may be less pronounced during childhood. These differences play a significant role in how the disease develops. This review presents a sex-based perspective for hematological and biochemical patterns, genetic risk factors, environmental, lifestyle, and parental risk factors, epigenetics and metabolites. Furthermore, males and females might have different responses to the same toxic, environmental, and hormonal exposures. Trying to understand these disparities better based on molecular mechanisms is considered an approach for precision medicine. Full article

Background/Objectives: Conventional workflows, peripheral blood smears, and bone marrow assessment supplemented by LDI-PCR, molecular cytogenetics, and array-CGH, are expert-driven in the face of biological and imaging variability. Methods: We propose an AI pipeline that integrates convolutional neural networks (CNNs) and transfer learning-based models with two explainable AI (XAI) approaches, LIME and Grad-Cam, to deliver both high diagnostic accuracy and transparent rationale. Seven public sources were curated into a unified benchmark (66,550 images) covering ALL, AML, CLL, CML, and healthy controls; images were standardized, ROI-cropped, and split with stratification (80/10/10). We fine-tuned multiple backbones (DenseNet-121, MobileNetV2, VGG16, InceptionV3, ResNet50, Xception, and a custom CNN) and evaluated the accuracy and F1-score, benchmarking against the recent literature. Results: On the five-class task (ALL/AML/CLL/CML/Healthy), MobileNetV2 achieved 97.9% accuracy/F1, with DenseNet-121 reaching 97.66% F1. On ALL subtypes (Benign, Early, Pre, Pro) and across tasks, DenseNet121 and MobileNetV2 were the most reliable, achieving state-of-the-art accuracy with the strongest, nucleus-centric explanations. Conclusions: XAI analyses (LIME, Grad-CAM) consistently localized leukemic nuclei and other cell-intrinsic morphology, aligning saliency with clinical cues and model performance. Compared with baselines, our approach matched or exceeded accuracy while providing stronger, corroborated interpretability on a substantially larger and more diverse dataset. Full article

This pre–post study aimed to determine whether interprofessional education (IPE) combining online and in-person instruction enhanced medical students’ empathy. The IPE program was conducted during the academic years 2022 and 2023 for medical (n = 240) and other healthcare students. Subjects discussed a case scenario involving a patient with chronic myeloid leukemia, sharing their ideas within their team and with other teams. The medical students’ empathy was assessed before and after the IPE program using the Japanese version of the Jefferson Scale of Empathy for Health Professions Students (JSE-HPS). Medical students provided written responses to the question, “What do you think is necessary for the care of patients with cancer, besides medical skills and knowledge?” Empathy-related terms were identified using frequency and co-occurrence analyses. The frequencies before and after the IPE were compared. The median JSE-HPS score rose from 98.0 to 114.0 (p < 0.001, Wilcoxon signed-rank test). The frequency of words categorized as demonstrating empathy increased from 37.9% to 52.9% after the IPE (p < 0.01, chi-square test). Our hybrid IPE program enhanced medical students’ empathy, which was supported by both quantitative and qualitative methods. Full article

Background/Objectives: Tyrosine kinase inhibitors (TKIs) have transformed the treatment of chronic myeloid leukemia (CML), yet emerging evidence indicates an increased risk of vascular adverse events, particularly peripheral artery disease (PAD). Reliable biomarkers for early detection of TKI-related vascular toxicity are still lacking. Methods: A cross-sectional study was conducted on 78 patients with chronic-phase CML treated at Dr. Soetomo General Hospital, Surabaya. PAD was confirmed using ankle–brachial index. Serum oxidized low-density lipoprotein (OxLDL) and interleukin-10 (IL-10) levels were measured using ELISA. Results: PAD was detected in 20% of subjects. The PAD group showed significantly higher OxLDL, lower IL-10, and a markedly elevated OxLDL/IL-10 ratio (all p < 0.001). OxLDL remained independently associated with PAD after adjustment (adjusted OR = 1.132, 95% CI 1.020–1.255, p = 0.019). OxLDL/IL-10 ratio yielded a good diagnostic value (sensitivity 87.5% and specificity of 88.7%). Conclusions: Elevated OxLDL and an increased OxLDL/IL-10 ratio are associated with PAD in CML patients receiving TKI therapy and demonstrated a good diagnostic performance for early detection of TKI-induced vascular toxicity. Full article

This manuscript presents the development of an electrochemical biosensor designed to detect K-562 chronic myeloid leukemia (CML) cells. The biosensor was made of highly oriented pyrolytic graphite (HOPG), functionalized with -OH and -COOH groups by surface etching with strong acids, and subsequently coated with modified titanium dioxide (TiO₂-m). TiO₂-m is TiO₂ modified during its synthesis process using carbon nanotubes functionalized with -OH and -COOH groups. These changes improve the electron transfer kinetics and physicochemical properties of the electrode surface. TiO₂-m improves the sensitivity and selectivity towards leukemic cells. The detection process involved three stages: cell culture, cell adhesion onto the TiO₂–m electrode, and measurement of the electrochemical signal. Fluorescence microscopy and SEM-EDS confirmed cell adhesion and pseudopod formation on the TiO₂-m surface, which is an important finding because K-562 cells are typically nonadherent. Cyclic voltammetry (VC) and differential pulse voltammetry (VDP) demonstrated rapid and sensitive detection of leukemic cells within the concentration range of 6250 to 1,000,000 cells/mL, achieving high reproducibility and strong linearity (R² = 98%) with a detection time of 25 s. The VC and VDP demonstrated rapid and sensitive detection of leukemic cells over a concentration range of 6250 to 1,000,000 cells/mL, achieving adequate reproducibility and stable linearity (R² = 98%), with a detection time of 25 s. These results indicate that the TiO₂-m biosensor is a promising platform for the rapid and efficient electrochemical detection of leukemia cells. Full article

In this paper, we study the ultimate dynamics of a 3D chronic myeloid leukemia (CML) model under the assumption that a tyrosine kinase inhibitor is administered. This model may exhibit an immune window. Our approach uses the localization method of compact invariant sets. We derive the ultimate upper bounds for quiescent leukemic cells, actively cycling (AC) leukemic cells, CML-specific immune effector cells (briefly, immune cells), and the lower bound for immune cells, which characterizes the persistent inner dynamics, including the attractor. Global conditions for leukemia eradication are obtained as global asymptotic stability conditions for the leukemia-free equilibrium point. In particular, it is shown that this global condition coincides with the local one, and, thus, these conditions are not improvable. We study the case in which the immune window exists and describe the situation in which the inner equilibrium point exists and is unique. We study its location with respect to the immune window and prove that it is locally asymptotically stable. By conducting a numerical simulation, we provide examples of leukemia eradication/relapse. Full article

Background: Tyrosine kinase inhibitors (TKIs) have transformed the prognosis of chronic myeloid leukemia (CML), but pediatric patients face unique challenges due to prolonged exposure. Early molecular response (EMR, BCR::ABL1 ≤ 10% at 3 months) is a recognized predictor of favorable outcomes in adults and has been correlated with improved responses in children. However, its relationship with achieving deep molecular remission (DMR, BCR::ABL1 ≤ 0.01%) in pediatric CML remains unclear. Methods: We performed a single-center, retrospective analysis of 103 pediatric patients with chronic-phase CML treated with frontline TKIs. Among them, 88 were evaluable for molecular response. BCR::ABL1 transcript levels were quantified by real-time quantitative PCR on the International Scale, and molecular responses were assessed. Associations between early molecular dynamics and long-term outcomes were evaluated using Kaplan–Meier and cumulative incidence analyses. Results: At 3 months, 64.8% achieved EMR. Early responders had significantly higher MMR rates at 12 months (80.8% vs. 5.6%; p = 0.00018) and DMR at 24 months (70.4% vs. 42.2%; p = 0.029). The ≥0.45-log reduction in BCR::ABL1 transcripts at 3 months predicted shorter times to MMR (median 11 vs. 29 months) and DMR (18 vs. 50 months), as well as higher overall MMR (p = 0.011) and DMR (p = 0.014) incidences. Bone marrow fibrosis correlated with inferior molecular outcomes (p = 0.017 for MMR). Conclusions: Early BCR::ABL1 decline kinetics independently predict molecular depth in pediatric CML. Quantitative early transcript reduction may guide risk-adapted management and optimize long-term TKI strategies in children. Full article

Background and Clinical Significance: Tyrosine kinase inhibitors (TKIs) have transformed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) into a largely manageable chronic disease. However, off-target toxicities are increasingly recognized; rarer complications such as bone marrow edema (BME) remain underreported. BME is a radiological syndrome characterized by excess intramedullary fluid on fat-suppressed T2/STIR magnetic resonance imaging sequences and may progress to irreversible osteochondral damage if unrecognized. We report a case series of TKI-associated BME and propose a practical diagnostic-therapeutic framework. Case Presentation: We describe three patients with Ph+ CML who developed acute, MRI-confirmed BME of the lower limb during TKI therapy. Case 1 developed unilateral then bilateral knee BME, temporally associated first with dasatinib and subsequently with imatinib; symptoms improved after TKI interruption, bisphosphonate therapy, and supportive measures, and did not recur after switching to bosutinib. Case 2 presented with proximal femoral BME during long-term imatinib; imatinib was stopped, intravenous neridronate administered, and bosutinib initiated with clinical recovery and later near-complete radiological resolution. Case 3 experienced multifocal foot and ankle BME during imatinib; symptoms resolved after drug discontinuation and bisphosphonate therapy, and disease control was re-established with bosutinib without recurrence of BME. All patients underwent molecular monitoring and mutational analysis to guide safe therapeutic switching. Discussion: Temporal association across cases and the differential kinase profiles of implicated drugs suggest PDGFR (and to a lesser extent, c-KIT) inhibition as a plausible mechanistic driver of TKI-associated BME. PDGFR-β blockade may impair pericyte-mediated microvascular integrity, increase interstitial fluid extravasation, and alter osteoblast/osteoclast coupling, promoting intramedullary edema. Management combining MRI confirmation, temporary TKI suspension, bone-directed therapy (bisphosphonates, vitamin D/calcium), symptomatic care, and, when required, therapeutic switching to a PDGFR-sparing agent (bosutinib) led to clinical recovery and preservation of leukemia control in our series. Conclusions: BME is an underrecognized, potentially disabling, TKI-related adverse event in CML. Prompt recognition with targeted MRI and a multidisciplinary, stepwise approach that includes temporary TKI adjustment, bone-directed therapy, and consideration of PDGFR-sparing alternatives can mitigate morbidity while maintaining disease control. Prospective studies are needed to define incidence, risk factors, optimal prevention, and management strategies. Full article

Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolysis, vaso-occlusion, and systemic inflammation. Epidemiological studies identified an increased risk of leukemia, especially acute myeloid leukemia (AML), in individuals with SCD, whereas data regarding other tumors are conflicting. SCD-associated AMLs frequently display high-risk features with unfavorable karyotypes and a dismal prognosis. SCD is associated with multiple phenomena linked to carcinogenesis in other contexts, including chronic inflammation, oxidative stress, ineffective erythropoiesis, accelerated hematopoietic aging, impaired tumor immunosurveillance, and increased clonal hematopoiesis. The role and respective contribution of these disease-intrinsic mechanisms in SCD remain to be studied. Although therapies used in SCD could theoretically modulate the risk of malignancies, no data exist to support an increased or reduced risk associated with their use. The most notable exception is hematopoietic stem cell transplantation and, to a lesser extent, gene therapy, for which the conditioning and/or procedure itself is known to increase the risk of leukemia. In sum, the effect of SCD on carcinogenesis is an emerging area of investigation with data supporting specificities in SCD-associated AML. Future research is required to determine the role of treatments to mitigate the increased risk and improve the outcome of SCD-associated AML. Full article

Artificial neural networks in drug discovery have shown remarkable potential in various areas, including molecular similarity assessment and virtual screening. This study presents a novel multimodal Siamese neural network architecture. The aim was to join molecular electrostatic potential (MEP) images with the texture features derived from reduced density gradient (RDG) diagrams for enhanced molecular similarity prediction. On one side, the proposed model is combined with a convolutional neural network (CNN) for processing MEP visual information. This data is added to the multilayer perceptron (MLP) that extracts texture features from gray-level co-occurrence matrices (GLCM) computed from RDG diagrams. Both representations converge through a multimodal projector into a shared embedding space, which was trained using triplet loss to learn similarity and dissimilarity patterns. Limitations associated with the use of purely structural descriptors were overcome by incorporating non-covalent interaction information through RDG profiles, which enables the identification of bioisosteric relationships needed for rational drug design. Three datasets were used to evaluate the performance of the developed model: tyrosine kinase inhibitors (TKIs) targeting the mutant T315I BCR-ABL receptor for the treatment of chronic myeloid leukemia, acetylcholinesterase inhibitors (AChEIs) for Alzheimer’s disease therapy, and heterodimeric AChEI candidates for cross-validation. The visual and texture features of the Siamese architecture help in the capture of molecular similarities based on electrostatic and non-covalent interaction profiles. Therefore, the developed protocol offers a suitable approach in computational drug discovery, being a promising framework for virtual screening, drug repositioning, and the identification of novel therapeutic candidates. Full article

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by uncontrolled proliferation of myeloid cells. MicroRNAs (miRNAs), small noncoding RNAs, regulate post-transcriptional gene expression by degrading target mRNAs or repressing translation. Dysregulated miRNA expression has been implicated in various malignancies, including CML, where they can function as oncogenes or tumor suppressors. This study aimed to investigate the relationship between miR-122-5p and cell division cycle 25A (CDC25A) in CML and to elucidate the regulatory mechanisms of miR-122-5p. This study integrates bioinformatics analysis with in vitro RT-qPCR validation in K562 chronic myeloid leukemia cells to explore the potential regulatory relationship between miR-122-5p and CDC25A. mRNA expression profiles were retrieved from the GSE100026 dataset in the Gene Expression Omnibus (GEO), and differentially expressed genes were identified using GEO2R. Quantitative real-time PCR (RT-qPCR) was performed to measure miR-122-5p, CDC25A, and cyclin-dependent kinase 4 (CDK4) expression levels. Bioinformatics analyses (miRNeT, miRDIP, TargetScan, BioGPS, GeneMANIA, STRING) were applied to predict molecular interactions and functional pathways. Public RNA-seq datasets and in silico tools were used to prioritize candidates; RT-qPCR in a single CML cell line (K562) provided in vitro expression validation. In K562 cells, miR-122-5p expression was significantly reduced, while CDC25A and CDK4 were markedly upregulated. Bioinformatics tools confirmed CDC25A as a potential miR-122-5p target. Functional enrichment indicated CDC25A involvement in cell cycle regulation and apoptosis. These findings suggest that miR-122-5p functions as a tumor suppressor in CML by targeting CDC25A. Modulating the miR-122-5p/CDC25A axis may provide potential molecular targets for inhibiting CML progression through regulation of cell cycle pathways. Findings are exploratory and based on bioinformatics with limited in vitro expression confirmation; functional studies are required to establish causality. Full article

Hematological malignancies such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphomas, and multiple myeloma remain difficult to model ex vivo because conventional two-dimensional (2D) cultures and murine systems fail to reproduce the spatial, metabolic, vascular, and immune complexity of human bone marrow and lymphoid niches. Recent advances in three-dimensional (3D) platforms—including spheroids, engineered organoid-like marrow models, and microfluidic niche-on-a-chip systems—now allow for a more physiological replication of stromal, endothelial, and immune interactions that drive resistance and relapse. In this review, we introduce explicit definitions distinguishing spheroids, organoid-like constructs, true hematopoietic organoids, and microfluidic devices to establish a unified framework for hematologic 3D modeling. We synthesize applications across AML, CML, lymphoma, and myeloma, highlighting mechanistic insights, strengths, and limitations unique to each disease. Finally, we outline a translational roadmap that integrates bioprinting, perfusable vasculature, immune reconstitution, and AI-driven analytics toward next-generation patient-specific platforms. These innovations position 3D marrow-mimetic systems as essential tools for precision oncology in blood cancers. Full article

Background/Objectives: Ponatinib (PON) is a potent anticancer drug widely used to treat chronic myeloid leukemia (CML). Although many cancer survivors benefit from such therapies, managing drug-induced side effects, especially cardiotoxicity, remains a major challenge. Despite its prevalence, the exact mechanisms underlying PON-induced cardiotoxicity have not been thoroughly investigated. Additionally, the potential of Bone Morphogenetic Protein 7 (BMP-7) to alleviate these cardiotoxic effects has yet to be explored. Methods: To address these essential questions, we conducted a study using C57BL/6 mice. Mice were treated with PON (25 mg/kg cumulative dosage) or a combination of PON and BMP-7 (600 μg/kg), alongside a suitable control group. Heart function was assessed by echocardiography. Different techniques were performed to evaluate the apoptotic pathway. Histological staining was performed to investigate structural changes. Results: PON treatment increased apoptotic cell death (increased expression of BAX and caspase-3) in the heart through the PTEN/Akt signaling pathway. Further, PON treatment led to increased cardiac hypertrophy, adverse remodeling, and reduced cardiac function. Importantly, BMP-7 markedly reduced PON-induced apoptosis (increased Bcl2 expression) and its downstream effects. Conclusions: These results suggest that BMP-7 might inhibit PON-induced cardiotoxicity. Furthermore, our findings pave the way for future translational studies with BMP-7, which can demonstrate the therapeutic potential of BMP-7 in a clinical setting. Full article

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by both an abnormal expansion of the granuloblastic clone and the pathognomonic presence of the Philadelphia (Ph) chromosome that generates the BCR::ABL1 oncoprotein. Despite the surfacing of tyrosine kinase Inhibitors (TKIs) in 2001, which changed the evolution of the disease, resistance due to point mutation or compound alteration during treatment with target therapy may occur. One of the mutations that is still an on-going challenge in clinical and scientific field is the T315I mutation, since it gives patients a poor prognosis attributable to acquired resistance to therapy. In the following narrative review, we will discuss the current knowledge on the T315I mutation, explore the most suitable treatment options, examine the role of third-generation tyrosine kinase inhibitors, and outline potential future therapeutic strategies. Full article

Imatinib (IMT) is a small-molecule tyrosine kinase inhibitor that primarily targets platelet-derived growth factor receptor-β and related kinases. Beyond its established efficacy in chronic myeloid leukemia, IMT has also demonstrated therapeutic benefits in gastrointestinal stromal tumors, dermatofibrosarcoma, acute lymphoblastic leukemia, and as a second-line treatment for aggressive systemic mastocytosis or as an anti-Mycobacterium agent. From a physicochemical perspective, IMT exhibits poor aqueous solubility but high membrane permeability, classifying it as a Biopharmaceutics Classification System Class II compound. Pharmacokinetically, IMT shows variable oral absorption and a prolonged terminal half-life, resulting in dose-dependent systemic exposure. Despite relatively high oral bioavailability, its clinical use requires large doses to achieve therapeutic efficacy, underscoring the need for advanced drug delivery strategies. Nano- and microscale delivery systems offer promising approaches to enhance tumor-specific accumulation through the enhanced permeability and retention effect while mitigating resistance mechanisms. However, achieving high drug loading introduces formulation challenges, such as controlling particle size distribution, polydispersity, and scalability. Moreover, designing carriers capable of controlled release without premature leakage remains crucial for maintaining systemic bioavailability and therapeutic performance. Emerging delivery platforms—including polymeric, lipid-based, carbon-derived, and stimuli-responsive nanocarriers—have shown significant potential in overcoming these limitations. Such systems can enhance IMT’s bioavailability, improve selective tumor targeting, and minimize systemic toxicity, thereby advancing its translational potential. This review aims to highlight the different biomedical applications of IMT and off-label uses, and to discuss current advances in drug delivery to optimize its clinical efficacy and safety profile. Full article