Search Results (987)

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML) characterized by chromosomal translocation forming the fusion protein that blocks the differentiation of myeloid progenitors and increases the self-renewal of leukemia cells. The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has dramatically improved outcomes in APL, making it a leading example of successful treatment through differentiation of cancer cells. However, life-threatening side effects and treatment resistance may develop; therefore, modulation of the safety and efficacy of these drugs may contribute to further improving treatment results. Recently, zinc, involved in the structure and function of transcription factors, has received special attention for its potential role in the development and treatment response of cancer. Zinc homeostasis is disrupted in APL, with intracellular accumulation stabilizing oncogenic proteins. Zinc depletion promotes degradation of PML–RARA and induces apoptosis, while supplementation enhances genotoxic stress in leukemic cells but protects normal hematopoiesis. Zinc also regulates key transcription factors involved in differentiation and proliferation, including RUNX2, KLF4, GFI1, and CREB. In this review, we examine how zinc may impact zinc-finger (ZnF) and non-ZnF transcription factors and differentiation therapy in APL, thereby identifying potential strategies to enhance treatment efficacy and minimize side effects. Full article

Fracture repair complications occur in 5–10% of cases, despite bone’s regenerative capacity. Bone marrow-derived (BM) stem cells have been extensively investigated for orthopedic applications but, given the critical role that periosteum plays in fracture repair, periosteal-derived (PO) cells offer a promising alternative cell source. This study compared the in vitro osteogenic capacities of equine BM and PO cells. Passage 3 cells from each source were maintained in osteogenic medium for up to 10 days. Osteogenesis was assessed by Runx2, Osterix, and alkaline phosphatase (ALP) mRNA up-regulation, induction of ALP activity, and matrix mineralization. Comparisons were made by paired t tests, repeated measures one-way or two-way ANOVAs, as indicated. BM cells proved superior to PO cells in osteogenesis assays. BM cells significantly up-regulated Runx2, Osterix, and ALP mRNAs, ALP activity, and secreted a mineralized matrix by day 10. PO cells did not. BMP-2 expression increased significantly in BM cells in osteogenic medium, whereas BMP-2 expression in PO cells was unchanged. Exogenous BMP-2 did not restore osteogenesis in periosteal cells, indicating that ex vivo expansion affects periosteal osteogenic capacity beyond BMP-2 downregulation. Clinical applications of PO cells will require the identification and exogenous provision of requisite stimulatory factors and substrates. Full article

Background: Wide application of genome sequencing technologies has highlighted extensive genetic diversity in Acute Myeloid Leukemia (AML), yet the specific roles of individual genes remain unclear. This systematic review and meta-analysis aims to provide robust evidence for the prognostic impact of somatic gene mutations in de novo AML patients, while also exploring the prevalence of these mutations. Methods: Eligible studies were identified from PubMed and Scopus, with a focus on those reporting the prognostic influence of somatic gene mutations on overall survival (OS) or relapse-free survival (RFS) when compared to wild-type carriers. We calculated the pooled prevalence with 95% confidence intervals to assess the frequency of these mutations, and the pooled Hazard Ratio (HR) to compare OS and RFS associated with specific gene mutations. Results: We evaluated 53 somatic gene mutations using 80 studies, involving 20,048 de novo AML patients. The analysis revealed that the most prevalent affected genes were NPM1 (27%), DNMT3A (26%), and FLT3-ITD (24%). Mutations in CSF3R, TET2, and TP53 were significantly associated with poorer OS or RFS (p < 0.05). Sensitivity analysis confirmed that ASXL1, DNMT3A, and RUNX1 mutations were consistently linked to inferior OS or RFS. In contrast, CEBPAdm mutations were associated with favorable OS [HR = 0.39 (0.30–0.50)] and RFS [HR = 0.44 (0.37–0.54)]. Subgroup analysis showed that FLT3-ITD mutations were consistently associated with worse OS or RFS across all subgroups, though no significant subgroup differences were noted. No significant impact on OS or RFS was observed for mutations in GATA2, FLT3-TKD, KRAS, NRAS, IDH1, and IDH2. Conclusions: These findings provide critical insights into AML prognosis, aiding clinical decision-making and improving risk stratification strategies. Full article

This review aims to provide an overview of the role of vitamin D in peri-implant and periodontal tissue. Electronic searches were carried out of the PubMed/Medline database. Since this is a narrative review, no systematic search, meta-analysis, or statistical analysis was performed. Vitamin D plays a crucial role in bone balance and metabolism, contributing to reducing early implant failure and improving dental implant osseointegration. Vitamin D deficiency poses a challenge to clinical outcomes, and its supplementation can be an effective alternative to overcome this limitation. The results reported in this article show that vitamin D application on implants can improve the osseointegration, bone-to-implant contact, implant stability, and bone density. Moreover, vitamin D supplementation can increase RUNX2, ALP, OPN, and OCN expression, contributing to periodontal tissue health and its regeneration. Together, findings provide an overview of these topics and present future perspectives for clinical practice in dentistry. Full article

Background/Objectives: Osteoarthritis (OA) is a progressive joint disease characterized by inflammation, cartilage degradation, and subchondral bone changes, for which effective disease-modifying therapies are lacking. Messenger RNA (mRNA)-based therapeutics offer a versatile approach to modulate joint pathology, but their application to OA remains limited. Methods: We evaluated intra-articular delivery of therapeutic mRNAs using polyplex nanomicelles, a non-inflammatory and minimally invasive carrier system, in a rat model of inflammation-driven OA induced by monosodium iodoacetate (MIA). Results: IL-1 receptor antagonist (IL-1Ra) mRNA reduced synovial inflammation and alleviated pain and swelling. RUNX1 mRNA, a transcription factor critical for chondrogenesis, supported chondrocyte viability, type II collagen expression, and cartilage structure. Under conditions of pronounced inflammation, however, the protective effects of RUNX1 mRNA alone were modest. Notably, combined administration of IL-1Ra and RUNX1 mRNAs produced synergistic therapeutic benefits, with enhanced chondroprotection and preservation of subchondral bone integrity. Conclusions: These findings suggest that while RUNX1 is essential for maintaining cartilage homeostasis, effective control of joint inflammation is required for its therapeutic activity. Dual mRNA therapy delivered by polyplex nanomicelles therefore represents a promising strategy to address the multifactorial pathology of OA. Full article

Runt-related transcription factor 1 (RUNX1) is a key transcription factor in hematopoiesis, producing multiple major isoforms, RUNX1A, B, and C, via alternative promoter usage and splicing. These isoforms have distinct roles in hematopoiesis and leukemogenesis. Imbalances in isoform expression, such as RUNX1A overexpression or RUNX1C loss, contribute to leukemogenesis in disorders. RUNX1 isoform expression is regulated by transcriptional, epigenetic, and splicing mechanisms and is further influenced by genome architecture. Pathogenic variants, including truncations and fusion proteins, disrupt isoform homeostasis and transcriptional control for the target genes in hematopoiesis. Recent therapeutic strategies aim to restore isoform balance rather than inhibit RUNX1 globally. Approaches include splice-switching oligonucleotides, CRISPR-based promoter modulation, and enhancer-targeted therapies. Understanding isoform-specific RUNX1 biology offers new opportunities for precision treatment of hematologic malignancies. Full article

Background: Cervical cancer (CC) ranks as the third most common cancer in incidence and mortality in females worldwide. Let-7c is a tumor suppressor miRNA, and its role has been little studied in CC. Runt-related transcription factor 1 (RUNX1) is upregulated in several human cancers, such as colorectal cancer. It is a transcription factor that promotes cell proliferation, metastasis, chemotherapy resistance and angiogenesis in colorectal cancer. In this study, we performed a bioinformatic analysis to understand how Let-7c and RUNX1 are involved in the development of CC. Methods: We performed a bioinformatic analysis of Let-7c in CC using GSE and TCGA datasets from GEO, KM-plotter, miRPathDB and Enrich databases. Then, we conducted a comprehensive analysis of RUNX1’s role in CC using TCGA, GSE and HPA datasets from OncoDB, CISTROME, ExPASy, Alibaba, ALGGEN, ENCODE, IGV, GEO, KM-plotter and DiseaseMeth databases. Results: We found that Let-7c expression is decreased in CC. Interestingly, we identified a transcription factor known as RUNX1, as a potential target of Let-7c. Finally, we suggest that RUNX1 could regulate the expression of several genes, promoting CC. Conclusions: The Let-7c/RUNX1 axis promotes CC. Full article

Articular cartilage regeneration remains a major challenge due to its limited self-repair capacity. Bone marrow-derived skeletal stem cells (SSCs) and mesenchymal stem cells (MSCs) are promising candidates for cartilage engineering, although they differ in their chondrogenic potential. This study explored whether co-culturing SSCs and MSCs in three-dimensional (3D) organoid systems under cartilage physioxia (5% O₂) and chondrogenic induction could improve cartilage tissue formation. SSCs, MSCs, and SSC–MSC co-cultures were characterized for morphology, phenotype, and differentiation capacity. Organoids were generated and cultured for 10 days, followed by analysis of morphology, viability, gene expression (SOX9, RUNX2, ACAN, COL2A1, COL10A1, PRG4, and PDPN), chondrocyte-associated antigens (CD44, CD105, CD146, and PDPN), and cartilage ECM proteins (aggrecan, collagen types I, II, and X, and PRG4). SSCs showed robust chondrogenic and osteogenic potential, while MSCs exhibited a balanced multipotency. Co-culture-derived organoids enhanced chondrogenesis and reduced adipogenesis, with higher expression of cartilage-specific ECM and lower hypertrophic marker levels. These findings highlight the functional synergy between SSCs and MSCs in co-culture, promoting the formation of stable, cartilage-like structures under physioxia. The approach offers a promising strategy for generating preclinical models and advancing regenerative therapies for hyaline cartilage repair. Full article

Background: Bone regeneration is a key therapeutic objective in periodontology, particularly in the treatment of alveolar defects caused by periodontal disease, dentoalveolar trauma, or surgical interventions. Among current regenerative strategies, collagen-enriched biomaterials have demonstrated an active role in modulating cellular behavior during bone repair. However, the specific effects of different collagen formulations on human dental pulp stem cells (hDPSCs) have not yet been fully characterized. Objective: To evaluate the impact of xenogeneic bone grafts with and without collagen—OsteoBiol^® Gen-Os^® (GO), OsteoBiol^® GTO^® (GTO), and Geistlich Bio-Oss^® (BO)—on cell viability, adhesion, migration, osteogenic differentiation, and mineralization potential of hDPSCs, and to explore the molecular mechanisms underlying their effects. Methods: In vitro assays were conducted to assess viability (MTT and fluorescence staining), adhesion (SEM), migration (wound healing assay), and mineralization (Alizarin Red S staining). Gene expression analyses (RT-qPCR) were performed for adhesion/migration markers (FN, SDF-1, COL1A1), angiogenic/proliferation markers (VEGF, FGF2), and osteogenic differentiation markers (RUNX2, ALP, COL1A1). Results: GO showed a higher early expression of genes associated with adhesion, migration, angiogenesis (FN, SDF-1, VEGF and FGF2: p < 0.05; COL1A1: p < 0.01), and osteogenic differentiation (7 days: COL1A1 and ALP (p < 0.001)); (14 days: RUNX2, ALP: p < 0.001; COL1A1: p < 0.05), indicating a sequential activation of molecular pathways and mineralization capacity comparable to the control group. GTO demonstrated the best biocompatibility, with significantly higher cell viability (p < 0.05), strong adhesion, and markedly increased mineralization at 21 days (p < 0.001), despite moderate early gene expression. BO showed reduced cell viability at 10 mg/mL (p < 0.05) and 20 mg/mL (p < 0.001), with mineralization levels similar to the control group. Conclusion: Collagen-based xenografts demonstrate favorable interactions with hDPSCs, enhancing viability and promoting osteogenic differentiation. Our findings suggest that beyond the presence of collagen, the specific formulation of these biomaterials may modulate their biological performance, highlighting the importance of material design in optimizing regenerative outcomes. Clinical Significance: The formulation of collagen in xenogeneic bone substitutes may be a determining factor in enhancing periodontal regenerative outcomes by modulating the early cellular response and osteogenic activity in stem cell-based tissue engineering. Full article

B-cell acute lymphoblastic leukemia (B-ALL) remains a major clinical challenge in hematologic oncology, characterized by a continuous evolution of molecular drivers that shape its heterogeneity across the age spectrum. Pediatric B-ALL is generally associated with high cure rates, while adult forms of the disease are often more aggressive and less responsive to treatment. This review examines the age-specific genetic and epigenetic landscapes that contribute to this disparity, revealing how the nature and timing of molecular alterations point to fundamentally different leukemogenic processes. Favorable genetic aberrations, such as ETV6::RUNX1 and hyperdiploidy, are predominant in children, whereas adults more frequently present with high-risk features, including BCR::ABL1 fusions and IKZF1 deletions. Epigenetic distinctions are similarly age-dependent, involving divergent patterns of DNA methylation, histone modifications, and non-coding RNA expression. For example, pediatric B-ALL frequently harbors mutations in epigenetic regulators like SETD2 and CREBBP, while adult B-ALL is more commonly affected by alterations in TET2 and IDH1/2. These molecular differences are not only prognostic but also mechanistic, reflecting distinct developmental trajectories and vulnerabilities. Understanding these age-driven transitions is essential for improving risk stratification and developing precision therapies tailored to the unique biology of B-ALL across the lifespan. Full article

Osteoblastogenesis plays a critical role in bone repair. Insulin and insulin-mimetic compounds, such as vanadium (IV) oxide acetylacetonate (VAC), have been reported to enhance bone healing in various models. This study aimed to evaluate the effects of vanadium compounds, VAC and vanadium (IV) oxide sulfate (VOSO₄), on osteoblast proliferation and function. MC3T3-E1 pre-osteoblast cells were treated with insulin, ascorbic acid, and varying concentrations of VAC or VOSO₄, and samples were collected at multiple time points over 21 days. We assessed cell proliferation, functional markers, and gene and protein expression. Our findings demonstrate that both VAC and VOSO₄ stimulate MC3T3-E1 proliferation, increase calcium and proteoglycan deposition, and enhance phosphorylation of Protein Kinase B (Akt) over time. Gene expression analysis revealed that VAC treatment upregulated RUNX2, BGLAP, and TWIST2 at Day 7 compared to controls, with sustained expression patterns observed at Day 10. These results align with existing literature, supporting that VAC and VOSO₄ promote osteoblastogenesis and may serve as effective adjuvants to accelerate bone regeneration during fracture healing. Full article

Scaffold architecture is a key determinant of cell behavior and tissue regeneration in bone tissue engineering, yet the influence of pore size under dynamic culture conditions remains incompletely understood. This study aimed to evaluate the effects of scaffold pore size on osteogenic differentiation of porcine bone marrow-derived mesenchymal stem cells (pBMSCs) cultured in a rotational oxygen-permeable bioreactor system (ROBS). Three-dimensionally (3D) printed beta-tricalcium phosphate (β-TCP) scaffolds with pore sizes of 500 µm and 1000 µm were seeded with pBMSC and cultured for 7 and 14 days under dynamic perfusion conditions. Gene expression analysis revealed significantly higher levels of osteogenic markers (Runx2, BMP-2, ALP, Osx, Col1A1) in the 1000 µm group, particularly at the early time point, with the later-stage marker Osteocalcin (Ocl) rising faster and higher in the 1000 µm group, after a lower expression at 7 days. ALP activity assays corroborated these findings. Despite having lower mechanical strength, the 1000 µm scaffolds supported a homogeneous cell distribution and high viability across all regions. These results suggest that larger pore sizes enhance early osteogenic commitment by improving nutrient transport and fluid flow in dynamic culture. These findings also support the use of larger-pore scaffolds in bioreactor-based preconditioning strategies and underscore the clinical importance of promoting early osteogenic differentiation to reduce in vitro culture time, an essential consideration for the timely preparation of implantable grafts in bone tissue engineering. Full article

Background/Objectives: Inherited platelet disorders (IPDs) are diverse conditions characterized by abnormalities in platelet count and function. Next-Generation Sequencing (NGS) shows promise as a diagnostic tool in the diagnosis of IPDs. This study aims to assess the clinical value and limitations of using a targeted NGS panel in diagnosing children with suspected IPDs. Methods: We conducted a retrospective study of 93 children evaluated for suspected IPDs. A targeted NGS panel of 14 IPD-associated genes (RUNX1, WAS, ADAMTS13, ANKRD26, CYCS, GATA1, GP1BA, GB1BB, GP9, ITGA2B, ITGB3, MASTL, MPL, MYH9) was performed. Results: Genetic variants were identified in 30 patients (32.3% of the cohort). A total of 37 variants, of which 15 (40.5%) were novel, were found across 11 of the 14 genes on the panel (all except MPL, CYCS, and RUNX1). Variants were most frequently found in ITGB3 (18.9% of variants), GP1BA (16.2%), and ADAMTS13 (16.2%) genes. The majority of variants (64.9%) were classified as variants of uncertain significance (VUS), followed by likely pathogenic (LP) (27%) and pathogenic (8.1%) variants. Most variants were in a heterozygous state (73%). Specific cases highlighted complex genetic scenarios, such as co-occurring variants, and the identification of pathogenic and LP variants in patients initially presenting with immune thrombocytopenia. Conclusions: NGS helps to identify genetic causes, assess risk, manage, and provide genetic counseling in the management of IPDs. However, the prevalence of VUS underscores the need for a multidisciplinary approach to evaluate NGS results accurately. Full article

Stauntonia hexaphylla (Thunb.) Decne (SH), a medicinal plant from the Lardizabalaceae family, holds traditional importance in East Asia for treating rheumatism. Steam treatment is commonly applied to enhance its medicinal properties, but the chemical and biological changes resulting from this process remain unexplored. This study compared steamed and untreated SH fruit (SHF) extracts, analyzing their chemical composition, antioxidant activity, and effects on bone health using in vitro models. Steamed SHF extracts exhibited increased levels of 5-hydroxymethylfurfural (5-HMF), total flavonoids, phenolics, and enhanced antioxidant activity. Bone health assessment using osteoclasts differentiated from RAW 264.7 cells and osteoblasts from MC3T3-E1 cells revealed that steamed extracts promoted alkaline phosphatase activity, calcium nodule formation, and collagen synthesis in osteoblasts while inhibiting tartrate-resistant acid phosphatase (TRAP) activity in osteoclasts. Additionally, steamed SHF extracts effectively modulated gene expression related to osteoclastogenesis and osteoblastogenesis by downregulating TRAP, NFTAc1, RANK, MMP9, c-Fos, and TRAF6 while upregulating ALP, Runx2, BGLAP, Col1a1, and OPG. The component 5-HMF played a pivotal role in promoting alkaline phosphatase and inhibiting TRAP activities. These findings suggest that steamed SHF may offer a promising therapeutic approach for postmenopausal osteoporosis. Full article

The epidermal growth factor receptor (EGFR), as an important target protein for inhibiting and intervening in osteoporosis, is associated with cell migration, proliferation, and apoptosis. Peptides derived from food have been shown to have a strong affinity for EGFR, thereby regulating downstream cellular-signaling pathways and participating in stimulating bone formation. However, it is still a “black box” as to how active peptides affect the conformational changes in the EGFR-binding domain when interacting with its ligand EGF. To shed light on the roles, peptides in EGFR binding, which is involved in the osteoblast differentiation, a high EGFR affinity soybean peptide (HEP) was isolated and purified from soy yogurt. Firstly, the osteogenic activity of HEP was identified through cellular alkaline-phosphatase (ALP) and calcium influx. HEP promoted ALP activity from 0.01897 ± 0.00165 to 0.04051 ± 0.00402 U/mg after 100 μM of peptide treatment, and free intracellular calcium ions and calcium deposition both increased in a dose-dependent manner at 1–100 μg/mL. Secondly, the interaction between HEP and EGFR was detected by bioinformatics, spectroscopy analysis, and Western blot. The Molecular docking results showed that HEP (VVELLKAFEEKF) exhibited high affinity among all the peptides, with -CDOCKER energy values of 184.077 kcal/mol on one EGFR. Moreover, a different loop conformation has been detected in HEP, comparing it to that of EGF, which influences HEP interactions with EGFR. GlU3, LEU4, and LEU5 (HEP) match GLU40, LEU26, and GLU40 (EGF). Moreover, the CD data showed that HEP could interact with extracellular domain protein of EGFR, but the secondary structure did not change after HEP was mixed with Mutant extracellular domain protein. Furthermore, treatment with HEP increased the expression of EGFR and the activation of the PI3K-RUNX2-signaling pathway. These results suggested that HEP may have the function of promoting bone remodeling, which could promote the binding between EGF and EGFR and may be used as a potential active factor for functional food development to prevent osteoporosis. Full article