Search Results (951)

Background: Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-cell ALL characterized by a gene expression profile similar to BCR::ABL1-positive leukemia, but lacking the BCR::ABL1 fusion gene. It is frequently associated with kinase-activating alterations, such as CRLF2 rearrangements, JAK-STAT pathway mutations, and ABL-class fusions. Patients with Ph-like ALL typically experience poor outcomes with conventional chemotherapy, underscoring the need for intensified and targeted therapeutic approaches. Methods: This review summarizes current evidence regarding the role of hematopoietic stem cell transplantation (HSCT) in patients with Ph-like ALL. We analyzed retrospective cohort studies, registry data, and ongoing clinical trials, focusing on transplant indications, molecular risk stratification, measurable residual disease (MRD) status, timing of transplant, and post-transplant strategies. Results: Retrospective data suggest that HSCT in first complete remission (CR1) may improve survival in patients with high-risk molecular lesions or MRD positivity at the end of induction. However, the lack of prospective data specific to Ph-like ALL limits definitive conclusions. Post-transplant relapse remains a challenge, and novel strategies, including the use of tyrosine kinase inhibitors or JAK inhibitors as post-HSCT maintenance therapy, are being explored. Emerging immunotherapies, such as chimeric antigen receptor (CAR) T cells, may reshape the therapeutic landscape and potentially alter the indications for transplantation. Conclusions: HSCT remains a crucial therapeutic option for selected patients with Ph-like ALL, particularly those with poor molecular risk features or persistent MRD. However, further prospective studies are needed to evaluate the indication for HSCT in CR1 and the potential integration of transplantation with targeted and immunotherapeutic strategies. Personalized treatment approaches based on genomic profiling and MRD assessment are essential to improve outcomes in this high-risk subset. Full article

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. While in vitro patient-derived xenografts (PDX) lines are useful for studying GBM, they often exclude astrocytes and macrophages, which contribute significantly to tumor growth, invasion, and chemoradioresistance. Integrating these cells into tumor models is difficult due to their need for serum, which triggers GBM-PDX lines to lose their stem-like properties. The aim of this study was to develop a serum-free triculture model of GBM-PDX lines, normal human astrocytes (NHAs), and macrophages. Serum-free media alternatives were formulated for NHAs and identified for THP-1 macrophages, then combined with GBM PDX media to establish “PSX,” an experimental maintenance media. Cells were transitioned to serum-free media alternatives and functionally assessed through several parameters unique to each cell type. In addition to assessing GBM “stemness,” a custom 350-gene NanoString chip was used to assess differential gene expression in monocultured PDX cells versus PDX cells exposed to NHAs and macrophages. PSX maintained canonical function in astrocytes and macrophages while preserving the stem-like properties of GBM-PDX cells. Tri-culturing all three cells increased the expression of stemness-associated transcription factors and increased the expression of genes related to stemness and hypoxia in GBM cells. GBM PDX cells exposed to NHAs and macrophages in direct triculture exhibit increases in markers of stemness and hypoxia. These findings suggest that the serum-free triculture model presented herein may better recapitulate the tumoral heterogeneity of GBM in vitro, providing a novel model to utilize in current research. Full article

X chromosome inactivation (XCI) is a fundamental epigenetic process that balances X-linked gene expression between females and males by silencing one X chromosome in female cells. Variability or skewing of XCI can influence the clinical presentation of X-linked disorders. Bain type X-linked intellectual disability syndrome (MRXSB), caused by mutations in the X-linked HNRNPH2 gene, is characterized by intellectual disability, developmental delay, and neurological abnormalities. In female patients, XCI heterogeneity complicates disease modeling and therapeutic development. Induced pluripotent stem cells (iPSCs) offer a unique platform to study patient-specific disease mechanisms, but the dynamics of XCI during iPSC reprogramming, maintenance, and differentiation are not fully understood. In this study, we generated 12 iPSC clones from fibroblasts of a female MRXSB patient heterozygous for the HNRNPH2 c.340C > T mutation. Four clones expressed the mutant HNRNPH2 allele and eight expressed the wild-type allele, indicating X chromosome reactivation (XCR) followed by random XCI during reprogramming. Importantly, these XCI patterns remained stable during long-term iPSC propagation and subsequent differentiation into the three germ layers and neural stem cells. Our findings provide new insights into XCI and XCR dynamics in the context of X-linked neurodevelopmental disorders and emphasize the importance of careful clone selection for accurate disease modeling using iPSC-based approaches. Full article

CD44 variants (CD44v) play essential roles in the promotion of tumor metastasis, maintenance of cancer stem cell properties, and resistance to treatments. Therefore, the development of anti-CD44v mAbs is essential for targeting CD44v-positive tumor cells. An anti-CD44v9 mAb, C₄₄Mab-1 (mouse, IgG₁, kappa), was previously established. C₄₄Mab-1 recognizes the variant exon 9-encoded region and applies to multiple research techniques. A mouse IgG_2a version of C₄₄Mab-1 (C₄₄Mab-1-mG_2a) was generated to evaluate the in vitro and in vivo antitumor activities using gastric and colorectal cancer cell lines. C₄₄Mab-1-mG_2a showed a reactivity to CD44v3–10-overexpressed Chinese hamster ovary-K1 (CHO/CD44v3–10), gastric cancer MKN45, and colorectal cancer COLO205 in flow cytometry. C₄₄Mab-1-mG_2a exhibited both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against CHO/CD44v3–10, MKN45, and COLO205. Furthermore, administration of C₄₄Mab-1-mG_2a significantly suppressed CHO/CD44v3–10, MKN45, and COLO205 xenograft tumor growth compared with control mouse IgG_2a. These results indicated that C₄₄Mab-1-mG_2a, which possesses ADCC/CDC activities, could be applied to the mAb-based therapy against CD44v9-positive carcinomas. Full article

Multipotent hematopoietic stem cells (HSC) reside in specialized niches of the bone marrow (BM). The maintenance of their stemness requires a precisely regulated bone marrow microenvironment (BMM), supported by mesenchymal stem cells (MSCs), stromal reticular cells, and endothelial and nerve cells located within the vascular and endosteal niches. The heterogeneity of the niche environment is caused by the diversity of cell populations from HSCs to more mature hematopoietic cell types and MSCs, which collectively influence the complex intercellular interactions involved in hematopoiesis. MSC subclusters in BM are characterized by the phenotypes of CXC-chemokine ligand 12, leptin receptor, neuron-glial antigen 2, and Nestin+ cells. The article presents a detailed characterization of individual stem cell types in the BM, their reciprocal interaction, and the possibility of in vitro simulation of the bone marrow niche as a dynamic structure. Development of a suitable simulation of the BMM is essential for advancing research into both physiological and pathological processes of hematopoiesis. The main goal is to simulate 3D cell culture using biomaterials that mimic the BM niche in the form of hydrogels and scaffolds, in combination with extracellular matrix components. Full article

This research delves into the complex relationship between progenitor cells and the differentiated cell types that make up the stomach. It highlights the need for further investigation into the mechanisms governing stomach development and how these mechanisms relate to the maintenance of the stomach in a healthy state. The transition from normal gastric mucosa to metaplasia involves significant alterations in the phenotype and function of gastric epithelial cells, including stem cells, mucous neck cells, chief cells, and parietal cells. The presented literature review provides an in-depth analysis of pyloric and pseudopyloric metaplasia, along with spasmolytic polypeptide-expressing metaplasia, focusing on their biological significance, underlying pathogenesis, diagnostic features, and prognostic implications. It explores the role of various gastric epithelial cell types in the pathogenesis of metaplasia, highlighting recent advances in cellular plasticity, molecular pathways, and the implications for gastric carcinogenesis. Full article

Non-CG DNA methylation plays a critical role in regulating root development and stress responses in Arabidopsis thaliana under cadmium (Cd²⁺) exposure. We compared wild type (WT) plants with the ddc triple mutant (deficient in DRM1, DRM2, and CMT3) to assess how epigenetic modifications affect the root apical meristem (RAM) under 100 µM and 150 µM CdCl₂ treatments. Cd²⁺ exposure led to RAM disorganization, reduced cortical cell number, and quiescent center (QC) cell loss in WT roots, while ddc mutants maintained meristem integrity and exhibited QC cell expansion. Auxin signaling, assessed via pDR5::GFP, was disrupted in WT roots at high Cd²⁺ levels but remained stable in ddc mutants. Similarly, WT roots showed elevated reactive oxygen species accumulation under stress, whereas ddc mutants displayed a reduced oxidative response. These results suggest that non-CG DNA methylation suppresses key regulators of stem cell maintenance, hormonal balance, and redox homeostasis during heavy metal stress. Loss of this methylation in the ddc mutant confers enhanced resilience to Cd²⁺ toxicity, highlighting an epigenetic mechanism underlying root stress adaptation. Full article

Human induced pluripotent stem cells (hiPSCs) hold immense promise for regenerative medicine. However, a critical barrier to the clinical application of hiPSCs is the difficulty in promoting robust cell proliferation while preserving their pluripotent state. Efficient hiPSC expansion without loss of pluripotency is crucial for generating high quality cells or therapeutic applications, disease modeling, and drug discovery. In our study, we investigated the effects of QuinoMit Q10^® fluid (QMF-Se), a nanoformulated supplement containing Ubiquinol (the active form of Coenzyme Q10) and Selenium, on hiPSC growth and maintenance in vitro. Interesting, QMF-Se supplementation significantly enhances hiPSC proliferation compared to control cultures. This increase in cell number was accompanied by heightened mitochondrial activity, suggesting improved cellular energy metabolism. Importantly, the expression of core pluripotency markers OCT4, NANOG, and SOX2 remained unaltered, confirming that the stem cells retained their undifferentiated status. Moreover, we observed that QMF-Se treatment conferred protective effects during the freeze–thaw process, reducing cell death and supporting post-thaw recovery. These results indicate that QMF-Se may improve both cell culture efficiency and cryopreservation outcomes. Overall, our findings highlight the potential of QMF-Se as a valuable additive for hiPSC culture systems, contributing to more efficient and reliable expansion protocols in regenerative medicine research. Full article

Heart disease remains a leading cause of morbidity and mortality worldwide, necessitating the development of in vivo models for therapeutic development. Advances in biomedical engineering in the past decade have led to the promising rise of human-based engineered cardiac tissues (hECTs) using novel scaffolds and pluripotent stem cell derivatives. This has led to a new frontier of human-based models for improved preclinical development. At the same time, there has been significant progress in elucidating the importance of the immune system and, in particular, macrophages, particularly during myocardial injury. This review summarizes new methods and findings for deriving macrophages from human pluripotent stem cells (hPSCs) and advances in integrating these cells into cardiac tissue. Key challenges include immune cell infiltration in 3D constructs, maintenance of tissue architecture, and modeling aged or diseased cardiac microenvironments. By integrating immune components, hECTs can serve as powerful tools to unravel the complexities of cardiac pathology and develop targeted therapeutic strategies. Full article

Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin lymphoma confined to the central nervous system. The cancer biology of PCNSL remains incomplete and is often associated with genetic aberrations with abnormal signaling pathways, cell differentiation, regulation of epigenetic modification, and the tumor microenvironment. Stereotactic brain biopsy remains the gold standard for the diagnosis of PCNSL. For patients ill-suited for biopsy, MYD88 and IL-10 may be important biomarkers to diagnose PCNSL. High-dose methotrexate-based polychemotherapy is currently the standard induction treatment for PCNSL, followed by consolidation treatments including autologous stem cell transplant and whole-brain radiotherapy. Some studies suggest that low-dose lenalidomide is recommended as a maintenance therapy for PCNSL. Currently, relapse rates of PCNSL range from 25 to 50% with poor prognosis. Insight research is necessary to identify novel targeted treatments to improve outcomes in relapsed/refractory disease, such as immunomodulatory drugs, immune checkpoint inhibitors, signaling pathway inhibitors, and chimeric antigen receptor T-cell therapy. Full article

Redox balance is essential for maintenance of the hematopoietic stem cell (HSC) pool, which ensures the lifelong hematopoiesis. However, oxidative attack induced by various physiopathological stresses always compromises HSC maintenance, while there remains lack of safe and effective antioxidative measures combating these conditions. Here, we show that ferulic acid (FA), a natural antioxidant abundantly present in Angelica sinensis which is a traditional Chinese herb commonly used for promotion of blood production, distinctively and directly promotes HSC maintenance and thereby boosts hematopoiesis at homeostasis, whether supplemented over the long term in vivo or in HSC culture ex vivo. Using a mouse model of acute myelosuppressive injury induced by ionizing radiation, we further reveal that FA supplementation effectively safeguards HSC maintenance and accelerates hematopoietic regeneration after acute myelosuppressive injury. Mechanistically, FA diminishes ferroptosis susceptibility of HSCs through limiting the labile iron pool (LIP), thus favoring HSC maintenance. In addition, the LIP limitation and anti-ferroptosis activity of FA is independent of nuclear-factor erythroid 2-related factor 2 (NRF2), probably relying on its iron-chelating ability. These findings not only uncover a novel pharmacological action and mechanism of FA in promoting HSC maintenance, but also provides a therapeutic rationale for using FA or FA-rich herbs to treat iron overload- and ferroptosis-associated pathologies such as acute myelosuppressive injury. Full article

Stem cells are essential for tissue maintenance, repair, and regeneration, yet their dysregulation gives rise to cancer stem cells (CSCs), which drive tumor progression, metastasis, and therapy resistance. Despite extensive research on stemness and oncogenesis, a critical gap remains in our understanding of how the transcriptomic landscapes of normal somatic stem cells (SSCs) diverge from those of CSCs to enable malignancy. This review synthesizes current knowledge of the key signaling pathways (Wnt, Notch, Hedgehog, TGF-β), transcription factors (Oct4, Sox2, Nanog, c-Myc, YAP/TAZ), and epigenetic mechanisms (chromatin remodeling, DNA methylation, microRNA regulation) that govern stemness in SSCs and are hijacked or dysregulated in CSCs. We highlight how context-specific modulation of these pathways distinguishes physiological regeneration from tumorigenesis. Importantly, we discuss the role of epithelial–mesenchymal transition (EMT), cellular plasticity, and microenvironmental cues in reprogramming and maintaining CSC phenotypes. By integrating transcriptomic and epigenetic insights across cancer biology and regenerative medicine, this review provides a framework for identifying vulnerabilities specific to CSCs while still preserving normal stem cell function. Understanding these distinctions is essential for the development of targeted therapies that minimize damage to healthy tissues and advance precision oncology. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid proliferation, invasiveness, therapeutic resistance, and an immunosuppressive tumor microenvironment. A subpopulation of glial stem-like cells (GSCs) within GBM tumors contributes significantly to tumor initiation, progression, and relapse, displaying remarkable adaptability to oxidative stress and metabolic reprogramming. Recent evidence implicates the atypical kinases RIOK1 and RIOK2 in promoting GBM growth and proliferation through their interaction with oncogenic pathways such as AKT and c-Myc. Concurrently, the redox-sensitive Nrf2/Keap1 axis regulates antioxidant defenses and supports GSC survival and chemoresistance. Additionally, aberrant activation of the canonical Wnt/β-catenin pathway in GSCs enhances their self-renewal, immune evasion, and resistance to standard therapies, particularly under oxidative stress conditions. This review integrates current knowledge on how redox homeostasis and key signaling pathways converge to sustain GSC maintenance and GBM malignancy. Finally, we discuss emerging redox-based therapeutic strategies designed to target GSC resilience, modulate the tumor immune microenvironment, and surmount treatment resistance. Full article

The capacity of plants to generate new organs and tissues throughout their life cycle depends on the activity of the stem cells contained in meristematic tissues. Plant stem cells are organized in small, clustered populations referred to as stem cell niches. In addition to generating new undifferentiated cells, stem cell niches also provide the positional information that maintains stem cell self-renewal properties and controls the non-cell-autonomous differentiation of surrounding tissues. In this review, we aim to analyze and discuss the most recent literature describing the molecular mechanism controlling the activity and the organization of the stem cell niche in the root of the model plant Arabidopsis thaliana (L.) Heynh. In particular, we will focus on the complex molecular regulatory networks that control the balance between stemness and differentiation in distal stem cells, as well as the maintenance of the mitotically inactive state of the quiescent center. Full article

Although chemotherapy is the preferred treatment for gastric cancer, the therapeutic drugs currently available have limited efficacy and severe side effects. Cancer stem cells within tumor masses have the distinctive properties of self-renewal, maintenance, and resistance to chemotherapy. Hence, agents capable of targeting stemness in gastric tumors with minimal side effects are urgently required. Enzymes that generate reactive oxygen species contribute to the high oxidation levels observed in tumors. Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2), an antioxidant transcription factor, regulates cancer stemness. Increasing evidence highlights the potential of nutritional supplementation to treat cancer stemness. ω-3 polyunsaturated fatty acids support human health and offer benefits for cancer treatment. Linolenic acid (LA), an ω-3 polyunsaturated fatty acid, inhibits the expression of proteins associated with stemness and promotes apoptosis in gastric cancer cells. Our findings indicated that LA treatment substantially inhibited key characteristics of gastric cancer stemness and induced oxidative stress and caspase-3-mediated apoptosis by downregulating Nrf2-mediated expression. These results suggest that LA is a promising nutritional supplement for targeting cancer stemness in the treatment of gastric cancer. Full article