Gastric cancer (GC) remains a highly aggressive malignancy with poor prognosis. Anoikis resistance is closely associated with tumor progression and metastasis, but the prognostic and functional relevance of anoikis-related genes (ARGs) in GC remains incompletely understood. Public transcriptomic, clinical, somatic mutation, and single-cell RNA sequencing (scRNA-seq) datasets were integrated to identify differentially expressed ARGs, develop an ARG-based risk model, and investigate its associations with tumor microenvironment (TME) features. In vitro experiments were performed to assess the effects of selected candidate genes on GC cell migration and invasion. Forty-five differentially expressed ARGs were identified in The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohort. An ARG-based risk model was developed using the TCGA-STAD cohort and evaluated in the GSE84437 cohort. The model was associated with overall survival and provided potential value for risk stratification, although its discriminative performance was modest. High-risk patients showed distinct immune, stromal, and somatic mutational features. Single-cell analysis suggested that ARG-related transcriptional programs were associated with stromal remodeling and endothelial-to-mesenchymal transition (EndMT)-associated features in the GC microenvironment. Among the core ARGs, EEF1A2 and TAGLN showed prognostic relevance and higher protein expression in GC tissues. Small interfering RNA (siRNA)-mediated knockdown of either gene reduced the migration and invasion of HGC-27 cells. These findings indicate that ARG-related molecular features are associated with GC prognosis and immune-stromal characteristics, while EEF1A2 and TAGLN may represent candidate genes related to GC cell migration and invasion.

Cancer represents a significant and growing public health emergency in Nigeria, where high mortality rates, late-stage presentation, inadequate infrastructure, prohibitive costs and pervasive stigma combine to produce a multidimensional crisis. While epidemiological data and health system analysis illuminate the scale of the problem, they fail to capture the deeper ethical, structural and existential realities that shape the lived experience of cancer. This paper employs key philosophical concepts, including distributive justice, social justice, structural violence, biopolitics, epistemic injustice, care ethics, existentialism, Ubuntu philosophy, vulnerability theory and the capabilities approach to analyze the complex realities of cancer in Nigeria. It is a critical reflection on the rationale for practices and policies that are often taken for granted, using the tools of formal philosophical inquiry, with a view to either grounding the practices in proper ethical understanding, or rethinking them along proper ethical lines. We argue that applying these philosophical frameworks reveal deep-seated inequities, challenges to patient agency, the corrosive effects of stigma rooted in epistemic failures, relational deficits in care, and the profound existential struggles patients and families face. By examining the interplay among scarce resources, cultural beliefs, systemic weaknesses, and fundamental questions of value and meaning, this paper argues that a philosophical perspective offers a roadmap for more humane, just, and culturally grounded reforms in cancer prevention, diagnosis, treatment, palliative care, and compassionate responses within the Nigerian context.

Extrachromosomal DNA (ecDNA) has emerged as a major contributor to cancer aggressiveness, yet its role extends far beyond its classical definition as a vehicle for oncogene amplification. Recent studies indicate that ecDNA functions as a dynamic regulatory platform that reshapes chromatin accessibility, enhancer activity, three-dimensional genome organization, nuclear architecture, and transcriptional output. Through these properties, ecDNA enables cancer cells to amplify oncogenic signaling, generate transcriptional plasticity, and rapidly adapt to selective pressures. In contrast to chromosomal amplification, ecDNA is structurally independent, frequently circular, acentromeric, and inherited through noncanonical mitotic behaviors, allowing unequal segregation, coordinated co-inheritance, and persistent propagation of advantageous regulatory states. Emerging evidence further shows that ecDNA can hijack pre-existing enhancers, rewire enhancer-oncogene communication, activate noncanonical regulatory elements, and assemble into transcriptionally active nuclear hubs and condensate-associated structures, thereby transforming genome rearrangement into epigenetic innovation. These mechanisms position ecDNA as a key driver of intratumoral heterogeneity, clonal evolution, metastatic adaptation, and therapeutic resistance. At the same time, the high transcriptional burden and specialized regulatory architecture of ecDNA-positive tumors may create selective vulnerabilities, including transcription-replication conflict and dependence on ecDNA-associated hubs, condensates, and regulatory modules. In this review, we synthesize current advances in the formation, regulation, inheritance, and functional consequences of ecDNA, with a particular focus on its emerging role as a platform for epigenetic reprogramming in cancer. We also discuss how this conceptual shift from copy-number biology to regulatory biology may redefine ecDNA as both a mechanistic framework for tumor plasticity and a potential frontier for precision oncology.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by the absence of actionable molecular targets, high metastatic propensity, and limited responsiveness to current immunotherapies. Although immune checkpoint inhibitors show promise, their clinical efficacy is constrained by low tumor immunogenicity and a highly immunosuppressive tumor microenvironment (TME). This study reports a hyaluronic acid (HA)-functionalized TiO₂@Cu₂-_XSe@HA nanosystem that promotes the coordinated induction of ferroptosis and cuproptosis, thereby enhancing sonodynamic immunotherapy against TNBC. It features a rationally designed Cu₂-_XSe/TiO₂ heterostructured nanosonosensitizer and an integrated therapeutic strategy combining ultrasound-activated sonodynamic effects with the coordinated induction of ferroptosis and cuproptosis. Under ultrasound irradiation, the Cu₂-_XSe/TiO₂ heterointerface promotes efficient electron transfer and reactive oxygen species (ROS) generation, markedly amplifying sonodynamic efficacy. Meanwhile, released Cu²⁺ depletes intracellular glutathione, disrupts redox homeostasis, thereby promoting copper-dependent proteotoxic stress. In parallel, Cu²⁺ induces autophagic degradation of glutathione peroxidase 4, further enhancing ferroptotic signaling. This coordinated induction effectively suppresses tumor growth, remodels the immunosuppressive TME, and potentiates antitumor immunity, as further corroborated by single-cell RNA sequencing. Collectively, this study provides a rational strategy for integrating sonodynamic therapy with dual non-apoptotic cell death pathways, offering a promising strategy to sensitize TNBC to immunotherapy.

Two-dimensional (2D) monolayer cultures remain the workhorse of colorectal cancer (CRC) research and high-throughput screening (HTS), yet they poorly recapitulate tissue architecture, extracellular matrix (ECM) cues, metabolic gradients, and multicellular heterogeneity that govern drug response in vivo. Over the past decade, three-dimensional (3D) culture systems-including spheroids, patient-derived organoids (PDOs), tissue-originated spheroids (CTOS), and collagen-embedded models-have revealed striking 2D vs. 3D discordance in proliferation, signaling, epithelial-mesenchymal transition (EMT), plasticity, and sensitivity to standard chemo- and targeted therapies. This review synthesizes how 3D CRC models are used to decode mechanisms of primary and acquired resistance to anti-CRC therapies, from metabolic phenotypes and ECM remodeling to EMT, polarity loss, and rare invasive trajectories identified by imaging and quantification of morphologic features of CRC cells grown in 3D. Parallel advances in PDO-based functional precision oncology demonstrate that organoid drug screens can prospectively predict patient response in advanced CRC, while 3D combination screens uncover format-specific synergies that are invisible in 2D. Building on this foundation, we highlight recent technical innovations and discuss how integrating morphometric, metabolic, and trajectory-level readouts can move CRC drug discovery "beyond live/dead." Rather than propose a single best model, we outline practical guidelines for matching 3D platform choice (cell lines vs. PDO/CTOS, collagen vs. Matrigel, static vs. live-imaging HTS) to mechanistic questions and therapeutic goals in CRC. We propose an integrated roadmap-matrix-embedded 3D cultures, high-content morphological endpoints, trajectory analytics, and rigorous HTS validation-to decode resistance mechanisms and prioritize clinically actionable combinations in CRC.

We report a 55-year-old man who developed nephrotic syndrome 52 months after allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia. He had chronic graft-versus-host disease controlled with low-dose prednisolone and tacrolimus. Asymptomatic proteinuria was detected five months before referral, followed by progressive edema, massive pleural effusion, and ascites. At presentation, laboratory testing showed profound hypoalbuminemia, mildly reduced kidney function, and nephrotic-range proteinuria. Kidney biopsy demonstrated membranous nephropathy, with periodic acid-methenamine silver staining showing spikes and bubbling of the glomerular basement membrane. Immunofluorescence showed granular capillary-wall immunoglobulin G staining with immunoglobulin G1 predominance over immunoglobulin G4, and protocadherin FAT1 immunofluorescence showed granular staining along the glomerular basement membrane. Prednisolone was increased from 5 to 30 milligrams per day while tacrolimus was continued, resulting in improved proteinuria, serum albumin, edema, and kidney function at five months without clinically significant infectious complications. We also reviewed 29 reported cases of protocadherin FAT1-associated membranous nephropathy after hematopoietic stem cell transplantation, including the present case. The review showed variable onset timing, substantial proteinuria at presentation, inconsistent immunoglobulin G4 positivity, and heterogeneous treatment with corticosteroids, rituximab, calcineurin inhibitors, and other regimens. Our case and review indicate that this disease can present late, cannot be excluded by non-immunoglobulin G4-predominant staining, and remains heterogeneous in diagnostic evaluation, treatment, and outcomes. Further accumulation of cases is needed to clarify the clinical spectrum and optimal management of this disease.

Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but many patients with large B cell lymphoma (LBCL) experience primary resistance or relapse. To uncover resistance mechanisms, here we examine pre-infusion tumor biopsies and observe that increased immunoregulatory macrophages correlate with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-γ) upregulates inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Proteomic profiling reveals that iNOS-expressing macrophages promote apoptosis and cell cycle arrest while downregulating protein synthesis machinery in CAR T cells. Metabolically, CAR T cells exhibit reduced glycolytic intermediates and altered tricarboxylic acid (TCA) cycle activity. Pharmacological inhibition of iNOS enhances CAR T cell treatment efficacy in vivo. Elevated levels of iNOS⁺CD14⁺ monocytes in leukaphereses are associated with non-durable responses to CAR T cells. Targeting iNOS in immunoregulatory macrophages, potentially by modulating CAR T-produced IFN-γ, could improve LBCL outcomes.

We developed a novel carbon nanoparticle-Fe (II) complex prepared via suspension injection (CNSI-Fe) to induce cancer cell ferroptosis through direct intratumoral delivery of ferrous iron. Preclinical studies have demonstrated that CNSI-Fe has promising antitumour effects, thereby prompting this first-in-human, single-arm, open-label, dose-escalation phase I trial in patients with refractory solid tumors. Primary objectives included assessments of safety and tolerability and the determination of dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Secondary objectives included the determination of preliminary antitumour efficacy and pharmacokinetics. Applying a 3 + 3 design across five doses (30-150 mg), a total of 19 enrolled patients received CNSI-Fe treatment. The MTD was not reached, and only one patient (in the 90 mg cohort) experienced DLT events. For all treated patients (n = 19), the common adverse events included injection site pain (89.5%), hypertension (52.6%), elevated serum iron levels (47.4%), and anemia (47.4%). Pharmacokinetic analysis revealed rapid iron absorption (peak time: 0.15-0.41 h) and clearance (half-life: 1.96-5.06 h), with peak serum concentrations ranging from 3520.33 to 13961.67 ng/mL. Preliminary efficacy estimates revealed an overall response rate of 10.5% and a disease control rate (DCR) of 84.2%. Notably, the DCR reached 100% in patients with lymph node and sarcoma lesions. Overall, CNSI-Fe demonstrated a favorable safety profile and promising antitumour activity (ClinicalTrials.gov identifier: NCT06048367), supporting further investigations in a phase II trial.

Cell differentiation, the process by which stem cells acquire specialized functions, underpins embryonic development, tissue homeostasis, and regeneration. This process is governed by evolutionarily conserved signaling pathways, including Wnt, Notch, Hedgehog, TGF-β, and Hippo, which integrate extracellular cues with intrinsic genetic programs to determine cell fate. Here, we provide a comprehensive overview of the molecular architecture of these pathways, spanning ligand-receptor interactions to downstream transcriptional regulation. We further highlight multilayered regulatory mechanisms such as epigenetic modifications, non-coding RNAs, feedback loops, and pathway crosstalk that fine-tune signaling outputs to ensure spatiotemporal precision in fate decisions. We also discuss how tissue-specific contexts and interactions among these pathways generate distinct differentiation outcomes in different organs and disease settings. Dysregulation of these networks contributes to diverse pathological states, driving uncontrolled proliferation in cancer, maladaptive remodeling in cardiovascular disease, neuronal loss in neurodegeneration, metabolic imbalance, digestive dysfunction, chronic inflammation in respiratory and autoimmune diseases, and skeletal disorders. Reflecting their clinical importance, we also summarize recent therapeutic advances, including small-molecule inhibitors, monoclonal antibodies, gene-based strategies, and pathway-modulating compounds, which target these pathways to restore normal cellular function. Particular attention is given to distinguishing preclinical findings from clinical applications and to the translational challenges of pathway-targeted therapies. Collectively, this review underscores the central role of differentiation-related signaling in health and disease and highlights emerging opportunities for therapeutic intervention.

CD24 is widely recognized as a developmental marker of early B-cell differentiation and is highly expressed in precursor B-cell acute lymphoblastic leukemia (B-ALL). However, CD24 expression alone does not fully explain its biological activity, suggesting that post-translational regulation, particularly glycosylation, may determine its immune-regulatory functions. Although the CD24-Siglec-10 axis has emerged as an important innate immune checkpoint, how developmental CD24 expression is functionally adapted during leukemogenesis remains poorly understood. Here, we propose a framework in which CD24 functions as a glyco-immune checkpoint whose activity is determined by functional glycoforms rather than protein abundance alone. We discuss how physiological CD24 expression during B-cell ontogeny may contribute to developmental immune tolerance and propose that this program can be retained, hijacked, or remodeled during leukemogenesis through altered glycosylation patterns. Such glyco-adaptation may enhance CD24-Siglec-10-mediated suppression of macrophage surveillance, allowing leukemia cells to evade innate immune recognition and persist as minimal residual disease. We further propose that glycosylation-dependent immune adaptation represents an additional layer of leukemia evolution that complements genetic and epigenetic alterations. This perspective integrates developmental biology, glycobiology, innate immunity, and leukemia biology to establish the emerging field of leukemia glycoimmunology. Finally, we discuss the translational implications of CD24 glycobiology, including glycoform-based biomarkers, functional immune profiling, glycosylation-directed therapeutic strategies, and modulation of glycan remodeling pathways. Understanding how glycosylation shapes CD24 function may provide new opportunities for precision immunotherapy in B-ALL.