Search Results (7,532)

Breast cancer remains a leading cause of mortality among women worldwide. The inherent heterogeneity in tumors among patients with breast cancer poses a challenge to effective therapeutic management. The extracellular matrix (ECM) is an important structural component of the tumor microenvironment (TME) that regulates cellular behavior. When the ECM adopts a stiff configuration, this coincides with biochemical remodeling in response to biomechanical cues that drive tumor cell invasion, immune evasion, and metastatic spread in breast cancer. Emerging studies suggest that patient ancestry significantly impacts ECM stiffness to contribute to disparities in breast cancer survival. In this review, we discuss recent advances in our understanding of how the tumor ECM orchestrates breast cancer invasion and metastasis through mechanotransduction signaling to promote breast cancer progression. We also discuss ancestry-associated differences in breast ECM architecture and agents targeting mechanotransduction signaling pathways with potential to treat breast cancer and improve patient outcomes. Collectively, this review will highlight the significance of tumor mechanobiology and present emerging therapies that target stiffness-sensitive mechanotransduction pathways. By integrating mechanistic insights with therapeutic innovation, we aim to support the development of ECM-targeted therapies to enable more efficacious treatment of aggressive breast cancer subtypes. Full article

Background: Alemtuzumab is a recombinant DNA-derived humanized monoclonal antibody directed against the 21–28 kd cell surface glycoprotein, CD52. Alemtuzumab is used as an organ anti-rejection therapy in transplant recipients. Neuro-ophthalmic adverse effects are rarely described, and, to our knowledge, accommodative spasm has not previously been reported in a transplant recipient. Case Description: A thirty-nine-year-old woman with genetically confirmed NPHP1-associated nephronophthisis, with stage F3 fibrosis, developed persistent bilateral blurred vision 72 h following alemtuzumab administration for a biopsy-proven acute cellular rejection, approximately six to seven weeks post-transplant. Initial attribution to hyperglycaemia and tacrolimus toxicity delayed recognition. Cycloplegic refraction confirmed a marked hyperopic shift (+2.75 D right eye, +2.50 D left eye) with significant improvement in visual acuity, consistent with accommodative spasm. Systemic evaluations excluded hyperglycaemia-related lens changes, calcineurin inhibitor neurotoxicity, and cytomegalovirus retinitis. MRI was not pursued in the absence of red flag neurological features, and because a definitive ophthalmic diagnosis had been made. Management and Outcome: The patient was managed expectantly, as cycloplegic refraction had already confirmed the diagnosis, and symptoms were improving. Therapeutic cycloplegia (e.g., atropine) was withheld to avoid impairing near vision and driving ability. Full resolution occurred within 4 to 6 weeks without intervention. Drug exposure to onset of symptoms was 72 h; onset of symptoms to diagnostic confirmation was 22 days; total symptom duration was 5.5 weeks, and recovery was 2 weeks after diagnosis. Conclusions: This case represents the first reported transplant case of alemtuzumab-associated accommodative spasm. Causality assessment supports a WHO-UMC classification of “Probable”, aligning with five Bradford–Hill considerations (temporality, biological plausibility, consistency, specificity, and analogy), but without statistical “strength of association” given that this is a single case report. Early cycloplegic refraction should be incorporated into the evaluation of post-alemtuzumab visual complaints, and clinicians should contribute to pharmacovigilance through structured reporting to capture these rare but important events. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking estrogen, progesterone, and HER2 receptors. This characteristic limits the effectiveness of hormonal and targeted therapies, and despite advances in chemotherapy (ChT), radiotherapy (RT), surgery, targeted therapy (TT) and immunotherapy (IT), clinical outcomes remain poor, highlighting an urgent need for new therapeutic strategies. The development of advanced nanotechnology-based strategies has opened new avenues for the diagnosis and therapy of TNBC. This review focuses on photothermal therapy (PTT) combined with nanotechnology-based strategies. PTT constitutes an emerging modality for oncological treatment that leverages light irradiation, mostly in the near-infrared (NIR) spectral region, to induce the localized thermal ablation of malignant tissues. When combined with gold nanoparticles (AuNPs), PTT is significantly potentiated. AuNPs have distinctive optical and physicochemical characteristics, rendering them highly effective as multifunctional nanoplatforms. Upon irradiation, AuNPs act as efficient photothermal agents, inducing localized hyperthermia. This thermal effect disrupts cellular homeostasis and initiates a cascade of cell death pathways, including apoptosis and necrosis, culminating in tumor regression. This review describes the latest therapeutic advances of PTT and AuNPs. As this innovative approach progresses toward clinical application, future studies and trials will be crucial in determining its potential for TNBC management and improving patient outcomes. Full article

Diabetic ketoacidosis (DKA) remains a life-threatening complication of diabetes mellitus with suboptimal outcomes despite standard management. Emerging evidence suggests that thiamine (vitamin B1) deficiency may play an under-recognized role in DKA pathophysiology and clinical course. This narrative review synthesizes current evidence regarding thiamine deficiency in diabetes and DKA, examining molecular mechanisms, clinical implications, and the rationale for thiamine supplementation as adjunctive therapy. Thiamine deficiency is highly prevalent in diabetes, with plasma concentrations reduced by approximately 75% compared to healthy controls. In DKA specifically, 25–35% of patients present with thiamine deficiency, which often worsens during insulin therapy. The primary mechanism involves hyperglycemia-induced downregulation of renal thiamine transporters (THTR-1 and THTR-2), resulting in 16–24-fold increased renal clearance and massive urinary losses. Thiamine pyrophosphate serves as an essential cofactor for three critical enzymes in glucose metabolism: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase. Deficiency impairs these pathways, causing pyruvate accumulation with conversion to lactate (resulting in lactic acidosis), compromised TCA cycle function (reducing ATP production by 40–48%), and decreased NADPH generation (increasing oxidative stress). Clinical manifestations include persistent metabolic acidosis despite standard therapy, myocardial dysfunction with elevated cardiac biomarkers, neurological impairment, and prolonged recovery times. Cellular studies demonstrate that thiamine supplementation significantly improves mitochondrial oxygen consumption in DKA patients. The high prevalence of thiamine deficiency in DKA, compelling biochemical rationale, excellent safety profile, and preliminary mechanistic evidence support the urgent need for large-scale randomized controlled trials examining thiamine supplementation to definitively establish efficacy, optimal dosing, and patient selection criteria. Full article

Recent evidence indicates that both epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET), are key mechanisms driving breast cancer (BC) metastasis. During EMT, epithelial BC cells acquire mesenchymal traits that enhance motility, invasiveness, and resistance to therapy. A deeper understanding of EMT regulation may therefore unveil novel therapeutic targets to limit disease progression. In this study, we analyzed the expression of key EMT-associated proteins, namely Vimentin, E-cadherin, Cytokeratin-18, and alpha-smooth muscle actin, in a cohort of 95 BC tissue samples and observed marked intra- and inter-tumoral heterogeneity. Notably, we found positive correlations between epithelial and mesenchymal markers, supporting the presence of hybrid epithelial/mesenchymal phenotypes and substantial cellular plasticity, which may contribute to BC heterogeneity. High heterogeneity in marker expression was also detected between tumor tissues and matched adjacent normal tissues. The unexpected complexity uncovered at the protein level prompted us to question whether single markers or limited proteomic panels are sufficient to capture the EMT landscape in BC. Through integrative bioinformatics, we defined a novel EMT gene signature significantly associated with prognosis. Functional enrichment revealed pathways related to extracellular matrix organization, proteoglycans, and intercellular communication, emphasizing the dynamic bidirectional crosstalk between BC cells and the tumor microenvironment. Moreover, we identified a gene cluster linked to cancer stem cell-like features, which may be clinically relevant for patient risk stratification. Overall, our findings underscore the complexity of EMT regulation in BC and introduce a new EMT signature with potential prognostic and therapeutic relevance. Full article

Liver fibrosis is a significant consequence of severe liver injury resulting from viral hepatitis, alcohol, and metabolic dysfunction. Progressive fibrosis and ultimate cirrhosis are leading causes of morbidity and mortality worldwide, generally irreversible and poorly targeted by current therapies. Traditional in vitro models and animal models mostly fail to fully recapitulate human multicellular crosstalk, extracellular matrix (ECM) remodeling, and the chronic, immune modulated nature of the disease. Recent advances in three-dimensional (3D) cell culture models including organoids, spheroids, bioprinted constructs, and organ-on-a-chip systems are advantageous for reconstructing cellular diversity and mechanical microenvironments to understand pathophysiology and aid in drug discovery. Emerging multi-organ models are capable of incorporating microbiome derived cues and using multi-omics readouts and imaging-enabled mechanistic dissection for more predictive anti-fibrotic screening. These technologies align well with the recent Modernization 3.0 regulation and New Approach Methodologies by the Food and Drug Administration (FDA) and recent EU Pharmaceutical Reform. This review summarizes the pathophysiology of liver fibrosis, the current landscape of 3D human liver models, and examines how microbiome interfaces modulate fibrogenesis. Full article

Introduction: The existence of primary adrenal gland lymphoma (PAGL) has been debated due to lack of lymphoid tissue in the adrenal glands. PAGL is extremely rare, accounting for less than 1% of all types of lymphomas. The aim of this study was to analyze patients with PAGL in Polish population. Material and Methods: We retrospectively reviewed 13 adult patients with PAGL diagnosed in Polish Hematological Centers. Results: A total of 13 patients (5 women and 8 men) with PAGL were included into the study. The median age at the diagnosis was 69.1 years (range: 31–85). The most common histological type was diffuse large B-cell lymphoma (DLBCL)-12 patients, the remaining one was diagnosed with Hodgkin lymphoma (HL). In 7 patients (54%), the left adrenal gland was involved; in 3 patients (23.5%), the right adrenal gland was involved; and 3 patients (23.5%) had bilateral lymphoma. Systemic symptoms (B symptoms) were observed in 11 out of 13 patients (85%). Two patients (15%) were treated with chemotherapy alone and the remaining eleven patients (85%) with immune and chemotherapy together (85%). During the follow-up period, 11 patients died, 8 had relapsed or refractory disease (62%), and 3 patients (23%) had relapse in central nervous system (CNS). The median progression-free survival (PFS) was 14.63 months, while the median overall survival (OS) was 20.30 months. Adrenalectomy of the involved adrenal gland was associated with shorter PFS (p = 0.0165), with trend of shorter OS. Achieving complete remission (CR) after front line treatment was associated with significantly longer OS (p = 0.0239) and PFS (p = 0.0152). Conclusions: Adrenal glands are extremely rare as primary locations of extranodal lymphoma. The prognosis of PAGL is generally poor. In this study, we described demographic, clinical, and pathological characteristics as well as factors that may affect survival among these groups. So far, it is the largest polish multicenter experience describing patients with PAGL. Full article

Human neuroglobin (Ngb) is a globin featuring a disulfide bond (Cys46–Cys55) and a redox-active cysteine residue (Cys120) and plays a dual role in cellular stress responses. In this study, we investigated how wild-type (WT) Ngb and its two mutants, C120S Ngb, in which Cys120 is replaced by serine, and A15C Ngb, which contains an engineered Cys15–Cys120 disulfide bridge, modulate oxidative stress in triple-negative breast cancer (MDAMB231) and hormone receptor-positive breast cancer (MCF-7) cells. In both cell lines, WT Ngb enhanced cell survival under H₂O₂-induced oxidative stress by scavenging reactive oxygen species (ROS) through oxidation of Cys120. In contrast, the C120S and A15C mutants lost this protective capacity and instead promoted apoptosis. Mass spectrometry analysis confirmed the oxidation of Cys120 to sulfenic acid in WT Ngb, whereas both mutants exhibited impaired redox activity, leading to elevated ROS levels, lipid peroxidation, and activation of caspase-9/3. AO/EB staining further revealed that WT Ngb attenuated DNA damage, while the mutants exacerbated apoptosis in both MDAMB231 and MCF-7 cells. These results demonstrate that Cys120 acts as a critical redox switch, dictating whether Ngb exerts cytoprotective or pro-apoptotic effects across different breast cancer cell types. Our findings suggest that WT Ngb may help protect normal tissues during cancer therapy, whereas engineered Ngb mutants could be used to selectively sensitize both triple-negative and hormone receptor-positive breast cancer cells to oxidative damage, offering a novel redox-targeted therapeutic strategy. Full article

Background: Boron neutron capture therapy (BNCT) represents a highly selective therapeutic modality for recalcitrant cancers, leveraging the nuclear reaction initiated by thermal neutron capture in boron-10 (¹⁰B) to deliver high-linear energy transfer radiation (α-particles and ⁷Li ions) directly within tumor cell boundaries. However, the widespread clinical adoption of BNCT is critically hampered by the pharmacological challenge of achieving sufficiently high, tumor-selective intracellular ¹⁰B concentrations (20–50 μg of ¹⁰B/g tissue). Conventional small-molecule boron carriers often exhibit dose-limiting non-specificity, rapid systemic clearance, and poor cellular uptake kinetics. Methods: To overcome these delivery barriers, we synthesized and characterized a novel dual-modality nanoplatform based on highly biocompatible, functionalized graphene oxide (GO). This platform was structurally optimized via covalent conjugation with high-boron content carborane clusters (dodecacarborane derivatives) for enhanced BNCT efficacy. Crucially, the nanocarrier was further decorated with plasmonic gold nanostructures (AuNPs), endowing the system with intrinsic surface-enhanced Raman scattering (SERS) properties, enabling real-time, high-resolution intracellular tracking and quantification. Results: We evaluated the synthesized GO@Carborane@Au nanoplatforms for their stability, cytotoxicity, and internalization characteristics. Cytotoxicity assays demonstrated excellent biocompatibility against the non-malignant human keratinocyte line (HaCaT) while showing selective toxicity (upon irradiation, if tested) and high cellular uptake efficiency in the aggressive human glioblastoma tumor cell line (T98G). The integrated plasmonic component allowed for the successful, non-destructive monitoring of nanoplatform delivery and accumulation within both HaCaT and T98G cells using SERS microscopy, confirming the potential for pharmacokinetic and biodistribution studies in vivo. Conclusions: This work details the successful synthesis and preliminary in vitro validation of a unique graphene oxide-based dual-modality nanoplatform designed to address the critical delivery and monitoring challenges of BNCT. By combining highly efficient carborane delivery with an integrated photonic trace marker, this system establishes a robust paradigm for next-generation theranostic agents, significantly advancing the potential for precision, image-guided BNCT for difficult-to-treat cancers like glioblastoma. Full article

Cellular senescence is a permanent cell cycle arrest that plays a critical role in the development and pathogenesis of age-related diseases. This paper aims to present the biological mechanisms of cellular senescence and the role of the senescence-associated secretory phenotype (SASP) in the pathogenesis of atherosclerosis, as well as to discuss therapeutic strategies targeting senescent cells in cardiovascular diseases. Different types of cellular senescence are described, including replicative, stress-induced, and oncogene-induced senescence, along with the composition and regulation of SASP and its impact on chronic inflammation, endothelial dysfunction, vascular remodeling, and plaque destabilization. The involvement of senescent endothelial cells, vascular smooth muscle cells, and macrophages in the initiation and progression of atherosclerosis is also discussed. The paper reviews current research on senolytic and senomorphic therapies and highlights emerging approaches such as immunosenolytic and epigenetic interventions. The therapeutic potential of these strategies in reducing chronic vascular inflammation and improving plaque stability, as well as their limitations and challenges in clinical application, is emphasized. Full article

Kidney organoids, as three-dimensional microstructures derived from human pluripotent stem cells or adult stem cells, precisely simulate the cellular heterogeneity, spatial conformation, and some physiological functions of human kidney units in vitro. Kidney organoids are three-dimensional microstructures derived from human pluripotent stem cells (hPSCs). They precisely simulate the cellular heterogeneity, spatial conformation, and key physiological functions of human kidney units in vitro. This technology, by replicating the interaction network between the glomerulus and renal tubules, provides an unprecedented window for observing the dynamic development and pathological processes of human kidneys. This technology replicates the interaction network between the glomerulus and renal tubules. It thereby provides an unprecedented window into human kidney development and disease. Based on the strong similarity between organoids and native organs, as well as the human genetic information they carry, both iPSC-derived and patient-specific organoids have demonstrated significant value in kidney disease modeling, drug toxicity testing, and the development of regenerative treatment strategies. This review systematically elucidates the key advancements in the field of kidney organoids, including optimized strategies for stem cell-directed differentiation, innovations in culture systems driven by biomaterials engineering, technological breakthroughs in disease model construction, and applications of organoids in drug screening platforms and regenerative medicine. Additionally, it analyzes translational challenges such as the lack of vascularization, insufficient functional maturity, and obstacles in standardized production. These insights will deepen the understanding of kidney pathological mechanisms and propel organoid technology towards substantial clinical therapeutic applications. This review summarizes how convergent technologies in stem cell biology and bioengineering aim to bridge this functional gap. We examine the use of advanced organoids in disease modeling and drug discovery. We also highlight their current limitations. Our focus is on the core translational bottlenecks: vascularization, long-term maturation, and scalable production. Overcoming these hurdles is essential to transform kidney organoids from a research tool into a platform for precision medicine and regenerative therapy. Full article

Background: The tumor microenvironment (TME) poses significant challenges to effective therapy, with cancer-associated fibroblasts (CAFs) playing a key role in tumor progression and drug resistance in triple-negative breast cancer (TNBC). Herein, a TME responsive nanocapsule, NPC-ABS/FDS, was developed utilizing baicalein, a CAFs modulator, and the cytotoxic drug doxorubicin to selectively target CAFs and tumor cells, respectively, in a stepwise manner. Methods: NPC-ABS/FDS was designed with CD13-mediated primary targeting for tumor accumulation and secondary targeting via σ-receptor binding (ABS nanoparticles) for CAFs and folate modification (FDS nanoparticles) for cancer cells. Physicochemical properties were assessed using TEM, particle size, and ζ-potential analyses. Fluorescence imaging evaluated tumor retention, while cellular uptake and TME modulation were analyzed in vitro and in vivo. Results: The successful preparation of NPC-ABS/FDS was demonstrated by its uniform morphology, stable characteristics, charge reversal, and increased particle size. Fluorescence imaging confirmed prolonged peritumoral retention. Cellular uptake increased 2.5-fold for baicalein in CAFs and 4.3-fold for doxorubicin in cancer cells. NPC-ABS/FDS downregulated α-SMA and FAP, reducing CAFs activation, improving intratumoral drug penetration, and enhancing CD8⁺ and CD4⁺ T cell infiltration while decreasing regulatory T cells. Conclusions: NPC-ABS/FDS effectively modulates multiple TME components, including CAFs and immune cells, and improves drug delivery in TNBC. These findings may support the development of improved therapeutic approaches for TNBC. Full article

Lactylation serves as a vital link between cellular metabolism and epigenetic regulation and plays a pivotal role in muscle biology. Muscle tissue is the primary site of lactate production; its unique metabolic environment confers dynamism, specificity and functional diversity for lactylation. Under physiological conditions, lactylation regulates myocyte energy metabolism, proliferation, differentiation, and exercise adaptation through a dynamic “writer–eraser–reader” mechanism. In pathological states, lactate imbalance directly contributes to the progression of various muscular disorders. For instance, diminished histone lactylation during muscle aging suppresses the expression of genes critical for DNA repair and protein homeostasis. Aberrant lactylation is involved in the development of insulin resistance and diabetic cardiomyopathy. Furthermore, lactylation exerts dual effects in cardiovascular diseases; it provides protection by enhancing the transcription of repair genes and simultaneously aggravates injury by promoting processes such as fibrosis and ferroptosis. Collectively, these findings underscore the importance of lactylation in muscular pathologies and provide a theoretical foundation for the development of therapies that target this modification process. As the regulatory mechanisms of lactylation have become clearer, precise interventions targeting specific modification sites are expected to open new therapeutic avenues for muscular diseases. Full article

Neuroblastoma is the most common extracranial solid tumor of childhood and remains a leading cause of cancer-related mortality in pediatric patients. Characterized by marked clinical and biological heterogeneity, the disease ranges from spontaneously regressing tumors in infants to highly aggressive, treatment-resistant malignancies in older children. Advances in molecular biology and genomics have significantly improved understanding of neuroblastoma pathogenesis, revealing the critical role of genetic and epigenetic alterations—such as MYCN amplification, ALK mutations, and chromosomal aberrations—in disease behavior and prognosis. Contemporary risk stratification systems now integrate clinical, biological, and molecular features to guide therapy more precisely. Management strategies have evolved toward risk-adapted, multimodal approaches. Low- and intermediate-risk patients often achieve excellent outcomes with surgery alone or limited chemotherapy, whereas high-risk neuroblastoma requires intensive multimodal treatment including induction chemotherapy, surgical resection, high-dose chemotherapy with autologous stem cell rescue, radiotherapy, and maintenance therapy. The incorporation of immunotherapeutic approaches, particularly anti-GD2 monoclonal antibodies, has significantly improved survival in high-risk disease. Emerging therapies such as targeted agents, radiopharmaceuticals, and cellular immunotherapies are further expanding the therapeutic landscape. Despite these advances, high-risk and relapsed neuroblastoma remain associated with substantial morbidity and mortality. Ongoing challenges include treatment resistance, long-term toxicity, and disparities in access to advanced therapies. Continued progress will depend on integrating molecular profiling into clinical decision-making, refining risk-adapted treatment strategies, and expanding international collaborative research efforts. This narrative review summarizes current knowledge on neuroblastoma epidemiology, biology, staging, and treatment, highlighting recent advances and future directions aimed at improving outcomes for affected children. Full article

Immunocompromised patients, including those with advanced HIV infection, hematologic malignancies treated with anti-CD20 monoclonal antibodies, or combined immunodeficiencies, are at increased risk of persistent SARS-CoV-2 infection. While long-term viral shedding has been described in these patients, the extent and nature of intra-host viral evolution during long-term infection remain insufficiently documented. In this study, we report longitudinal genomic analyses of SARS-CoV-2 from three immunocompromised individuals with persistent COVID-19: (i) a female patient with follicular lymphoma receiving bendamustine-rituximab therapy with 9 months of persistence, (ii) a male patient with advanced HIV infection following prolonged antiretroviral therapy interruption with 10 months of persistence, and (iii) a female patient with Good’s Syndrome characterized by combined humoral and cellular immune deficiency with apparently four years of persistence. Replication-competent virus was detected over extended periods. Sequential whole-genome sequencing revealed the gradual accumulation of non-synonymous mutations across multiple viral genes, consistent with ongoing viral replication and intra-host diversification in the absence of effective immune control. Although based on a limited number of cases, these findings provide descriptive evidence that persistent SARS-CoV-2 infection in immunocompromised hosts can be associated with sustained viral evolution. This work highlights the importance of continued virological monitoring in selected patients with prolonged infection and contributes to the understanding of SARS-CoV-2 dynamics in settings of impaired immunity. Full article