Search Results (60)

Background/Objectives: Premalignant laryngeal lesions carry a variable risk of malignant transformation to squamous cell carcinoma. Identifying reliable biomarkers that predict malignant transformation could improve patient management and surveillance strategies. The objective of this work is to perform a systematic review of the literature on biomarkers that predict malignant transformation of premalignant laryngeal lesions. Methods: We conducted a systematic review following PRISMA 2020 guidelines. The PubMed, Scopus and Embase databases, and Google Scholar were searched for studies published between January 2011 and November 2025. Studies investigating biomarkers that predict malignant transformation of histopathologically confirmed premalignant laryngeal lesions were included. Risk of bias was assessed using the ROBINS-I tool. Results: From 166 initially identified records, 11 studies met the inclusion criteria, including 730 patients. These studies investigated diverse biomarker categories such as protein markers (cortactin, FAK, NANOG, SOX2, CSPG4), immune markers (tumor-infiltrating lymphocytes, immune gene signatures), microRNAs (miR-183-5p, miR-155-5p, miR-106b-3p), and genetic markers (chromosomal instability, PIK3CA amplification and mutations, FGFR3 mutations). Five studies provided adequate follow-up data on transformation outcomes. Most studies showed a moderate to serious risk of bias primarily due to limited confounder control and incomplete reporting. Conclusions: While several promising biomarker candidates have been identified, the evidence base remains limited due to small sample sizes, heterogeneous methodologies, and inadequate follow-up data. Cortactin/FAK protein expression and immune signatures are the most promising but require validation in larger, well-designed prospective cohorts. Full article

Osteosarcoma (OSA) is an aggressive primary bone cancer mainly affecting the pediatric population. Despite intensive multimodal treatments, therapeutic progress has remained limited for decades, resulting in high recurrence rates, poor prognosis driven by metastatic progression, and severe chemotherapy-associated toxicities. To advance the development of more effective and safer therapeutic strategies, our recent studies identified Chondroitin Sulfate Proteoglycan (CSPG)4 as a relevant mediator of the malignant behavior of OSA cells. Targeting CSPG4 DNA-based vaccine demonstrated encouraging antitumor activity against OSA. Nevertheless, since single-agent immunotherapies are often constrained by tumor immune escape, the need for rational combinatorial strategies is of utmost importance. In this perspective, we broaden our analysis to include other potentially complementary targets beyond CSPG4, which may contribute to OSA pathogenesis. Among these, the cystine/glutamate antiporter xCT and Toll-like Receptor 2 (TLR2) emerge as particularly promising due to their established role in tumor progression, therapy resistance, and immune modulation. We discuss the contribution of all these molecules in major hallmarks of OSA—(1) proliferative and survival advantages, (2) metastasis and angiogenesis, and (3) immune evasion—and examine potential strategies for their combined targeting. By leveraging knowledge gained from other cancer models and integrating it with the distinct biological and clinical features of OSA, this perspective seeks to outline rational and innovative combinatorial strategies that may overcome current therapeutic limitations and ultimately improve patient outcomes. Full article

Background: Cancer stem cells (CSCs) are key drivers of tumorigenesis and metastasis. However, the precise roles of CSC-associated genes in these processes remain unclear. Methods: This study integrates cancer stem cell biomarkers and clinical data from The Cancer Genome Atlas (TCGA) specific to bladder cancer (BLCA). By combining differentially expressed genes (DEGs) from TCGA-BLCA samples with CSC-related biomarkers, we conducted comprehensive functional analyses and developed an 8-gene prognostic signature through Cox regression, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox regression. This model was validated with GEO datasets (GSE13507 and GSE32894), and the single-cell RNA seq dataset GSE222315 was subsequently analyzed to characterize the signature genes and elucidate their interactions. And a nomogram was created to stratify TCGA-BLCA patients into risk categories. The ‘oncoPredict’ algorithm based on the GDSC2 dataset assessed drug sensitivity in BLCA. Result: From the TCGA cohort, 665 CSC-related genes were identified, with 120 showing significant differential expression. The 8-gene signature (ALDH1A1, CBX7, CSPG4, DCN, FASN, INHBB, MYC, NCAM1) demonstrated strong predictive power for overall survival in both TCGA and GEO cohorts, as confirmed by Kaplan–Meier and ROC analyses. The nomogram, integrating age, tumor stage and risk scores, demonstrated high predictive accuracy. Additionally, the oncoPredict algorithm indicated varying drug sensitivities across patient groups. Based on retrospective data, we identified a novel CSC-related prognostic signature for BLCA. This finding suggests that targeting these genes could offer promising therapeutic strategies. Full article

Arteriovenous malformations (AVMs) are congenital vascular anomalies defined by abnormal direct connections between arteries and veins due to their complex structure or endovascular approaches. Pharmacological strategies targeting the underlying molecular mechanisms are thus gaining increasing attention in an effort to determine the mechanism involved in AVM regulation. In this study, we examined 30 human tissue samples, comprising 10 vascular samples, 10 human fibroblasts derived from AVM tissue, and 10 vascular samples derived from healthy individuals. The pharmacological agents thalidomide, U0126, and rapamycin were applied to the isolated endothelial cells (ECs). The pharmacological treatments reduced the proliferation of AVM ECs and downregulated miR-135b-5p, a biomarker associated with AVMs. The expression levels of angiogenesis-related genes, including VEGF, ANG2, FSTL1, and MARCKS, decreased; in comparison, CSPG4, a gene related to capillary networks, was upregulated. Following analysis of these findings, skin samples from 10 AVM patients were reprogrammed into induced pluripotent stem cells (iPSCs) to generate AVM blood vessel organoids. Treatment of these AVM blood vessel organoids with thalidomide, U0126, and rapamycin resulted in a reduction in the expression of the EC markers CD31 and α-SMA. The establishment of AVM blood vessel organoids offers a physiologically relevant in vitro model for disease characterization and drug screening. The authors of future studies should aim to refine this model using advanced techniques, such as microfluidic systems, to more efficiently replicate AVMs’ pathology and support the development of personalized therapies. Full article

Targeting fibrosis in Duchenne muscular dystrophy (DMD)-associated cardiomyopathy is a critical outstanding clinical issue, as cardiac failure remains a leading cause of death despite advances in supportive care. This study evaluates the therapeutic efficacy of CSPG4-targeted chimeric antigen receptor (CAR) T cells in reducing cardiac fibrosis and improving heart function in a preclinical model of the disease. DMD is a progressive genetic disorder characterized by degeneration of skeletal and cardiac muscle. Cardiomyopathy, driven by fibrosis and chronic inflammation, is a leading contributor to mortality in affected patients. Proteoglycans such as CSPG4, critical regulators of extracellular matrix dynamics, are markedly overexpressed in dystrophic hearts and promote pathological remodeling. Current treatments do not adequately target the fibrotic and inflammatory processes underlying cardiac dysfunction. CSPG4-specific CAR-T cells were engineered and administered to dystrophic mice. Therapeutic efficacy was assessed through histological, molecular, and echocardiographic analyses evaluating cardiac fibrosis, inflammation, innervation, and overall function. Treatment with CSPG4 CAR-T cells preserved myocardial integrity, improved cardiac performance, and reduced both fibrosis and inflammatory markers. The therapy also restored cardiac innervation, indicating a reversal of neural remodeling commonly seen in muscular dystrophy-related cardiomyopathy. CSPG4-targeted CAR-T therapy offers a novel, cell-based strategy to mitigate cardiac remodeling in dystrophic hearts. By addressing core fibrotic and inflammatory drivers of disease, this approach represents a significant advancement in the development of precision immune therapies for muscular dystrophies and cardiovascular conditions. Full article

Heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PGs) are essential regulators of many biological processes including cell differentiation, signalization, and proliferation. PGs interact mainly via their glycosaminoglycan (GAG) chains, with a large number of ligands including growth factors, enzymes, and extracellular matrix components, thereby modulating their biological activities. HSPGs and CSPGs share a common tetrasaccharide linker region, which undergoes modifications, particularly the phosphorylation of the xylose residue by the kinase FAM20B. Here, we demonstrated that FAM20B gain-of-function decreased, in a dose dependent manner, the synthesis of both CS- and HS-attached PGs. In addition, we showed that blockage of GAG chain synthesis by FAM20B was suppressed by the mutation of aspartic acid residues D289 and D309 of the catalytic domain. Interestingly, we bring evidence that, in contrast to FAM20B, expression of the 2-phosphoxylose phosphatase XYLP increases, in a dose dependent manner, GAG chain synthesis and rescues the blockage of GAG chains synthesis induced by FAM20B. In line with previous reports, we found that FAM20B loss-of-function reduced GAG chain synthesis. Finally, we found that FAM20B inhibited proliferation and migration of glioblastoma cells, thus revealing the critical role of GAG chains of PGs in glioblastoma cell tumorigenesis. This study revealed that both gain- and loss-of-function of FAM20B led to decreased GAG chain synthesis, therefore suggesting that a balance between phosphorylation and dephosphorylation of the xylose by FAM20B and XYLP, respectively, is probably an essential factor for the regulation of the rate of PG synthesis. Full article

Fruit cracking is very common in the production and cultivation of citrus, and can lead to decreases in its yield and quality. Bacteria can easily invade cracked fruit and cause mildew, accelerate the spread of diseases and pests, affect the appearance of the fruit, and reduce its economic benefits. In order to explore a method for alleviating citrus cracking, the Lane Late navel orange, which is a citrus that easily cracks, was studied via treatment with 1.0 g·L⁻¹ chelated calcium (Ca) or 50 mg·L⁻¹ gibberellin (GA₃). The fruit cracking rate, external and internal quality, active oxygen metabolism and expression levels of related genes, cell wall structure components, and metabolism-related enzyme activity and the expression levels of related genes were determined. The results showed that Ca and GA₃ treatment significantly reduced the fruit cracking rate and increased the longitudinal and transverse diameter, single-fruit weight, pulp quality, and peel quality, but had no significant effect on the internal quality of the fruit. Ca and GA₃ treatment also improved the activities of antioxidant enzymes (SOD and CAT), enhanced the scavenging ability for active oxygen species, and thus reduced the contents of H₂O₂ and MDA and decreased the superoxide anion production rate. At the same time, Ca and GA₃ treatment decreased the activities of protopectin-degrading enzymes (PME, PL, and PG) and cellulase (CX), prevented the degradation of pectin and cellulose in the cell wall, and increased their contents in the peel, thus improving the ductility and toughness of the peel and reducing the occurrence of cracked fruit. Ca and GA₃ treatment significantly increased the relative expression levels of antioxidase-related genes (CsSOD and CsCAT) in fruit peel and decreased the relative expression levels of CsPPO and cell wall metabolism-related genes (CsPME, CsPL, CsPG, and CsCX). In summary, this study confirmed that exogenous calcium and gibberellin can reduce the fruit cracking rate by regulating the scavenging ability for active oxygen species and the cell wall metabolism of the Lane Late navel orange at the physiological and molecular level, laying a theoretical foundation for further analysis of citrus fruit cracking mechanisms and clarifying that spraying exogenous calcium and gibberellin on the citrus fruit surface is an effective production measure for preventing and alleviating fruit cracking. In particular, gibberellin is better than exogenous calcium. Full article

Peripheral nerve regeneration remains a major challenge in neuroscience, despite advancements in understanding its mechanisms. Current treatments, including nerve transplantation and drug therapies, face limitations such as invasiveness and incomplete recovery of nerve function. Physical therapies, like pulsed electromagnetic fields (PEMF) and low-intensity ultrasound (LIPUS), are gaining attention for their potential to enhance regeneration. This study analyzes the effects of PEMF and LIPUS on gene expression in human primary Schwann cells, which are crucial for nerve myelination and repair. Key genes involved in neurotrophin signaling (NGF, BDNF), inflammation (IL-1β, IL-6, IL-10, TNF-α, TGF-β), and regeneration (CRYAB, CSPG, Ki67) were assessed. The results of this study reveal that combined PEMF and LIPUS therapies promote Schwann cell proliferation, reduce inflammation, and improve the regenerative environment, offering potential for optimizing these therapies for clinical use in regenerative medicine. Full article

Arteriovenous malformations (AVMs) are characterized by direct connections between arteries and veins without intervening capillaries, with the concomitant formation of abnormal vascular networks associated with angiogenesis. However, the current understanding of the diagnosis and treatment of AVMs is limited, and no in vitro disease models exist at present for studying this condition. In this study, we produced endothelial cells (ECs) in two-dimensional cultures and three-dimensional (3D) blood vessel organoids (BVOs), comparing gene expression profiles between normal and AVM organoids. The normal and AVM organoids were examined via immunofluorescence staining using CD31 and phalloidin. The AVM organoids showed significantly higher expression levels of CD31 and phalloidin than the normal organoids. Genes such as FSTL1, associated with angiogenesis, showed significantly higher expression in the AVM organoids than in the normal organoids. In contrast, the MARCKS gene exhibited no significant difference in expression between the two types of organoids. The capillaries and related CSPG4 genes exhibited the lowest expression in the 3D AVM organoids. Furthermore, hsa-mir-135b-5p, a small RNA related to AVMs, showed elevated expression in AVM tissues and significantly higher levels in 3D AVM organoids. In our study, we were able to successfully establish AVM organoids (hBVOs) containing ECs and mural cells through advancements in stem cell and tissue engineering. These organoids serve as valuable models for investigating disease mechanisms, drug development, and screening potential therapeutic interventions in drug discovery. These findings contribute essential insights for the development of treatment strategies targeting AVMs. Full article

Many central nervous system (CNS) disorders lack approved treatment options. Previous research demonstrated that peptide CAQK can bind to chondroitin sulfate proteoglycans (CSPGs) in the extracellular matrix of the CNS. In vivo studies have investigated CAQK conjugated to nanoparticles containing therapeutic agents with varying methodologies/outcomes. This paper presents the first systematic review assessing its properties, applications, and outcomes secondary to its use. Following PRISMA guidelines, a comprehensive search was performed across multiple databases. Studies utilizing CAQK as a therapeutic agent/homing molecule in animal/human models were selected. Sixteen studies met the inclusion criteria. Mice and rats were the predominant animal models. All studies except one used CAQK to deliver a therapeutic agent. The reviewed studies mostly included models of brain and spinal cord injuries. Most studies had intravenous administration of CAQK. All studies demonstrated various benefits and that CAQK conjugation facilitated localization to target tissues. No studies directly evaluated the effects of CAQK alone. The data are limited by the heterogeneity in study methodologies and the lack of direct comparison between CAQK and conjugated agents. Overall, these findings present CAQK utilization to deliver a therapeutic agent as a promising targeting strategy in the management of disorders where CSPGs are upregulated. Full article

Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody–drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape. Full article

Wagner syndrome is a rare autosomal dominant vitreoretinopathy caused by mutations in chondroitin sulphate proteoglycan 2 (CSPG2)/Versican (VCAN). Here, we present a retrospective case series of a family pedigree with genetically confirmed Wagner syndrome (heterozygous VCAN exon 8 deletion), as follows: a 34-year-old mother (P1), 12-year-old daughter (P2), and a 2-year-old son (P3). The phenotype included early-onset cataract (P1), optically empty vitreous with avascular membranes (P1, 2), nasal dragging of optic nerve heads associated with foveal hypoplasia (P1, 2), tractional retinoschisis on optical coherence tomography (P2), and peripheral circumferential vitreo-retinal interface abnormality resembling white-without-pressure (P3) progressing to pigmented chorio-retinal atrophy (P1, 2). P2 developed a macula-off retinal detachment, which was treated initially with encircling band + vitrectomy + gas, followed by vitrectomy + heavy silicone oil tamponade for re-detachment from new inferior breaks. Strong vitreo-retinal adhesion was noted intraoperatively, which prevented the separation of posterior hyaloid beyond the equator. Electroretinograms from P1&2 demonstrated attenuated b-waves, a-waves, and flicker responses in light- and dark-adapted conditions, suggestive of generalised retinal dysfunction. Our patients demonstrated the clinical spectrum of Wagner syndrome, highlighting nasal dragging with foveal disruption as a distinguishing feature from other inherited vitreoretinopathies. Surgical outcomes demonstrate significant challenges in managing vitreo-retinal traction and need for further research into strategies to prevent sight loss. Full article

Most epithelial ovarian cancer (EOC) patients are diagnosed with peritoneal dissemination. Cellular interactions are an important aspect of EOC cells when they detach from the primary site of the ovary. However, the mechanism remains underexplored. Our study aimed to reveal the role of chondroitin sulfate proteoglycan 4 (CSPG4) in EOC with a major focus on cell–cell interactions. We examined the expression of CSPG4 in clinical samples and cell lines of EOC. The proliferation, migration, and invasion abilities of the CSPG4 knockdown cells were assessed. We also assessed the role of CSPG4 in spheroid formation and peritoneal metastasis in an in vivo model using sh-CSPG4 EOC cell lines. Of the clinical samples, 23 (44.2%) samples expressed CSPG4. CSPG4 was associated with a worse prognosis in patients with advanced EOC. Among the EOC cell lines, aggressive cell lines, including ES2, expressed CSPG4. When CSPG4 was knocked down using siRNA or shRNA, the cell proliferation, migration, and invasion abilities were significantly decreased compared to the control cells. Proteomic analyses showed changes in the expression of proteins related to the cell movement pathways. Spheroid formation was significantly inhibited when CSPG4 was inhibited. The number of nodules and the tumor burden of the omentum were significantly decreased in the sh-CSPG4 mouse models. In the peritoneal wash fluid from mice injected with sh-CSPG4 EOC cells, significantly fewer spheroids were present. Reduced CSPG4 expression was observed in lymphoid enhancer-binding factor 1-inhibited cells. CSPG4 is associated with aggressive features of EOC and poor prognosis. CSPG4 could be a new treatment target for blocking peritoneal metastasis by inhibiting spheroid formation. Full article

Steroid-induced cataracts (SIC) are defined as cataracts associated with the administration of corticosteroids. Long-term glucocorticoid treatment for inflammatory diseases reportedly increases the risk of SIC, and steroids can induce cataracts by disrupting ocular growth factor balance or homeostasis. In this study, we verified the effect of chondroitin sulfate proteoglycan 5 (CSPG5) using dexamethasone (dexa)-treated human lens epithelial (HLE-B3) cells and the lens epithelium from the anterior capsule of SIC patients obtained during cataract surgery. CSPG5 expression increased in the lens epithelium of SIC patients. The downregulation of CSPG5 suppressed the dexa-induced epithelial–mesenchymal transition (EMT)-related protein expression and motility in HLE-B3 cells. The disruption of the transcription factors EZH2 and B-Myb downregulated CSPG5, dexa-induced fibronectin expression, and cell migration in HLE-B3 cells, reaffirming that CSPG5 expression regulates EMT in lens epithelial cells. Taken together, these results indicate that the steroid-induced effects on lens epithelial cells are mediated via alterations in CSPG5 expression. Therefore, our study emphasizes the potential of CSPG5 as a therapeutic target for the prevention and treatment of SIC. Full article

Background: Demyelinating diseases represent a broad spectrum of disorders and are characterized by the loss of specialized glial cells (oligodendrocytes), which eventually leads to neuronal degeneration. Stem cell-based regenerative approaches provide therapeutic options to regenerate demyelination-induced neurodegeneration. Objectives: The current study aims to explore the role of oligodendrocyte-specific transcription factors (OLIG2 and MYT1L) under suitable media composition to facilitate human umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) differentiation toward oligodendrocyte for their potential use to treat demyelinating disorders. Methodology: hUC-MSCs were isolated, cultured, and characterized based on their morphological and phenotypic characteristics. hUC-MSCs were transfected with OLIG2 and MYT1L transcription factors individually and in synergistic (OLIG2 + MYT1L) groups using a lipofectamine-based transfection method and incubated under two different media compositions (normal and oligo induction media). Transfected hUC-MSCs were assessed for lineage specification and differentiation using qPCR. Differentiation was also analyzed via immunocytochemistry by determining the expression of oligodendrocyte-specific proteins. Results: All the transfected groups showed significant upregulation of GFAP and OLIG2 with downregulation of NES, demonstrating the MSC commitment toward the glial lineage. Transfected groups also presented significant overexpression of oligodendrocyte-specific markers (SOX10, NKX2.2, GALC, CNP, CSPG4, MBP, and PLP1). Immunocytochemical analysis showed intense expression of OLIG2, MYT1L, and NG2 proteins in both normal and oligo induction media after 3 and 7 days. Conclusions: The study concludes that OLIG2 and MYT1L have the potential to differentiate hUC-MSCs into oligodendrocyte-like cells, which is greatly facilitated by the oligo induction medium. The study may serve as a promising cell-based therapeutic strategy against demyelination-induced neuronal degeneration. Full article