Search Results (388)

Introduction: Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a benign proliferation of the melanin-producing retinal pigment epithelium (RPE). Although often a benign and incidental finding, multifocal CHRPE may mimic lesions associated with familial adenomatous polyposis (FAP). Case Description: We describe an 8-year-old girl presenting with optic disc pallor and widespread multifocal bear track CHRPE observed bilaterally on dilated fundoscopy. Fundus autofluorescence (FAF) imaging showed uniform areas of hypoautofluorescence corresponding to the bear track lesions. Spectral domain optical coherence tomography (SD-OCT) demonstrated normal lamination without atrophy. The full-field electroretinogram (ffERG) was within normal limits. Whole-genome sequencing (WGS) revealed a likely pathogenic heterozygous variant in the STAG2 gene (c.3222dup, p.Ser1075IlefsTer12). Conclusions: We present a rare case of bilateral, panretinal bear track CHRPE in a child with a likely pathogenic variant in STAG2. Using multimodal imaging, we contrast bear track lesions of the retina with FAP-associated CHRPE. We also present possible ophthalmic manifestations in carriers of pathogenic STAG2 variants. Full article

The breast microbiome remains stable throughout a woman’s life. The breast is not a sterile organ, and its microbiota exhibits a distinct composition compared to other body sites. The breast microbiome is a community characterized by an abundance of Proteobacteria and Firmicutes, which represent the result of host microbial adaptation to the fatty acid environment in the tissue. The breast microbiome demonstrates dynamic adaptability during lactation, responding to maternal physiological changes and infant interactions. This microbial plasticity modulates local immune responses, maintains epithelial integrity, and supports tissue homeostasis, thereby influencing both breast health and milk composition. Disruptions in this balance, the dysbiosis, are closely linked to inflammatory breast conditions such as mastitis. Risk factors for breast cancer (BC) include genetic mutations, late menopause, obesity, estrogen metabolism, and alterations in gut microbial diversity. Gut microbiota can increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties. Perturbations of this set of bacterial genes and metabolites, called the estrobolome, increases circulating estrogens and the risk of BC. Fusobacterium nucleatum has recently been associated with BC. It moves from the oral cavity to other body sites hematogenously. This review deals with the characteristics of the breast microbiome, with a focus on F. nucleatum, highlighting its dual role in promoting tumor growth and modulating immune responses. F. nucleatum acts both on the Wnt/β-catenin pathway by positively regulating MYC expression and on apoptosis by inhibiting caspase 8. Furthermore, F. nucleatum binds to TIGIT and CEACAM1, inhibiting T-cell cytotoxic activity and protecting tumor cells from immune cell attack. F. nucleatum also inhibits T-cell function through the recruitment of myeloid suppressor cells (MDSCs). These cells express PD-L1, which further reduces T-cell activation. A deeper understanding of F. nucleatum biology and its interactions with host cells and co-existing symbiotic microbiota could aid in the development of personalized anticancer therapy. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by the accumulation of fibrotic tissue in the lungs, leading to impaired gas exchange and respiratory failure, with a poor prognosis and limited treatment options. Oleuropein, a compound extracted from olive leaves, demonstrates a range of pharmacological activities, including benefits for non-alcoholic fatty liver disease and cardiac fibrosis. This study investigates the therapeutic potential of oleuropein for IPF and its underlying mechanisms. We first established a bleomycin-induced mouse model of pulmonary fibrosis and evaluated the in vivo efficacy of oleuropein. Our findings demonstrated that oleuropein significantly alleviated lung fibrosis and improved pulmonary function. Through in vitro experiments, we found that oleuropein inhibited TGF-β1-induced fibroblast migration, activation, autophagy, and apoptotic resistance, and mechanistically, oleuropein could regulate the TGF-β1/Smad and TGF-β1/mTOR signaling pathways in fibroblasts. Additionally, molecular docking analysis indicated that FAP-α is a potential target of oleuropein, displaying strong binding affinity. The effects of oleuropein on fibroblasts were markedly disrupted in FAP-α knockout cells. In conclusion, oleuropein exerts its beneficial effects by targeting FAP-α and inhibiting TGF-β1-related signaling pathways, improving the pathological characteristics of pulmonary fibrosis in mouse models, and demonstrating promising application prospects for the treatment of IPF. Full article

Chronological age is an imprecise proxy for reproductive capacity, necessitating biomarkers that reflect the underlying pathophysiology of the ovary. Fibrotic remodeling of the ovarian stroma is a key hallmark of biological ovarian aging, yet it cannot be assessed by current clinical tools. This study aimed to identify and validate a novel serum biomarker for fibrotic ovarian aging by applying supervised machine learning (ML) to human ovarian transcriptomic data. Transcriptomic data from the Genotype-Tissue Expression (GTEx) database were analyzed using ML algorithms to identify candidate genes predictive of ovarian aging, and finally, fibroblast activation protein (FAP) and collectin-11 (COLEC11) were selected for clinical validation. In a cross-sectional study, serum levels of FAP and COLEC11, along with key hormonal indices, were measured in two nested patient cohorts, and their associations with ovarian reserve and clinical parameters were analyzed. Serum FAP levels did not correlate with age but showed a strong inverse correlation with anti-Müllerian hormone (AMH) (r = −0.61, p = 0.001), a finding accentuated in women with decreased ovarian reserve (DOR). While COLEC11 correlated with age, it failed to differentiate DOR status. FAP levels were independent of central hormonal regulation, consistent with preclinical fibrotic models. Circulating FAP reflects age-independent, fibrotic ovarian aging, offering stromal-specific information not captured by conventional hormonal markers. This study provides the first clinical validation of FAP as a biomarker for ovarian stromal aging, holding potential for improved reproductive risk assessment. Full article

A multimodal approach is recommended to optimize perioperative pain control in animals, although opioid use in horses remains limited due to the risks of central nervous system (CNS) stimulation and reduced intestinal motility. A group of 19 healthy, male, mixed-breed horses were divided into two groups and medicated with acepromazine (0.05 mg kg⁻¹) and detomidine (10 µg kg⁻¹), with methadone (0.05 mg kg⁻¹) (ADM) or saline (ADS) administered intravenously (IV). Physiological variables, intestinal motility, gastric distention, and facial pain (EQUUS-FAP) were evaluated one day before (DB), before the surgical procedure (BS), and at 1, 2, 4, 6, and 8 h (T1h–T8h) after administration (ADM-ADS). Results are presented as means with standard deviation or medians with an interquartile range. Analysis of variance, the Mann–Whitney, and Durbin tests were applied (p < 0.05). Intestinal motility was reduced at T1h and T2h, returning to baseline by T6h and T8h in both groups. Ultrasonographic examination revealed reduced motility, with less significant changes in the left ventral colon (LVC), right ventral colon (RVC), and cecum. Gastric dilatation was more pronounced in the ADM group at T1, 4, 6, and 8h. EQUUS-FAP scores were significantly lower in ADM at T2, 4, and 6h. ADM protocol may aid chemical restraint and analgesia without increasing hypomotility. Full article

Fibro-adipogenic progenitor cells (FAPs) support muscle tissue homeostasis, regulate muscle growth, injury repair, and fibrosis, and activate muscle progenitor cell differentiation to promote regeneration. We aimed to investigate the effects of co-culturing FAPs with muscle satellite cells (MuSCs) on myogenic differentiation. Proteomic profiling of co-culture supernatants identified significant DCX, IMP2A, NUDT16L1, SLC38A2, and IL-6 upregulation. Comparative transcriptomics of mono-cultured versus co-cultured MuSCs revealed differential expression of oxidative stress-related genes (HMOX1, ALOX5, GSTM3, TRPM2, PADI1, and CTSL). Pathway enrichment analyses highlighted cell cycle regulation, TNF signaling, and ferroptosis. Gene ontology analysis of MuSCs indicated significant gene enrichment in myosin-related components. Combined transcriptomic and proteomic analyses demonstrated HO-1 downregulation at the transcriptional and translational levels, with altered pathways being predominantly related to myosin filament, muscle system process, and muscle contraction cellular components. HO-1 knockdown reduced intracellular iron accumulation in MuSCs, suppressing iron-dependent autophagy. This alleviated oxidative stress and promoted myogenic differentiation. Exogenous IL-6 (0.1 ng/mL) downregulated HO-1 expression, initiating an identical regulatory cascade, while HO-1 overexpression reversed the IL-6-mediated reduction in the expression of the autophagy markers LC3 and ATG5, suppressing myogenic enhancement. This establishes the co-culture-induced IL-6/HO-1 axis as a core regulator of iron-dependent oxidative stress and autophagy during myogenic differentiation. Full article

Heterotopic ossification (HO) refers to the pathological formation of bone in soft tissues, typically following trauma, surgical procedures, or as a result of genetic disorders. Notably, injuries to the central nervous system significantly increase the risk of HO, a condition referred to as neurogenic HO (NHO). This review outlines the cellular and molecular mechanisms driving HO, focusing on the inflammatory response, progenitor cell reprogramming, and current treatment strategies. HO is primarily fuelled by a prolonged and dysregulated inflammatory response, characterized by sustained expression of osteoinductive cytokines secreted by M1 macrophages. These cytokines promote the aberrant differentiation of fibro-adipogenic progenitor cells (FAPs) into osteoblasts, leading to ectopic mineralization. Additional factors such as hypoxia, BMP signalling, and mechanotransduction pathways further contribute to extracellular matrix (ECM) remodelling and osteogenic reprogramming of FAPs. In the context of NHO, neuroendocrine mediators enhance ectopic bone formation by influencing both local inflammation and progenitor cell fate decisions. Current treatment options such as nonsteroidal anti-inflammatory drugs (NSAIDs), radiation therapy, and surgical excision offer limited efficacy and are associated with significant risks. Novel therapeutic strategies targeting inflammation, neuropeptide signalling, and calcium metabolism may offer more effective approaches to preventing or mitigating HO progression. Full article

Lung cancer is one of the most common cancers and the leading cause of cancer-related death worldwide. Despite advancements, the overall survival rate for lung cancer remains between 10% and 20% in most countries. However, recent progress in diagnostic tools and therapeutic strategies has led to meaningful improvements in survival outcomes, highlighting the growing importance of personalized management based on accurate disease assessment. ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) has become essential in the management of lung cancer, serving as a key imaging modality for initial diagnosis, staging, treatment response assessment, and follow-up evaluation. Recent developments in radiomics and artificial intelligence (AI), including machine learning and deep learning, have revolutionized the analysis of complex imaging data, enhancing the diagnostic and predictive capabilities of FDG PET/CT in lung cancer. However, the limitations of FDG, including its low specificity for malignancy, have driven the development of novel oncologic radiotracers. One such target is fibroblast activation protein (FAP), a type II transmembrane glycoprotein that is overexpressed in activated cancer-associated fibroblasts within the tumor microenvironment of various epithelial cancers. As a result, FAP-targeted radiopharmaceuticals represent a novel theranostic approach, offering the potential to integrate PET imaging with radioligand therapy (RLT). In this review, we provide a comprehensive overview of FDG PET/CT in lung cancer, along with recent advances in AI. Additionally, we discuss FAP-targeted radiopharmaceuticals for PET imaging and their potential application in RLT for the personalized management of lung cancer. Full article

Pilomatricomas are benign tumors originating from hair follicle matrix cells and represent the most common skin tumors in pediatric patients. Pilomatricomas may be associated with genetic syndromes such as myotonic dystrophy, familial adenomatous polyposis (FAP), Turner syndrome, Rubinstein–Taybi syndrome, Kabuki syndrome, and Sotos syndrome. This study reviews the literature on pilomatricomas occurring in syndromic contexts and presents a novel case linked to Apert syndrome. A systematic review was conducted using PubMed and Cochrane databases, focusing on case reports, case series, and reviews describing pilomatricomas associated with syndromes. A total of 1272 articles were initially screened; after removing duplicates and excluding articles without syndromic diagnoses or lacking sufficient data, 81 full-text articles were reviewed. Overall, 96 cases of pilomatricomas associated with genetic syndromes were identified. Reports of patients with Apert syndrome who do not develop pilomatricomas are absent in the literature. Pilomatricomas predominantly affect pediatric patients, with a slight female predominance, and are often the first manifestation of underlying genetic syndromes. Our study highlights previously unreported associations of pilomatricoma with Apert syndrome, providing molecular insights. This study contributes to understanding the clinical and molecular features of pilomatricomas in syndromic contexts and underscores the importance of genetic analysis for accurate diagnosis and management. Full article

Targeted radioligand therapy (RLT) is an emerging field in anticancer therapeutics with great potential across tumor types and stages of disease. While much progress has focused on agents targeting somatostatin receptors and prostate-specific membrane antigen (PSMA), the same advanced radioconjugation methods and molecular targeting have spurred the development of numerous theranostic combinations for other targets. A number of the most promising agents have progressed to clinical trials and are poised to change the landscape of positron emission tomography (PET) imaging. Here, we present recent data on some of the most important emerging molecular targeted agents with their exemplar clinical images, including agents targeting fibroblast activation protein (FAP), hypoxia markers, gastrin-releasing peptide receptors (GRPrs), and integrins. These radiopharmaceuticals share the promising characteristic of being able to image multiple types of cancer. Early clinical trials have already demonstrated superiority to ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) for some, suggesting the potential to supplant this longstanding PET radiotracer. Here, we provide a primer for practicing radiologists, particularly nuclear medicine clinicians, to understand novel PET imaging agents and their clinical applications, as well as the availability of companion targeted radiotherapeutics, the status of their regulatory approval, the potential challenges associated with their use, and the future opportunities and perspectives. Full article

Background: In patients with familial adenomatous polyposis (FAP), the duodenum is another high-risk region for malignancy after the large bowel. However, endoscopic and surgical management differs for papillary lesions and adenomas located in other parts of the duodenum. The aim of the study was to present the principles of the endoscopic surveillance of extrapapillary polyps based on a single-center 14-year observational study. Methods: The retrospective analysis was carried out in 2010–24 on a group of 45 people enrolled in endoscopic surveillance of the upper gastrointestinal tract due to FAP. The evaluation was aimed at detecting the malignant transformation of extrapapillary duodenal adenomas, with a radical removal of high-risk lesions. The severity of polyposis in the subsequent years of observation as well as the effectiveness of routine polypectomy on downstaging according to the Spiegelmann score were also assessed. Results: Invasive duodenal cancer was not detected in any case; however, high-grade dysplasia (HGD) was confirmed in five patients. The severity of polyposis and the number of polyps with HGD increased in following examinations, but routine polypectomy performed mainly during the 4th and 5th endoscopies allowed for a transient decrease in the Spiegelman score. Finally, progression of duodenal polyposis was observed in 18 patients, another 4 experienced regression (downstaging) and in 23 cases the stage of severity did not change. In addition, five patients were diagnosed with LST-G lesions, which were removed without recurrence. Conclusions: The patient’s age correlates with the severity of polyposis and the risk of malignancy, but routine endoscopic resections eliminate potentially invasive lesions and contribute to disease regression expressed by the Spiegelmann score. The radical endoscopic therapy of extrapapillary duodenal lesions limits the indications for surgical procedures. Full article

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, comprises embryonal (ERMS) and alveolar (ARMS) subtypes with distinct histopathological features, clinical outcomes, and therapeutic responses. To better characterize their molecular distinctions, we performed untargeted plasma proteomics and metabolomics profiling in children with ERMS (n = 18), ARMS (n = 17), and matched healthy controls (n = 18). Differential expression, functional enrichment (GO, KEGG, RaMP-DB), co-expression network analysis (WGCNA/WMCNA), and multi-omics integration (DIABLO, MOFA) revealed distinct molecular signatures for each subtype. ARMS displayed elevated oncogenic and stemness-associated proteins (e.g., cyclin E1, FAP, myotrophin) and metabolites involved in lipid transport, fatty acid metabolism, and polyamine biosynthesis. In contrast, ERMS was enriched in immune-related and myogenic proteins (e.g., myosin-9, SAA2, S100A11) and metabolites linked to glutamate/glycine metabolism and redox homeostasis. Pathway analyses highlighted subtype-specific activation of PI3K-Akt and Hippo signaling in ARMS and immune and coagulation pathways in ERMS. Additionally, the proteomics and metabolomics datasets showed association with clinical parameters, including disease stage, lymph node involvement, and age, demonstrating clear molecular discrimination consistent with clinical observation. Co-expression networks and integrative analyses further reinforced these distinctions, uncovering coordinated protein–metabolite modules. Our findings reveal novel, subtype-specific molecular programs in RMS and propose candidate biomarkers and pathways that may guide precision diagnostics and therapeutic targeting in pediatric sarcomas. Full article

Fusobacterium nucleatum and activating mutations in the Kirsten rat sarcoma virus oncogene homolog (KRAS) are increasingly recognized as cooperative drivers of colorectal cancer (CRC). F. nucleatum promotes tumorigenesis via adhesion to epithelial cells, modulation of the immune microenvironment, and delivery of virulence factors, while KRAS mutations—present in 60% of CRC cases—amplify proliferative signaling and inflammatory pathways. Here, we review the molecular interplay by which F. nucleatum enhances KRAS-driven oncogenic cascades and, conversely, how KRAS mutations reshape the tumor niche to favor bacterial colonization. We further discuss the use of KRAS as a prognostic biomarker and explore promising non-antibiotic interventions—such as phage therapy, antimicrobial peptides, and targeted small-molecule inhibitors—aimed at selectively disrupting F. nucleatum colonization and virulence. This integrated perspective on microbial–genetic crosstalk offers novel insights for precision prevention and therapy in CRC. Full article

Cancer remains a leading global health burden, profoundly affecting patient survival and quality of life. Current treatments—including chemotherapy, radiotherapy, immunotherapy, and surgery—are often limited by toxicity or insufficient specificity. Conventional chemotherapy, for instance, indiscriminately attacks rapidly dividing cells, causing severe side effects. In contrast, peptide-based therapeutics offer a paradigm shift, combining high tumour-targeting precision with minimal off-target effects. Their low immunogenicity, multi-pathway modulation capabilities, and adaptability for diagnostics and therapy make them ideal candidates for advancing oncology care. Innovative peptide platforms now enable three transformative applications: (1) precision molecular diagnostics (e.g., ¹⁸F-PSMA-1007 for prostate cancer detection), (2) targeted therapies (e.g., BT5528 and SAR408701 targeting tumour-specific antigens), and (3) theranostic systems (e.g., RAYZ-8009 and ¹⁷⁷Lu-FAP-2286 integrating imaging and radiotherapy). Despite their promise, peptides face challenges like metabolic instability and short half-lives. Recent advances in structural engineering (e.g., cyclization and D-amino acid incorporation) and delivery systems (e.g., nanoparticles and PEGylation) have significantly enhanced their clinical potential. This review highlights peptide-based agents in development, showcasing their ability to improve early cancer detection, reduce metastasis, and enhance therapeutic efficacy with fewer adverse effects. Examples like CLP002 underscore their role in personalised medicine. By overcoming current limitations, peptide drugs are poised to redefine cancer management, offering safer, more effective alternatives to conventional therapies. Their integration into clinical practice could mark a critical milestone in achieving precision oncology. Full article

Osteoarthritis (OA) is the most common chronic arthropathy worldwide. OA synovitis is a common feature that predicts the development and progression of symptoms and joint damage. Although the OA synovium is a target for novel therapies, the development of ex vivo models remains an area requiring further research. We aim to develop a 3D tissue explant culture model of human OA synovium that preserves the architecture and cellular heterogeneity of the original tissue in vitro. We derived tissue explant models from seven patients with OA and followed the culture for up to 10 days, assessing their morphology and cellular composition by immunohistochemistry (IHC) and flow cytometry, respectively. IHC analysis of explant cultures showed that tissue integrity and viability were maintained in our in vitro system. Furthermore, cellular heterogeneity was essentially unchanged when considering CD4⁺ T cells, CD8⁺ T cells, and myeloid fractions in our model. No significant variation was observed in the CD90⁺ and CD90^-CD55⁺ fractions, which also maintained an activated state as indicated by high levels of FAP expression. An ex vivo OA synovial tissue explant model can maintain pathological tissue integrity for 10 days in culture. This simple and reliable culture system may be useful for analyzing the pathogenesis of OA disease and for the development and testing of therapeutic drugs. Full article