Search Results (299)

Pancreatic ductal adenocarcinoma (PDAC) is an invasive cancer with poor survival outcomes and limited treatment options. This systematic review aimed to identify and evaluate tissue-based biomarkers with potential applications in fluorescence-guided surgery (FGS), an approach that enables real-time intraoperative tumour visualisation to improve surgical precision. A systematic review was conducted in accordance with PRISMA guidelines and registered on PROSPERO (CRD420251056295). A comprehensive literature search was conducted across MEDLINE, Embase, and Cochrane Library databases from 1980 to January 2026 and was updated in March 2026. The EU Clinical Trials Registers were also searched for biomarker-targeted clinical trials. The TASC-T (Theranostic Target Selection Criteria) scoring system was used to assess biomarker suitability. EGFR, MSLN, CEA, and integrin αvβ6 scored highest, reflecting their strong potential as theranostic targets. MUC1 and uPAR also demonstrated high positivity and accessibility for imaging and therapy. While CA19-9 is a widely used serum biomarker, its role as a tissue target appears limited because of its high expression in benign conditions. EGFR and αvβ6 are both undergoing evaluation in phase II clinical trials and have emerged as promising targets for FGS in PDAC. This review highlights the need for standardised protocols and collaborative research to expand the clinical utility of these biomarkers. The methods and scoring criteria used in this review provide a transferable framework for identifying tissue biomarkers in other cancers and disease states. Full article

Background: Gastric and gastroesophageal junction adenocarcinomas remain major causes of cancer- related mortality worldwide. Although perioperative chemotherapy, HER2-directed therapy, Claudin-18.2 (CLDN18.2)-targeted treatment, immune checkpoint inhibition, and anti-angiogenic therapy have improved outcomes in selected patients, clinically actionable targets are absent, heterogeneous, or lost in many high-grade, diffuse, poorly cohesive, signet-ring-cell micropapillary, hepatoid, and sarcomatoid carcinomas. Additional histopathology-assessable biomarkers that can support both molecular imaging and targeted therapy are of considerable clinical interest. Methods: Integrin αvβ6 is an epithelial-specific adhesion receptor that is minimally expressed in most normal adult tissues but becomes markedly upregulated during epithelial carcinogenesis, tissue remodeling, invasion, and activation of transforming growth factor-β signaling. This retrospective histopathological and immunohistochemical study evaluated integrin αvβ6 expression by immunohistochemistry in 53 formalin-fixed paraffin-embedded diagnostic specimens of untreated primary gastric or gastroesophageal junction adenocarcinoma. Tumors were classified according to the WHO Classification of Tumors of the Digestive System, 5th edition. Membranous integrin αvβ6 staining intensity and the percentage of positive tumor cells were recorded, and an H-score was calculated. Expression patterns were compared descriptively with histological subtype, differentiation grade, HER2 status, and CLDN18.2 expression. Results: Integrin αvβ6 immunoreactivity was detected in 49 of 53 tumors (92.5%), the clinically more relevant moderate to strong expression (H-score > 100) was present in 27 of 53 cases (50.9%), and strong expression was present in 13 of 53 cases (24.5%). Expression was not confined to conventional intestinal-type tumors; among carcinomas containing a signet-ring-cell component, 14 of 16 assessable cases (87.5%) showed integrin αvβ6 positivity, with 8 of 16 (50.0%) showing moderate to strong staining. By comparison, HER2 positivity was identified in 4 of 53 cases (7.5%; 4 of 52 assessable cases, 7.7%), and clinically relevant CLDN18.2 positivity, defined as moderate-to-strong membranous staining in at least 75% of tumor cells, was present in 7 of 38 assessable cases (18.4%). Conclusions: Integrin αvβ6 is frequently expressed in gastric and gastroesophageal junction adenocarcinoma, with moderate to strong expression in approximately half of all cases and in half of signet ring cell-containing tumors, including aggressive histological subtypes that often lack established therapeutic targets. The precise H-Score threshold for theranostic eligibility remains to be determined. The findings support integrin αvβ6 as a promising biomarker for histopathology-based screening, PET-based whole-body target assessment, and future targeted radionuclide therapy. Integration of immunohistochemistry and integrin αvβ6- targeted PET imaging will be essential to validate integrin αvβ6 as a candidate biomarker and to optimize radionuclide selection in gastric cancer, particularly with moderate to strong expression. Full article

Periodontitis is a chronic inflammatory disease driven largely by dysregulated host responses that lead to destruction of periodontal tissues. Integrins are heterodimeric transmembrane receptors that regulate cell adhesion and bidirectional signaling in epithelial cells, immune cells, periodontal ligament fibroblasts, and osteoclasts. During disease progression, integrin-related responses may shift across overlapping molecular phases. Epithelial integrins such as α3β1 and α6β4 support barrier integrity, whereas α5β1 may facilitate microbial interaction and inflammatory signaling. β2 integrins and α4β1 contribute to leukocyte recruitment and inflammatory amplification, whereas increased α9β1-associated signaling and reduced αvβ6-mediated regulation of transforming growth factor β (TGF-β) may promote inflammatory persistence. Matrix-associated integrins, including α2β1 and α11β1, support extracellular matrix (ECM) organization and mechanotransduction, whereas αvβ3 cooperates with Receptor activator of nuclear factor kappa B ligand (RANKL) to promote osteoclast activity and alveolar bone resorption. Impaired β1 integrin-dependent signaling and potentially reduced αvβ5-associated efferocytosis may contribute to defective resolution and regeneration. Importantly, integrin expression, activation, and downstream signaling are distinct, and the strength of evidence varies among integrin subtypes. This review proposes a conceptual framework in which periodontitis reflects a dynamic imbalance in integrin-mediated processes that link inflammation, bone resorption, and regenerative failure, rather than being a direct equivalent of clinical periodontal stages or grades. Full article

Myalgic Encephalomyelitis (ME) is a chronic, multisystem disease characterized by systemic metabolic dysfunction and post-exertional malaise (PEM). In this study, we investigated the dysregulation of irisin, an exercise-induced myokine, and its potential antagonism by thrombospondin-1 (TSP-1). In a cross-sectional study (92 ME patients vs. 44 sedentary healthy controls), plasma irisin and TSP-1 levels were measured at baseline and after a 90 min mechanical stress challenge applied to induce PEM. ME patients exhibited significantly lower baseline irisin (p < 0.05) and a blunted exertional response (p < 0.05). Paradoxically, baseline irisin was an independent predictor of fatigue severity (β = 0.728, p = 0.018), with moderate-to-severe patients showing elevated levels of both irisin and TSP-1 (p < 0.05), suggesting a compensatory but ineffective response. Functional cellular dielectric spectroscopy indicated that TSP-1 inhibits irisin signaling in a concentration-dependent manner. Irisin signaling was markedly reduced by both αvβ5 blockade and HSP90α inhibition in this experimental system, consistent with a diminished ability to counteract TSP-1. Collectively, these findings support a model in which dysregulation of the irisin–TSP-1 axis contributes to metabolic dysfunction in ME. Elevated circulating TSP-1 levels are associated with symptom severity and are linked to impaired irisin signaling in an HSP90α- and αvβ5-dependent context. This interaction is consistent with defective metabolic adaptation and highlights a potential therapeutic target that warrants further validation to restore energy homeostasis. Full article

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with limited therapeutic options and poor clinical outcomes. The aim of this research is to assess the prevalence, intensity, and distribution of integrin αvβ6 expression in TNBC using immunohistochemistry and to evaluate its potential as a predictive biomarker for αvβ6-targeted radionuclide therapy and other αvβ6-targeted theranostic approaches. Immunohistochemical analysis of integrin αvβ6 was performed on formalin-fixed, paraffin- embedded tumor samples from 48 patients with histologically confirmed TNBC. Staining intensity and the proportion of positive tumor cells were assessed using a semi-quantitative scoring system, and expression patterns were analyzed with regard to cellular localization and intratumoral heterogeneity. Moderate to strong integrin αvβ6 expression was observed in 43.8% of cases, with strong expression (≥50% of tumor cells) present in 25%. Expression was predominantly membranous, with occasional cytoplasmic staining, and demonstrated marked inter- and intratumoral heterogeneity. Integrin αvβ6 is frequently expressed in TNBC and represents a promising biomarker for patient selection in αvβ6-targeted radionuclide imaging and therapy. These findings provide a strong biological rationale for the clinical translation of integrin-targeted radioligands and support the development of personalized radiotheranostic strategies in TNBC. Full article

IGF1 plays a critical role in cell proliferation and survival. Previous studies show that IGF1 binds to integrin αvβ3 and induces αvβ3-IGF1-IGF1R ternary complex formation. However, how IGF1 binding to αvβ3 leads to IGF1R activation is unclear. Previous studies showed that Gα13, a guanine nucleotide-binding protein of the G12 class of Gα proteins, binds to the integrin β3 tail through the EEE motif upon fibrinogen binding to integrin αIIbβ3 and induces RhoA activation. We discovered that the EEE/AAA mutation of the β3 tail inhibited IGF1-induced cell survival, suggesting that Gα13 binding to the β3 tail is required for IGF1 signaling. Since RhoA activation may not be directly involved in IGF1R activation, we studied if Gα13 binds to molecules other than RhoA. Since Gα13 binds to several cytoplasmic tyrosine kinases, we studied if Gα13 binds to the IGF1R kinase by a docking simulation. The simulation predicted that Gα13 binds to the IGF1R kinase through a new binding site. Mutating the predicted Gα13 binding site in the IGF1R kinase (residues 1020-1022) or the predicted IGF1R kinase binding site in Gα13 (residues 260-279) inhibited Gα13 binding to the IGF1R kinase, which is consistent with the docking model. Notably, the Gα13(260-279A) mutant inhibited IGF1-induced cell survival. We propose that IGF1 binding to αvβ3 induces Gα13 binding to the β3 tail and subsequent Gα13 binding to the IGF1R kinase, leading to IGF1R activation. Interestingly, Gα13(260-279A) mutation inhibited cell survival due to a constitutively active Gα13(Q226L) mutant. We propose that Gα13(Q226L) induces its effect by binding to the IGF1R kinase. We propose that the Gα13 binding site of the IGF1R kinase or the IGF1R binding site in Gα13 may be a novel therapeutic target. Full article

Thyroid cancer is the most common malignancy of the endocrine system and represents a biologically heterogeneous disease driven by the interplay between endocrine regulation, oncogenic signaling pathways, and tumor microenvironment dynamics. Although most follicular cell-derived thyroid cancers follow an indolent clinical course, a subset progresses toward aggressive, therapy-refractory phenotypes, underscoring the need for refined molecular understanding and improved biomarkers. This review comprehensively examines the molecular determinants of thyroid cancer progression, with particular emphasis on Thyroid Hormone (TH) signaling, the Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)/AKT pathways, and the emerging role of microRNAs (miRNAs). We discuss how oncogenic alterations, most notably the ^V600EBRAF mutation, act as central drivers of tumor initiation and aggressiveness by sustaining MAPK/ERK signaling, promoting dedifferentiation, metabolic reprogramming, immune evasion, and resistance to targeted therapies. The cooperative role of PI3K/AKT signaling in reinforcing survival, invasion, and treatment resistance is highlighted, emphasizing the network-level integration of oncogenic pathways rather than linear dependency on single drivers. In parallel, thyroid hormones exert context-dependent effects on tumor biology through both genomic actions mediated by nuclear thyroid hormone receptors and non-genomic mechanisms initiated at the integrin αvβ3 receptor, linking endocrine status to cancer progression and therapeutic response. Finally, we review the expanding evidence supporting miRNAs as critical regulators of thyroid carcinogenesis and as promising diagnostic, prognostic, and predictive biomarkers. The clinical validation of miRNA-based panels and circulating miRNAs offers new opportunities to improve preoperative risk stratification, reduce overtreatment, and guide personalized therapeutic strategies. Collectively, these insights support a multidimensional framework for understanding thyroid cancer progression and highlight future directions for precision oncology. Full article

¹⁸F-fluorodeoxyglucose (FDG) PET/CT is widely used for the evaluation of pulmonary lesions but lacks specificity, as increased FDG uptake is frequently observed in inflammatory and reparative processes. This limitation may lead to false-positive interpretations and unnecessary surgical resections. This study aimed to evaluate the immunohistochemical expression of integrin α_vβ₆ in 18 surgically resected pulmonary lesions that were falsely classified as malignant on FDG PET/CT, in order to find out if ⁶⁸Ga-Trivehexin PET/CT could have superior preoperative diagnostic specificity. Histopathological examination classified all lesions as non-neoplastic inflammatory processes of varying etiologies. Integrin α_vβ₆ expression was detected in all immunohistochemically examined tissue specimens (18/18 cases (100%)), with moderate membranous overexpression in 2/18 cases (11.11%) and strong membranous overexpression in 16/18 cases (88.89%) observed in the alveolar and bronchial epithelium of inflammatory lung lesions. Our findings indicate that integrin α_vβ₆ is upregulated not only in neoplastic lung tissue but also in inflammatory lesions, suggesting that integrin α_vβ₆ may have limited specificity for distinguishing primary neoplastic from inflammatory pulmonary lesions when used alone. Its interpretation requires integration with other clinical imaging modalities and histopathological data. Full article

We utilized molecular dynamics (MD) simulations to explore the interaction of the RGD peptide with the αvβ3 integrin receptor, a key process for targeted drug delivery to tumors. The goal of these simulations was to model the transport of boron atoms by the RGD peptide and to characterize the binding event between this vector and its receptor. The study focused on the interaction processes and spatial arrangements of the solvated RGD–integrin system. Simulations were run for 100 ns to achieve relaxed-state configurations. Our model featured two RGD peptides: one pre-localized within the integrin’s binding site and another initially positioned externally. The external peptide was observed to diffuse freely and subsequently bind to the αvβ3 integrin. This spontaneous binding event provides valuable insights into the pharmacological specificity and mechanisms of the RGD–integrin interaction, informing the design of effective drug delivery systems. Full article

Galectin-3 (Gal3) is one of the most pro-inflammatory proteins and a biomarker of inflammatory diseases and cancer. Previous studies showed that Gal3 binds to αv and β1 integrins, but it is unclear how Gal3 binds to integrins. Here, we show that Gal3 bound to soluble αvβ3 and αIIbβ3 integrins in 1 mM Mn²⁺ in cell-free conditions in a glycan-independent manner. Docking simulation predicts that Gal3 binds to the classical RGD-binding site (site 1) of αvβ3, but the predicted Gal3-binding site does not include galactose-binding site. RGDfV or eptifibatide inhibited Gal3 binding to αvβ3 and αIIbβ3, respectively, but lactose, a pan-galectin inhibitor, did not inhibit Gal3 binding to integrins. Point mutations of the predicted site 1 binding interface of Gal3 effectively inhibited Gal3 binding to site 1. Site 2 is involved in pro-inflammatory signaling (e.g., TNF and IL-6 secretion), and we previously showed that pro-inflammatory cytokines (e.g., CCL5 and TNF) bind to site 2 and allosteric integrin activation. Docking simulation predicted that Gal3 binds to site 2 of αvβ3 and α5β1. We found that Gal3 induced allosteric activation of soluble integrins αvβ3, αIIbβ3, and α5β1 in 1 mM Ca²⁺ in cell-free conditions. Point mutations in the predicted site 2 binding interface inhibited Gal3-induced integrin activation, suggesting that Gal3 binding to site 2 is required for Gal3-induced integrin activation. Known anti-inflammatory agents, Ivermectin, NRG1, and FGF1, inhibited integrin activation induced by Gal3 in αvβ3 and αIIbβ3. These findings suggest that Gal3 binding to site 2 may be a potential mechanism of pro-inflammatory and pro-thrombotic action of Gal3. Full article

Background/Objectives: Amelogenesis imperfecta (AI) is a heterogeneous group of rare hereditary conditions mainly affecting the quantity and/or quality of tooth enamel. Its phenotypic expression is diverse, as is the mutational spectrum of the AI-causing genes and mutations. Integrins are cell-surface receptors that mediate adhesion between cells and between cells and the extracellular matrix. Among these, mutations in integrin αvβ6 have been shown to cause AI; however, phenotypic variation exists between the knockout mouse model and human cases, as well as among different human AI families. Methods: We recruited AI families and performed mutational analysis using whole exome sequencing. Results: We identified compound heterozygous ITGB6 mutations in two families. In Family 1, a paternally transmitted nonsense mutation (NM_000888.5: c.1060C>T, p.(Gln354*)) and a maternally transmitted missense mutation (NM_000888.5: c.2312A>G, p.(Asn771Ser)) were identified; in Family 2, a paternal missense mutation (NM_000888.5: c.1693T>C, p.(Cys565Arg)) and a maternal frameshift mutation (NM_000888.5: c.2091delC, p.(Asn698Metfs*13)) were identified, each causing AI in the respective proband. Both probands exhibited generalized hypoplastic and hypomineralized AI, but no other extraoral symptoms. Conclusions: This report will not only expand the known mutational spectrum of the ITGB6 gene but also provide evidence for the genotype–phenotype correlations, thereby improving our understanding of the functional role of ITGB6 during amelogenesis. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and imposes a high economic and social burden on healthcare systems. In Brazil, the consistent increase in costs associated with AD hospitalizations, coupled with the absence of curative therapies and population aging, reinforces the need for low-cost, broadly applicable preventive strategies. This study investigated the role of irisin, a myokine induced by physical activity, in the prevention of AD, integrating epidemiological and bioinformatic analyses. Public data on the nutritional status of the Brazilian population in the early 2000s and on AD hospitalizations approximately 20 years later were analyzed, assessing the temporal association using a lagged Spearman correlation. Additionally, genes associated with AD were analyzed through protein–protein interaction networks and functional enrichment. Structural models of irisin and the integrin αV/β5 receptor were employed in molecular docking and molecular dynamics analyses. Historical data indicated a high prevalence of excess weight in the early 2000s (46.7% ± 4.2% of the adult population) and a strong positive correlation with AD hospitalizations two decades later (ρ = 0.88; p = 0.033). Functional analyses revealed enrichment of pathways related to neurodegeneration, neurotrophins, and neuronal plasticity, involving proteins such as BDNF, AKT, ERK1/2, and CREB. Docking and molecular dynamics indicated a stable interaction of irisin with the αV/β5 receptor, suggesting activation of neuroprotective pathways. The findings reinforce physical exercise as a strategic public health tool for the prevention of AD, providing an epidemiological and molecular basis to reduce the future burden of the disease, thereby shifting the focus of public health policy from treatment to prevention. Full article

Gut ischemia/reperfusion (I/R) injury releases damage-associated molecular patterns (DAMPs), such as extracellular cold-inducible RNA-binding protein (eCIRP). Milk fat globule–epidermal growth factor VIII-derived oligopeptide 3 (MOP3) is a novel peptide enabling macrophage uptake of eCIRP via αvβ3-integrin. MOP3 reduces inflammation in gut I/R, but its mechanisms are not completely understood. We hypothesized MOP3 promotes macrophage polarization toward an anti-inflammatory, M2-like phenotype in gut I/R. We induced gut I/R in mice through 60 min of superior mesenteric artery occlusion followed by 4 h of reperfusion. Intestines were evaluated for macrophage polarization by flow cytometry and immunofluorescence histology. Peritoneal cavity macrophages were isolated from mice and treated with eCIRP, MOP3, α_vβ₃-antibody, and/or naïve IgG for 4 or 24 h. Polarity was assessed by flow cytometry, qPCR, and ELISA. Compared to the sham, the M2 proportion after gut I/R decreased by 22.7%, and the M1 proportion increased by 241%. MOP3 treatment increased the M2 proportion by 64.3%, and the M1 proportion decreased by 22.7%. In eCIRP-stimulated macrophages, MOP3 treatment increased M2-like and reduced M1-like cell-surface markers, gene expression, and cytokine levels. α_vβ₃ antibody dramatically reduced MOP3′s effects. MOP3 promotes M2 polarization through α_vβ₃ integrin-mediated clearance of eCIRP, a novel mechanism whereby MOP3 reduces gut I/R injury. Full article

End-stage liver disease caused by advanced fibrosis and cirrhosis remains a major global burden, yet its treatment is limited by donor organ shortages. Bioengineered liver scaffolds offer a promising alternative, but their efficacy is often limited by thrombosis, insufficient vascularization, and poor graft integration due to inadequate endothelialization. To overcome these challenges, we employed LXW7 αvβ3 integrin targeting peptide with high endothelial cell specificity and low platelet affinity to enhance re-endothelialization and hemocompatibility of decellularized liver scaffold (DLS) and thereby improve hepatic integration and function. LXW7 was covalently conjugated to the decellularized rat liver scaffold via EDC/NHS-mediated carbodiimide coupling and subsequently reseeded with human umbilical vein endothelial cells (HUVECs) and cultured in a perfusion bioreactor to promote endothelialization. LXW7 immobilization significantly improved HUVECs attachment and proliferation, achieving approximately 81% vascular coverage, while sustaining the endothelial function. Ex vivo blood perfusion showed minimal thrombus formation and markedly reduced platelet adhesion, demonstrating enhanced hemocompatibility. Following confirmation of endothelialization, scaffolds were recellularized with hepatocellular carcinoma (HepG2) cells and HUVECs. LXW7 modified scaffolds promote organized hepatocyte distribution, sustained albumin expression, and increased urea secretion. In vivo implantation of LXW7-DLS into the omentum of mice promoted robust host endothelial recruitment and enhanced neovascularization, highlighting the scaffold’s excellent biocompatibility and good integration with surrounding tissues. Moreover, in vivo implantation of LXW7 recellularized scaffolds into a thioacetamide-induced fibrotic mouse liver resulted in reduced collagen deposition and lowered serum ALT/AST levels, demonstrating hepatic regeneration and extracellular matrix remodeling. Overall, our results showed that LXW7-modified DLS promotes stable endothelialization, improves hemocompatibility, and enhances hepatic function, underscoring its translational potential for the development of vascularized transplantable liver grafts. Full article