Search Results (257)

Eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) are immune-mediated disorders of the gastrointestinal (GI) tract that, despite involving different tissues, are increasingly recognized to coexist. Epidemiologic studies demonstrate a bidirectional association, with patients affected by one condition showing a higher-than-expected prevalence of the other, suggesting shared susceptibility rather than incidental overlap. Genetic and epigenetic data support partial convergence in immune regulatory pathways, while epithelial barrier dysfunction and antigen-driven immune activation emerge as common upstream features. Overlapping cytokine networks, including IL-4, IL-13, and IL-23 signaling, contribute to chronic inflammation in both diseases, although differences in tissue environment and immune dominance give rise to distinct inflammatory phenotypes and clinical behavior. Clinical outcomes in patients with dual diagnoses appear heterogeneous, with available data suggesting neither uniformly worsened nor clearly protective disease courses, underscoring the complexity of shared immune mechanisms operating within different anatomic contexts. Beyond inflammatory activity, coexistence of EoE and IBD poses important nutritional and quality-of-life challenges, as overlapping dietary restrictions and chronic symptoms increase the risk of malnutrition, micronutrient deficiencies, and psychosocial burden. Current therapies remain disease-specific, with strong evidence supporting proton pump inhibitors, swallowed topical steroids, dietary therapy, and dupilumab in EoE, and biologics and small molecules targeting TNF-α, IL-12/23, IL-23, integrins, and JAK–STAT signaling in IBD, while evidence guiding treatment in patients with dual diagnosis remains limited. Together, current evidence supports a framework of shared immune machinery with tissue-specific expression that explains coexistence while preserving the distinct identities of EoE and IBD. By integrating emerging genetic, immunologic, and clinical evidence, this review aims to provide a framework for understanding and managing patients with coexisting EoE and IBD. Full article

Introduction: Live attenuated vaccines (LAVs) are generally avoided in patients with inflammatory bowel disease (IBD) receiving immunomodulatory therapy due to concerns about infection risk. However, real-world data evaluating their safety in this population remain limited. We aimed to assess adverse outcomes following LAV administration in IBD patients treated with biologic agents. Methods: We conducted a retrospective cohort study using the TriNetX multi-institutional database. Adults with IBD receiving immunomodulatory therapy were categorized into two cohorts: those who received an LAV and those who did not. Biologic therapies included tumor necrosis factor inhibitors (infliximab, and adalimumab), integrin antagonists (vedolizumab), interleukin (IL)-12/23 inhibitors (ustekinumab), IL-23 inhibitors (risankizumab, and guselkumab), and Janus kinase inhibitors (tofacitinib, and upadacitinib). LAVs included measles–mumps–rubella (MMR), varicella (Varivax), and yellow fever vaccines. Propensity score matching was performed based on age, sex, IBD subtype (Crohn’s disease vs. ulcerative colitis), and biologic class. Patients with outcomes prior to the risk window were excluded. Adverse outcomes within six months included hospitalization, emergency department (ED) visits, fever, rash, and encephalitis. Results: A total of 672 patients were included in each propensity-score-matched cohort. Live attenuated vaccine (LAV) administration was not associated with significantly increased adverse outcomes compared with no LAV exposure during the six-month follow-up period. Hospitalization occurred in 14.9% versus 15.3% of patients, respectively (risk ratio [RR] 0.97; 95% confidence interval [CI] 0.75–1.25; p = 0.819), while emergency department visits occurred in 12.6% vs 11.3% (RR 1.12; 95% CI 0.84–1.50; p = 0.450). There were no significant differences in fever (3.6% vs. 3.3%; RR 1.09; 95% CI 0.62–1.93; p = 0.764) or rash (4.0% vs. 2.7%; RR 1.50; 95% CI 0.83–2.70; p = 0.172). No cases of measles, mumps, rubella, varicella, yellow fever, or encephalitis were identified in either cohort during follow-up. Conclusions: LAVs were not associated with an increased risk of adverse outcomes within one day to six months among IBD patients receiving immunomodulatory therapy. These real-world findings suggest comparable short-term outcomes between the cohorts of patients with IBD receiving biologic or targeted synthetic therapy who met the predefined eligibility criteria including age ≥ 18 years, and vaccination occurring between two weeks and six months after biologic initiation regarding LAV use in patients with IBD receiving biologic agents. Full article

Post-infectious bronchiolitis obliterans (PIBO) is a severe chronic airway disease in children following lower respiratory tract infections. Human adenovirus (HAdV) and Mycoplasma pneumoniae (MP) are the major associated pathogens, with geographic variations in their relative importance. This review analytically compares the mechanistic divergence and convergence between HAdV and MP. Both pathogens converge on MyD88/NF-κB/MAPK signaling and neutrophil-driven inflammation, but diverge in initial host engagement (CAR/integrins vs. TLR2/6 and CARDS toxin) and inflammasome activation (TLR9-related vs. NLRP3-related). This review aims to propose an integrative model linking acute immune activation to fibrotic bronchiolar narrowing and to evaluate the risk factors for PIBO. Genetic susceptibility and epigenetic regulation help explain population differences in PIBO risk and geographic distribution. Despite progress, significant knowledge gaps remain, including the lack of single-cell resolution studies, the absence of co-infection animal models, and uncertainty regarding the long-term efficacy of targeted immunomodulatory therapies. Addressing these gaps is essential for improving early diagnosis and clinical outcomes. 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

Chondrosarcoma (CHS), the second most common primary malignant cartilage tumor, is largely resistant to conventional therapies, making surgical resection the standard treatment. Proton therapy offers a physical advantage through the Bragg peak, enabling targeted irradiation while sparing surrounding tissues. However, differential biological responses between malignant and normal cartilage cells remain poorly understood. In this study, CHS SW1353 cells and normal chondrocytes (MC615) were exposed to proton irradiation. Biological responses were assessed via clonogenic survival, cell viability, apoptosis (caspase 3/7), micronucleus formation, cell cycle profiling, and oxidative stress markers. Proteomic changes were analyzed using mass spectrometry and bioinformatics. CHS cells exhibited higher radioresistance (D₁₀ = 6.45 Gy) than normal chondrocytes (D₁₀ = 5.08 Gy), oxidative stress adaptation, G1 arrest and proteomic plasticity, whereas normal chondrocytes displayed increased oxidative stress, extracellular matrix fragility and impaired integrin signaling. Notably, the tumor-specific increased levels of Tyrosine-protein kinase Fyn and Yes1-associated transcriptional regulator (YAP1) signaling suggest molecular drivers of radioresistance. Overall, proton irradiation elicits distinct biological and proteomic responses in malignant versus normal cartilage cells. These findings highlight potential radiosensitization targets, including Fyn/Src and YAP1/Hippo pathways, while underscoring the need to optimize proton therapy to enhance tumor control while minimizing damage to healthy cartilage. 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

Background and Objectives: Cutaneous melanoma (CM) is one of the most aggressive skin malignancies due to its rapid progression and high therapeutic resistance. Growing evidence demonstrates that the tumor microenvironment (TME)—comprising diverse immune, stromal, vascular, and epidermal cell populations alongside various cytokines and growth factors, as well as extracellular matrix (ECM) components—plays a crucial role in tumor heterogeneity, metastatic potential, and response to therapy. This review aims to synthesise current knowledge on the cellular and non-cellular constituents of the CM microenvironment and clarify their contributions to tumor progression, immune evasion, and treatment resistance. Materials and Methods: We conducted a narrative review of recent experimental, clinical, and translational studies investigating melanoma–microenvironment interactions, integrating evidence from in vitro, in vivo, and human tissue analyses. Results: Melanoma exhibits marked intra-tumoral heterogeneity driven by genetic, epigenetic, and microenvironmental influences. Cancer-associated fibroblasts, adipocytes, endothelial cells, and keratinocytes are reprogrammed by melanoma cells to promote invasion, angiogenesis, and metastasis. Immune subsets play divergent roles: neutrophils, M2 macrophages, myeloid-derived suppressor cells, and tolerogenic dendritic cells foster immune suppression, while lymphocytes—particularly CD8⁺ T cells, TFH cells, and B cells —are associated with improved outcomes but often become dysfunctional. ECM remodeling, including collagen deposition, integrin signaling, and increased matrix stiffness, actively remodels the tissue to support tumor growth and immune evasion. Hypoxia-inducible factor (HIF)-mediated signaling drives cell dedifferentiation, angiogenesis, and metabolic changes that contribute to treatment resistance. Consequently, emerging therapeutic strategies are moving beyond targeting tumor cells alone to focus on modulating TME components, counteracting immunosuppression, hypoxia, metabolic reprogramming, and extracellular vesicle signaling. Conclusions: The TME profoundly modulates tumor behavior and therapeutic response. A deeper understanding of the reciprocal interactions between melanoma cells and their microenvironmental components may enable the development of more effective strategies for early detection, prognosis, and personalized therapies. Full article

Extracellular matrix (ECM) stiffening is a defining biophysical feature of solid tumors that reshape gene regulation through mechanotransduction. Increased collagen crosslinking and stromal remodeling enhance integrin engagement, focal-adhesion signaling and force transmission to the nucleus, where key hubs such as lysyl oxidase (LOX), focal adhesion kinase (FAK) and the Hippo co-activators YAP1 and TAZ (WWTR1) promote proliferation, invasion, stemness and therapy resistance. Here, we synthesize evidence that quantitative changes in matrix stiffness remodel the miRNome and lncRNome in both tumor and stromal compartments, including extracellular vesicle cargo that reprograms metastatic niches. To address heterogeneity in experimental support, we classify mechanosensitive ncRNAs into studies directly validated by stiffness manipulation (e.g., tunable hydrogels/AFM) versus indirect associations based on mechanosensitive signaling, and we summarize physiological versus pathophysiological stiffness ranges across tissues discussed. We further review competing endogenous RNA (ceRNA) networks converging on mechanotransduction nodes and ECM remodeling enzymes, and discuss translational opportunities and challenges, including targeting mechanosensitive ncRNAs, combining ncRNA modulation with anti-stiffening strategies, delivery barriers in dense tumors, and the potential of circulating/exosomal ncRNAs as biomarkers. Overall, integrating ECM mechanics with ncRNA regulatory circuits provides a framework to identify feed-forward loops sustaining aggressive phenotypes in rigid microenvironments and highlights priorities for validation in physiologically relevant models. Full article

Photodynamic therapy (PDT) is a technique based on the use of photosensitizers activated by light to destroy cancer cells in the presence of oxygen. This enables localized cancer treatment and, in some settings, fluorescence-guided visualization. However, the efficacy and clinical translation of PDT have been limited by the low specificity of traditional photosensitizers. The aim of the study is to create a ligand-guided PDT approach for pancreatic ductal adenocarcinoma (PDAC) using a peptide-conjugated photosensitizer binding to integrin αvβ6, which is a receptor linked to tumor growth and prevalent in PDAC cells. Current treatment options for this tumor are limited, with surgical resection and chemotherapy only effective when the tumor is detected early. Given the limited treatment options for PDAC, PDT via αvβ6 offers a new pathway for precision treatment. The cyclic peptide cyclo[FRGDLAFp(NMe)K], recognized for its high affinity to αvβ6, was chosen to guide a phthalocyanine-class photosensitizer toward αvβ6-expressing PDAC models. The PDT approach was further refined by developing 3D spheroid models and in vivo BxPc3 xenograft models in NOD/SCID mice, where its therapeutic efficacy was assessed. In the absence of a non-targeted control photosensitizer, a contribution from non-specific accumulation and EPR effects in the in vivo setting cannot be fully ruled out. This study highlights the potential of a peptide-guided photosensitizer, demonstrating uptake and photodynamic activity in spheroids, with moderate in vivo results addressing tumor microenvironment challenges. Optimization of PDT dosing, laser precision, and preclinical models, such as patient-derived xenografts, are crucial to enhance clinical translation. Full article

Background: Platelet hyperreactivity contributes to occlusive thrombus formation in vessels, precipitating acute cardiovascular events such as myocardial infarction and stroke. Traditional Chinese Medicine (TCM) has been used for centuries, and numerous TCM herbs have been reported to exert anti-inflammatory and anticoagulant effects. Objectives: We sought to identify key compounds within the TCM-derived herbal extracts that regulate platelet activity. Methods: Crude and fractioned herbal extracts were screened for their ability to inhibit platelet activation in response to multiple agonists. Platelet aggregation and flow cytometry were used to assess the potency and selectivity of the compounds within the extracts. Results: Three extracts, di gu pi (DGP), san qi (SQ), and zi cao (ZC), demonstrated inhibitory activity and were subsequently fractionated. Fractions derived from DGP, the root bark of Lycium chinense, inhibited platelet aggregation and suppressed integrin activation and granule secretion downstream of collagen receptor signaling. Further analysis identified the oxidized lipids 9(S)-hydroxy-9Z,11E-octadecadienoic acid (9-HODE), 13(S)-HODE, and 13(S)-hydroxy-9Z,11E,15Z-octadecatrienoic acid (13-HOTrE) as constituents of the bioactive fractions. Both 13-HODE and 13-HOTrE selectively inhibited collagen-mediated platelet aggregation without affecting thrombin-induced activation. Conclusions: Collectively, these findings identify oxylipins in TCM as promising candidates for the development of antiplatelet therapies targeting platelet activity and thrombosis. These oxylipins may represent novel approaches for thrombosis and have high therapeutic potential for development as next-generation antiplatelet drugs. Full article

The extracellular matrix (ECM) is a dynamic, tissue-specific network that integrates biochemical and mechanical cues to regulate cell behavior and organ homeostasis. Increasing evidence indicates that dysregulated ECM remodeling is an upstream driver of chronic human diseases rather than a passive consequence of injury. This review summarizes principles of ECM organization, mechanotransduction, and pathological remodeling and highlights translational opportunities for ECM-targeted therapies, biomaterial platforms, and precision diagnostics. We conducted a narrative synthesis of foundational and recent literature covering ECM composition and turnover, stiffness-dependent signaling, and disease-associated remodeling across fibrosis/cardiovascular disease, cancer, and metabolic disorders, together with advances in ECM-based biomaterials, drug delivery, and ECMderived biomarkers and imaging. Across organs, a self-reinforcing cycle of altered matrix composition, excessive crosslinking, and stiffness-dependent mechanotransduction (including integrin–FAK and YAP/TAZ pathways) sustains fibroinflammation, myofibroblast persistence, and progressive tissue dysfunction. In tumors, aligned and crosslinked ECM promotes invasion, immune evasion, and therapy resistance while also shaping perfusion and drug penetration. Translational strategies increasingly focus on modulating ECM synthesis and crosslinking, normalizing rather than ablating matrix architecture, and targeting ECM–cell signaling axes in combination with anti-fibrotic, cytotoxic, or immunotherapeutic regimens. ECM biology provides a unifying framework linking pathogenesis, therapy, and precision diagnostics across chronic diseases. Clinical translation will benefit from standardized quantitative measures of matrix remodeling, mechanism-based biomarkers of ECM turnover, and integrative imaging–omics approaches for patient stratification and treatment monitoring. Full article

Background/Objectives: Vedolizumab (VDZ), a monoclonal antibody targeting α4β7 integrin, is used in Crohn’s disease (CD) management, yet patients’ responses vary, underscoring the need for pharmacogenomic (PGx) markers. This study aimed to identify PGx pathways associated with suboptimal VDZ response using a rare-variant analytical framework. Methods: DNA from 63 CD patients treated with VDZ as first-line advanced therapy underwent whole-exome sequencing. Clinical response at week 14 classified patients as optimal responders (ORs) or suboptimal responders (SRs). Sequencing data were processed using GATK Best Practices, annotated with variant effect predictors, and filtered for rare damaging variants (damaging missense and high-confidence loss-of-function; minor allele frequency < 0.05). Variants were mapped to genes specific for SRs and ORs, and analyzed for pathway enrichment using the Reactome database. Rare-variant burden and composition differences were assessed with Fisher’s exact test and SKAT-O gene-set association analysis. Results: Suboptimal VDZ response was associated with pathways related to membrane transport (ABC-family proteins, ion channels), L1–ankyrin interactions, and bile acid recycling, while optimal response was associated with pathways involving MET signaling. SKAT-O identified lipid metabolism-related pathways as significantly different—SRs harbored variants in pro-inflammatory lipid signaling and immune cell trafficking genes (e.g., PIK3CG, CYP4F2, PLA2R1), whereas ORs carried variants in fatty acid oxidation and detoxification genes (e.g., ACADM, CYP1A1, ALDH3A2, DECR1, MMUT). Conclusions: This study underscores the potential of exome-based rare-variant analysis to stratify CD patients and guide precision medicine approaches. The identified genes and pathways are potential PGx markers for CD patients treated with VDZ. Full article

Osteoarthritis (OA) is a multifactorial degenerative joint disease in which aberrant mechanical cues act in concert with metabolic dysregulation and chronic low-grade inflammation, with chondrocyte hypertrophy representing a key pathological event driving cartilage degeneration. Alterations in extracellular matrix (ECM) properties—including mechanical loading, stiffness and viscoelasticity, topological organization, and surface chemistry—regulate hypertrophic differentiation and matrix degradation in a zone-, stage-, and scale-dependent manner. Microscale measurements often reveal localized stiffening in superficial zones during early OA, whereas bulk tissue testing can show softening or heterogeneous changes in deeper zones or advanced stages, highlighting the context-dependent nature of ECM mechanics. These biophysical signals are sensed by integrin-based adhesion complexes, primary cilia, mechanosensitive ion channels (TRP/Piezo), and the actin cytoskeleton–nucleus continuum, and are transduced into intracellular pathways with zone- and stage-specific effects, governing chondrocyte fate under physiological and osteoarthritic conditions. Mechanism-based anti-hypertrophic strategies include biomimetic scaffold design for focal defects, dynamic mechanical stimulation targeting early OA, and multimodal approaches integrating mechanical cues with biochemical factors, gene modulation, drug delivery, or cell-based therapies. Collectively, this review provides an integrated mechanobiological framework for understanding cartilage degeneration and highlights emerging opportunities for disease-modifying interventions targeting chondrocyte hypertrophy. Full article

Glycation-induced modifications of extracellular matrix (ECM) proteins, including collagen, are increasingly recognized as critical modulators of cellular behavior, particularly in pathophysiological contexts such as aging and diabetes. While their impact on general cell adhesion has been explored, the specific consequences for mesenchymal stem cell (MSC) mechanotransduction remain poorly defined. In this study, we investigated the temporal and mechanistic aspects of adhesion and mechanosensitive signaling in adipose-derived MSCs (ADMSCs) cultured on native versus glycated collagen substrates. Our findings identify two temporally distinct adhesion mechanisms: an initial pathway mediated by the receptor for advanced glycation end-products (RAGE), which is activated within the first 30 min following substrate engagement, and a later-stage adhesion process predominantly governed by integrins. Immunofluorescence analysis demonstrated maximal nuclear localization of YAP/TAZ transcriptional regulators during the initial adhesion phase, coinciding with RAGE engagement. This nuclear enrichment was progressively attenuated as integrin-mediated focal adhesions matured, suggesting a dynamic shift in receptor usage and mechanotransductive signaling. Interestingly, glycated collagen substrates accelerated early cell attachment but impaired focal adhesion maturation, suggesting a disruption in integrin engagement. Endogenous collagen synthesis was consistently detected at all examined time points (30 min, 2 h, and 5 h), suggesting a constitutive biosynthetic activity that remains sensitive to the glycation state of the substrate. Atomic force microscopy (AFM) demonstrated that glycation disrupts collagen fibrillogenesis: while native collagen forms a well-organized network of long, interconnected fibrils, GL-1 substrates (glycated for 1 day) displayed sparse and disordered fibrillary structures, whereas GL-5 substrates (5-day glycation) exhibited partial restoration of fibrillar organization. These matrix alterations were closely associated with changes in adhesion kinetics and mechanotransduction profiles. Taken together, our findings demonstrate that collagen glycation modulates both adhesion dynamics and mechanosensitive signaling of MSCs through a dual-receptor mechanism. These insights have significant implications for the design of regenerative therapies targeting aged or metabolically compromised tissues, where ECM glycation is prevalent. Full article

Inflammatory bowel disease (IBD) management traditionally focuses on intestinal inflammation, yet extraintestinal manifestations can substantially impair patient quality of life. In this perspective, we emphasize the broad systemic impact of IBD—from highly prevalent conditions such as anemia, metabolic dysfunction-associated steatotic liver disease, or fatigue to rare but severe complications like interstitial lung disease and drug-induced glomerulonephritis. We review underlying mechanisms linking gut inflammation to distant organs, including immune dysregulation, microbial translocation, and metabolic derangements. Advances in diagnostics—such as biomarker panels, high-resolution imaging, and genomic/microbiome profiling—enable early detection and risk stratification. Emerging therapies, including targeted biologics (anti-TNF, anti-integrin, anti-IL-23), JAK and S1P modulators, precision nutrition, and microbiome modulation, offer new opportunities to address systemic inflammation. A multidisciplinary framework integrating gastroenterology with hepatology, hematology, neurology, nephrology, endocrinology, dermatology, pulmonology, and cardiology is essential to recognize hidden complications, facilitate timely intervention, and deliver personalized, comprehensive care for IBD. Full article