Search Results (1,460)

Background/Objectives: Chronic kidney disease of unknown etiology (CKDu) disproportionately affects young male agricultural workers who are otherwise healthy. There is a scarcity of biomarkers for early detection of this type of kidney disease. We hypothesized that small extracellular vesicles (sEVs) released into urine may provide novel biomarkers. Methods: We obtained two urine samples at the start and the end of a workday in the fields from a limited set of workers with and without kidney impairment. Isolated sEVs were characterized for size, surface marker expression, and purity and, subsequently, their lipid composition was determined by mass spectrometry. Results: The number of particles per ml of urine normalized to osmolality and the size variance were larger in workers with possible CKDu than in control workers. Surface markers CD9, CD63, and CD81 are characteristic of sEVs and a second set of surface markers suggested the kidney as the origin. Differential expression of CD25 and CD45 suggested early inflammation in CKDu workers. Of the twenty-one lipids differentially expressed, several were bioactive, suggesting that they may have essential functions. Remarkably, fourteen of the lipids showed intermediate expression values in sEVs from healthy individuals with acute creatinine increases after a day of work. Conclusions: We identified twenty-one possible lipid biomarkers in sEVs isolated from urine that may be able to distinguish agricultural workers with early onset of CKDu. Differentially expressed surface proteins in these sEVs suggested early-stage inflammation. This pilot study was limited in the number of workers evaluated, but the approach should be further evaluated in a larger population. Full article

Background/Objectives: Affecting close to one-third of the global population, metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disorder linked to metabolic risk factors such as obesity and insulin resistance. Liver fibrosis is a key determinant of prognosis, and its progression increases the risk of liver-related and overall mortality. This exploratory research evaluated the potential impact of a 3-month intervention involving dietary counseling and liraglutide therapy on liver fibrosis and related metabolic markers in patients with MASLD and obesity without diabetes. Methods: In this prospective, single-arm exploratory intervention, 28 adult patients with MASLD and obesity received structured dietary counseling and daily subcutaneous liraglutide for 12 weeks. Liver fibrosis was assessed using non-invasive indices (FIB-4, APRI, BARD, ELF) and transient elastography performed with the FibroScan^® device (Echosens, Paris, France). Results: After 3 months, a significant reduction in liver stiffness (−7.14%, p < 0.05) and ELF score (from 6.71 to 6.63; −1.2%, p < 0.05) was observed. APRI (p = 0.06) and FIB-4 (p = 0.09) showed trends toward improvement, while the BARD score and AST/ALT ratio remained unchanged. Conclusions: Short-term liraglutide therapy combined with lifestyle modification may improve early-stage liver fibrosis in patients with MASLD and obesity, as indicated by reductions in liver stiffness and ELF score. These preliminary findings highlight the potential of advanced non-invasive fibrosis markers in monitoring treatment response. However, as an exploratory study, results should be interpreted with caution, and larger, long-term trials are needed to confirm these observations and evaluate efficacy in patients with more advanced fibrosis stages. Full article

Background/Objectives: Heart transplantation (HTx) is a lifesaving procedure for end-stage heart failure patients; however, postoperative infections remain a major challenge due to immunosuppressive therapy and surgical complications. Traditional biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT) have limitations in distinguishing infections from systemic inflammatory response syndrome (SIRS). Emerging markers such as Presepsin and interleukin-6 (IL-6) may improve diagnostic accuracy. This study aimed to evaluate the kinetics and reliability of these four inflammatory biomarkers in heart transplant recipients in the immediate postoperative period. Methods: This retrospective observational study included 126 patients who underwent HTx at Policlinic of Bari between January 2022 and November 2024. Patients were categorized into infected (n = 26) and non-infected (n = 100) groups based on clinical and microbiological criteria. Biomarkers (CRP, PCT, Presepsin, and IL-6) were measured preoperatively and on postoperative days (PODs) 1, 2, 3, 4, 5, and 10. Statistical analyses included the Mann–Whitney U test and logistic regression to identify the independent predictors of infection. Results: CRP and PCT levels differed significantly between the groups only on day 10, limiting their use as early infection markers. In contrast, Presepsin levels were significantly elevated in infected patients from day 1 (p < 0.001), whereas IL-6 levels showed significant differences from day 3 onward. Presepsin showed the strongest association with infection in the early postoperative phase. Conclusions: Presepsin and IL-6 outperformed CRP and PCT in detecting early postoperative infections in heart transplant recipients. Their early elevation supports their use as reliable markers for guiding timely clinical intervention and improving patient outcomes. Further research is needed to validate these findings in larger cohorts and with different immunosuppressive regimens. Full article

Background/Objectives: Eph receptor A5 (EphA5) is a receptor tyrosine kinase that is implicated in multiple malignancies, although its role in endometrial cancer (EC) remains unclear. The aim of this study was to investigate the clinicopathological significance of EphA5 expression in EC and explore its association with proliferative and metabolic markers. Methods: We retrospectively analyzed 75 EC tissue samples from treatment-naïve patients by using immunohistochemistry and H-score quantification. Associations between EphA5 expression and clinicopathological parameters were assessed through logistic regression analysis. Kaplan–Meier analysis was used to evaluate survival outcomes. Correlation analysis, stratified according to cancer stage, was used to explore biomarker interactions. Results: High EphA5 expression levels were significantly associated with elevated Ki-67 expression (adjusted odds ratio (aOR): 1.08 per 1-point H-score increase, p = 0.024) and decreased pAMPK expression (aOR: 0.89 per 1-point H-score increase, p = 0.024), indicating its involvement in proliferative and metabolic pathways. Paradoxically, patients with high EphA5 levels had significantly better overall survival probabilities (H-score > 105, log-rank p = 0.007). Stage-specific analyses suggested that EphA5 levels correlated with proliferation in early-stage disease and epithelial–mesenchymal transition in advanced stages. Conclusions: EphA5 may act as a context-dependent biomarker in EC. Despite its positive correlation with proliferation and negative association with metabolic stress signaling, high EphA5 expression levels were predictive of a favorable prognosis. 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

The development of scalable, non-invasive tools to assess tumor responsiveness to structurally active immunoformulations remains a critical unmet need in solid tumor immunotherapy. Here, we introduce a real-time, ex vivo functional system to classify tumor cell lines exposed to a phospholipoproteomic platform, without relying on cytotoxicity, co-culture systems, or molecular profiling. Tumor cells were monitored using IncuCyte^® S3 (Sartorius) real-time imaging under ex vivo neutral conditions. No dendritic cell components or immune co-cultures were used in this mode. All results are derived from direct tumor cell responses to structurally active formulations. Using eight human tumor lines, we captured proliferative behavior, cell death rates, and secretomic profiles to assign each case into stimulatory, inhibitory, or neutral categories. A structured decision-tree logic supported the classification, and a Functional Stratification Index (FSI) was computed to quantify the response magnitude. Inhibitory lines showed early divergence and high IFN-γ/IL-10 ratios; stimulatory ones exhibited a proliferative gain under balanced immune signaling. The results were reproducible across independent batches. This system enables quantitative phenotypic screening under standardized, marker-free conditions and offers an adaptable platform for functional evaluation in immuno-oncology pipelines where traditional cytotoxic endpoints are insufficient. This approach has been codified into the STIP (Structured Traceability and Immunophenotypic Platform), supporting reproducible documentation across tumor models. This platform contributes to upstream validation logic in immuno-oncology workflows and supports early-stage regulatory documentation. Full article

Chronic inflammatory response syndrome (CIRS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are debilitating multisystem illnesses that share overlapping symptoms and molecular patterns, including immune dysregulation, mitochondrial impairment, and vascular dysfunction. This review provides a chronological synthesis of biomarker development in CIRS, tracing its evolution from early functional tests such as visual contrast sensitivity (VCS) to advanced transcriptomic profiling. Drawing on peer-reviewed studies spanning two decades, we examine the layered integration of neuroendocrine, immunologic, metabolic, and genomic markers that collectively support a multisystem model of innate immune activation specific to environmentally acquired illness. Particular focus is given to the Gene Expression: Inflammation Explained (GENIE) platform’s use of transcriptomics to classify disease stages and distinguish CIRS from other fatiguing conditions. While ME/CFS research continues to explore overlapping pathophysiologic features, it has yet to establish a unified diagnostic model with validated biomarkers or exposure-linked mechanisms. As a result, many patients labeled with ME/CFS may, in fact, represent unrecognized CIRS cases. This review underscores the importance of structured biomarker timelines in improving differential diagnosis and guiding treatment in complex chronic illness and highlights the reproducibility of the CIRS framework in contrast to the diagnostic ambiguity surrounding ME/CFS. Full article

Background: Dopamine participates in the cognitive cerebellar role and in cerebellum development. The trace amine-associated receptor (TAARs, TAAR1-TAAR9) system contributes to dopamine signaling tuning. So, the aim of the present study is the analysis of the TAARs’ gene expression and functional associations in prenatal and neonatal mouse cerebellums. Methods: The transcriptomic data represented in the GEO repository was performed to identify Taars expression and co-expression patterns in embrionic and postnatal mouse cerebellum. Results: Open transcriptomic data analysis showed cerebellar expression of the Taar5 gene mRNA both in prenatal and early postnatal samples. The identified Taar5 expression was confirmed by RT-PCR in P5 mice. We identified the association between Taar5 expression and the expression of proliferation-related genes in late prenatal E13.5 samples, which was replaced by co-expression with genes involved in metabolism in P5–6 samples. These associations are suggested to mirror the previously identified Taar5 expression in Purkinje cells, which proliferate at the E13.5 and mature in the postnatal period. However, the analysis of TAAR5 co-expression with markers of different cell populations revealed the pronounced co-expression of TAAR5 in the P5–6 cerebellum with microglial markers, which is shifted to the association with astroglial markers in P10. Conclusions: The Taar5 gene was found to be active in the cerebellum samples taken around birth, and its co-expression pattern differs in the embryo stage and the early days after birth. We suggest that the Taar5 receptor may be involved in cerebellum development; however, further research is necessary to elucidate its role in this process. Full article

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, often fatal congenital disorder characterized by severe neonatal respiratory distress and associated with complex multisystem malformations. In approximately 90% of cases, the condition is linked to deletions or mutations affecting the FOXF1 gene or its upstream enhancer region on chromosome 16q24.1. This review analyzes reported prenatal cases with 16q24.1 deletion involving FOXF1, aiming to identify recurrent sonographic features and elucidate the underlying genomic and epigenetic mechanisms. We reviewed prenatal cases reported in the literature involving deletions of the 16q24.1 region, including the FOXF1 gene. Here, we expand the case series by reporting a fetus with increased nuchal translucency measuring 8 mm and a de novo 16q24.1 deletion. We identified nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward. Prenatal diagnosis of ACDMPV based solely on ultrasound findings is challenging. In most reported cases, the pregnancy was carried to term, with the diagnosis being confirmed by post-mortem histopathological examination. In the only case in which the pregnancy was terminated at 14 weeks’ gestation, histological examination of the fetal lungs, despite them being in the early stages of development, revealed misaligned pulmonary veins in close proximity to the pulmonary arteries and bronchioles. Evidence highlights the significance of non-coding regulatory regions in the regulation of FOXF1 expression. Differential methylation patterns, and possible contributions of parental imprinting, highlight the complexity of FOXF1 regulation. Early detection through array comparative genomic hybridization (array CGH) or next-generation sequencing to identify point mutations in the FOXF1 gene, combined with increased awareness of ultrasound markers suggestive of the condition, could improve the accuracy of prenatal diagnosis and genetic counseling. Further research into the epigenetic regulation of FOXF1 is crucial for refining recurrence risk estimates and improving genetic counseling practices. Full article

Background: Atypical carcinoid of the thymus is an exceptionally rare neuroendocrine tumor originating from neuroendocrine cells within the thymus. These tumors often present with no symptoms or with nonspecific clinical signs, making early diagnosis particularly challenging. Despite their rarity, atypical carcinoids are clinically significant due to their aggressive nature and relatively poor prognosis. Early detection and appropriate management are therefore crucial to improving patient outcomes. Results: In this report, we present the case of a 64-year-old patient in whom an atypical carcinoid of the thymus was incidentally discovered following a thoracic computed tomography scan performed for unrelated reasons. Imaging revealed a suspicious anterior mediastinal mass, which was subsequently surgically resected. Histopathological examination, supported by immunohistochemical analysis, confirmed the diagnosis of an atypical carcinoid of the thymus. The tumor demonstrated coexpression of epithelial and neuroendocrine markers, consistent with this rare entity. Conclusions: This case adds to the limited body of literature on atypical carcinoid of the thymus and highlights the importance of considering this diagnosis when evaluating anterior mediastinal masses. It also underscores the value of thorough radiological and pathological assessment in identifying early-stage disease, which may significantly influence prognosis and therapeutic strategies. Full article

The tumor microenvironment (TME) in advanced solid tumors is determined by immune checkpoints (PD-1, CTLA-4, and CD95) and cytokine networks (IL-2, IL-10, and TNF-α) that drive CD8+ T cell exhaustion, metabolic reprogramming, and apoptosis resistance, enabling immune evasion. Some studies revealed PD-1/CD95 co-expression is a marker of T cell dysfunction, while CTLA-4 upregulation correlates with suppressed early T cell activation. IL-10 has emerged as a potential biomarker for chemoresistance and tumor aggressivity, consistent with its role in promoting anti-apoptotic signaling in cancer stem cells (CSCs). Engineered IL-2 variants and TNF-α modulation are highlighted as promising strategies to revitalize exhausted CD8+ T cells and disrupt CSC niches. This prospective single-center study investigated the dynamic TME alterations in 16 patients with immunotherapy-naïve stage IV non-small-cell lung cancer (NSCLC) and metastatic melanoma treated with anti-PD-1 nivolumab. The longitudinal immunophenotyping of peripheral blood lymphocytes (via flow cytometry) and serum cytokine analysis (via ELISA) were performed at the baseline, >3, and >6 months post-treatment to evaluate immune checkpoint co-expression (PD-1/CD95 and CTLA-4/CD8+) and the cytokine profiles (IL-2, IL-10, and TNF-α). Full article

Background and Aims: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease frequently associated with fatigue and mild cognitive impairment. Brain-derived neurotrophic factor (BDNF) plays key roles in neuroplasticity, immune regulation, and metabolism. This study aimed to evaluate plasma BDNF levels in early-stage PBC and examine their clinical and biochemical associations. Methods: In this observational study, plasma BDNF, IL-6, and IL-18 concentrations were measured by ELISA in 45 patients with early-stage PBC and 31 age- and sex-matched healthy controls (mean age 60.5 years; 96% women). All participants underwent liver elastography using point shear wave elastography (ElastPQ), Doppler ultrasound, laboratory testing, and assessment of cognitive function (PHES) and fatigue severity (MFIS). Non-invasive fibrosis scores (APRI, FIB-4) were calculated. Results: Median plasma BDNF concentrations were significantly higher in PBC patients than in controls [median: 21.04 ng/mL (IQR: 10.68–38.07) vs. 5.80 ng/mL (IQR: 4.58–7.54); p < 0.0001]. In PBC patients, higher BDNF levels correlated inversely with liver stiffness measured by ElastPQ (R = −0.39, p = 0.0258), spleen dimensions, splenic vein flow volume (R = −0.49, p = 0.0018), suggesting an association with milder liver fibrosis and early hemodynamic alterations. A trend toward association between BDNF and IL-6 levels was observed in multivariate analysis. No significant associations were found between BDNF concentrations and markers of hepatocellular injury, cognitive performance, or fatigue severity. Conclusions: Plasma BDNF concentrations are elevated in early-stage PBC and inversely correlate with liver fibrosis severity. No significant associations were found with hepatocellular injury, cognitive function, or fatigue. These findings suggest that BDNF may play a protective role against hepatic fibrogenesis, or alternatively, that BDNF concentrations may decline with advancing liver disease. Further studies are needed to clarify its significance in PBC. Full article

Osteolforte, a compound with potential bone-regenerative properties, was investigated for its effects on human bone marrow stromal cells (hBMSCs). This study aimed to evaluate its impact on cell viability, osteogenic differentiation, and both gene and protein expression using a combination of assays, including CCK-8, Alizarin Red S staining, Quantitative Real-Time PCR (qRT-PCR), and Western blot analysis. The results demonstrated that Osteolforte significantly enhanced osteogenic differentiation in hBMSCs. Alizarin Red S staining revealed increased mineralization, indicating elevated calcium deposition. Gene expression analysis showed an upregulation of key osteogenic markers, including runt-related transcription factor-2 (RUNX-2), collagen type I (COL-1), and bone morphogenetic protein-2 (BMP-2), supporting the role of Osteolforte in promoting osteoblastic activity. In particular, the elevated expression of RUNX-2—a master transcription factor in osteoblast differentiation along with COL-1, a major bone matrix component, and BMP-2, a key bone morphogenetic protein—highlights the compound’s osteogenic potential. In conclusion, Osteolforte enhances early-stage osteogenesis and mineralization in hBMSCs and represents a promising candidate for bone regeneration. Full article

Acute pancreatitis (AP) is among the most frequent gastroenterology emergencies, with hospital admission rates on the rise in recent decades. However, a specific treatment for this condition is still lacking. Mitochondrial damage induced by oxidative stress is regarded as the key event in the pathophysiology and initiation of cellular damage in AP. In the early stages of AP, the oxidant–antioxidant balance changes rapidly, and there are significant data regarding the reduced serum levels of antioxidants, with this event being correlated with the clinical severity of pancreatitis. Therefore, addressing oxidative stress could represent a potential therapeutic target in AP. In this comprehensive review, we aimed to provide an update on current evidence regarding clinical and experimental data on antioxidant use in AP, focusing on human studies investigating the effects of single and combined antioxidant supplementation. Although a multitude of animal studies demonstrated that antioxidant therapy has beneficial effects in experimental AP by reducing oxidative injury, inflammatory markers, and ameliorating histological outcomes, human trials showed predominantly conflicting results, with some studies suggesting benefit while others showed no effect, or even potential harm, when antioxidants were administered in high doses or in combination. Moreover, some antioxidants with beneficial results in experimental settings did not show the same efficacy when translated to human studies, which may be a consequence of either inappropriate dosage, route of administration and duration of therapy, or altered pharmacodynamics in vivo. In conclusion, oxidative stress plays a key role in the pathophysiology of AP by enhancing acinar cell injury, inflammation, and systemic complications. Future studies should be centered on optimized dosing strategies, early administration protocols, targeted patient selection, and delivery methods of proper pharmaceutical forms. Full article

This study investigated the effects of Bothrops moojeni (B. moojeni) venom and its high- (HMM) and low-molecular mass (LMM) fractions on human osteoclast (OC) differentiation and function in vitro, aiming to identify novel therapeutics for bone disorders. Venom preparations were applied at 5 µg/mL (crude venom and HMM) or 1 µg/mL (LMM) from day 4 of peripheral blood mononuclear cell (PBMC) differentiation through terminal OC formation, enabling evaluation across early differentiation, fusion, and maturation stages. RNA sequencing revealed 7793 genes common to all experimental groups, with unique gene expression signatures of 149 (control), 221 (HMM), 248 (crude venom), and 60 (LMM) genes, reflecting distinct molecular responses. The negative control PBMC group exhibited 1013 unique genes enriched in immune-related pathways, consistent with their undifferentiated state. Crude venom induced the broadest transcriptional modulation, upregulating key fusion (CD47) and resorption (CTSK) genes, and altering markers of OC differentiation. The HMM fraction predominantly influenced inflammatory and osteoclastogenic pathways, notably TNF and NF-κB signaling, while the LMM fraction selectively regulated fusion-related genes (e.g., CD44) and immune pathways, indicating targeted modulation of OC activity. Cytokine profiling showed that crude venom and HMM suppressed osteoclastogenic cytokines such as IL-1β and IL-6, supporting their potential use in inflammatory bone diseases. Pathway enrichment analyses confirmed these differential effects on immune response and bone resorption mechanisms. Together, these results demonstrate that B. moojeni venom and its fractions differentially impact OC biology, with crude venom exerting broad effects and HMM and LMM fractions offering more specific modulation. Future studies will isolate bioactive components and assess therapeutic efficacy in animal models of osteoporosis and rheumatoid arthritis. Full article