Biomedicines最新文献

Background/Objectives: It is unclear whether assessment of phasic atrial function could improve risk stratification for new-onset atrial fibrillation (AF) in patients with newly diagnosed cardiac sarcoidosis (CS). We aimed to investigate the prognostic value of left atrial (LA) phasic dysfunction by cardiac magnetic resonance (CMR) for new-onset AF in newly diagnosed patients with CS. Methods: 78 patients with CS, without a prior history of AF, were studied using CMR feature tracking. Over a 4-year follow-up period, AF was documented by Holter monitoring and interrogation of intracardiac devices. Clinically silent CS was defined as CS in patients with biopsy-proven extracardiac sarcoidosis, with no cardiac symptoms, but with abnormalities on CMR or positron emission tomography consistent with CS. Results: Patients with clinically manifest CS were younger (mean age 56 vs. 51 years, p = 0.018), had poorer ventricular function, higher extent of atrial late gadolinium enhancement and significantly lower LA reservoir, conduit and booster function compared to patients with clinically silent CS. Over a 4-year follow-up period, 39% of patients with clinically manifest CS and 29.7% of patients with clinically silent CS developed AF. LA reservoir strain was a strong predictor of AF in the entire cohort. In subgroup analysis, age (HR 1.30, 95% CI 1.02-1.65, p = 0.030) and LA reservoir strain (HR 0.63, 95% CI 0.44-0.90, p = 0.011) were independent predictors of AF in patients with clinically silent CS, whereas baseline NT-proBNP (HR 1.003, 95% CI 1.001-1.006, p = 0.017) predicted AF in patients with clinically manifest CS. Conclusions: Reduced LA reservoir strain on CMR predicts new-onset AF in patients with newly diagnosed CS. The predictive value of LA reservoir strain is strongest in clinically silent CS and decreases with disease progression in clinically manifest CS.

Inflammatory Bowel Diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are chronic, immune-mediated disorders marked by persistent and recurrent inflammation of the gastrointestinal tract. Over the past two decades, major advances in understanding the immunologic and molecular pathways that drive intestinal injury have transformed the therapeutic landscape. This progress has enabled the development of novel biologics and small-molecule agents that more precisely target dysregulated immune responses, thereby improving clinical outcomes and quality of life for many patients. Despite these therapeutic advances, IBD remains a highly heterogeneous condition. Patients differ widely in disease phenotype, progression, and response to specific treatments. Consequently, selecting the most effective therapy for an individual patient requires careful consideration of clinical features, molecular markers, and prior treatment history. The shift toward personalized, prediction-based treatment strategies aims to optimize the timing and choice of therapy, minimize unnecessary exposure to ineffective drugs, and ultimately alter the natural course of disease. In this review, we provide a comprehensive overview of current evidence guiding drug positioning in IBD, with particular emphasis on biologic therapies and small-molecule inhibitors. We also examine emerging biomarkers, clinical predictors of response, and real-world factors that influence therapeutic decision-making. Finally, we discuss the challenges and limitations that continue to hinder widespread implementation of personalized strategies, underscoring the need for further research to integrate precision medicine into routine IBD care.

Background/Objectives: Patients in need of specialized palliative care are clinically highly complex, with pain being the most prevalent problem. Furthermore, in these patients, a self-report for characterization of pain could be difficult to obtain. This cross-sectional, exploratory study investigates the use of clinical parameters and peripheral blood biomarkers for potentially identifying and characterizing pain (assessed using Pain Assessment in Advanced Dementia (PAINAD) and Numeric Scale (NS)) in patients under palliative care, including a population with dementia where pain is often underdiagnosed. Methods: Fifty-three patients with non-oncological diseases were analyzed in a cross-sectional study using medical and nursing records. Among previous biomarkers related to monocytes and platelets assessed by flow cytometry, we selected the most significative ones for pain characterization in a logistic regression analysis (multivariate analysis), alongside patient-specific characteristics such as renal function, nutritional status, and age. Results: Our exploratory findings suggest strong relationships between chronic pain and advanced age, reduced glomerular filtration rate (GFR), and malnutrition within this cohort. Furthermore, the percentage of lymphocytes, total and classical monocytes, the relative expression in monocytes of CD206, CD163, the CD163/CD206 ratio, and the relative expression in platelets of CD59 emerged as potential predictors of pain. Statistical analyses highlighted the challenges of multicollinearity among variables such as age, GFR, and nutritional status. A classification model further suggested that all patients over 65 years in our specific sample reported pain. Conclusions: This pilot study provides preliminary support for prior evidence linking chronic pain to aging, nutritional deficits, and renal impairment, and highlights potential novel peripheral blood biomarkers for pain assessment. This work emphasizes the promise of clinical and molecular biomarkers to improve pain detection and management, contributing to personalized and effective palliative care strategies.

Background/Objectives: We aimed to assess the risks and benefits of early, intermediate, and late vesicoamniotic shunting (VAS) for lower urinary tract obstruction (LUTO) treated at a single center. Methods: A retrospective analysis of 104 fetuses with LUTO that underwent VAS was carried out. The investigation covered the time between the first VAS and postnatal hospital discharge. The cases were analyzed in three groups: Group I fetuses underwent their first intervention ≤ 16 + 0 weeks; Group II fetuses underwent intervention between 16 + 1 and 24 + 0 weeks; and Group III fetuses underwent intervention > 24 + 0 weeks of gestation. Maternal morbidity, pre- and postnatal complications, fetal and neonatal mortality, and urological and renal outcomes were assessed. Results: All mothers tolerated the procedures well. Mean gestational age at delivery was 35.4 weeks of gestation. In total, 78 of 104 children were born alive (75%). Postnatal survival was 72 of 78 (92.3%). Overall survival was 72 of 104 (69.2%). Overall, 61.2% of children survived from Group I; 69% of children survived from Group II; and 100% of Group III children survived from the first VAS to postnatal hospital discharge. A total of 41 of 72 survivors (56.9%) were discharged with normal renal function. For 80%, normal renal function was highest after early VAS ≤ 16 + 0 weeks of gestation (Group I), whereas 31% of Group II and 61% of Group III survived with normal renal function. Postnatal pulmonary hypoplasia occurred in 13.3% of the cases of Group I, 40% of Group II, and 23.1% of Group III. Conclusions: The findings of this retrospective study confirm that VAS ≤ 16 + 0 weeks of gestation is the best chance for preserved renal function after birth. However, when LUTO is treated later in gestation, fetuses can also benefit from VAS. Pre-interventional sonography may aid in selecting those with the highest chances for a better renal outcome.

Background/Objectives: Obsessive-compulsive disorder (OCD) is a chronic psychiatric illness with intrusive obsessions and compulsive behaviors severely impacting daily functioning and quality of life. The purpose of this narrative review is to present an updated summary of available evidence on third-generation antipsychotics (TGAs) as augmentation strategies for SRI-refractory OCD. Methods: The literature was reviewed using the PubMed database to recognize studies on the use of TGAs in treatment-resistant OCD. Only articles in the English language and on human participants were included. Results: We included nine reports in our review. More numerous (five reports) and higher evidence-level reports were retrieved for aripiprazole, which consistently shows high response rates compared to placebo and other antipsychotics. Two cohort studies were included on brexpiprazole, with no active or placebo comparator. These showed varying but high response rates. One cohort study reported a response rate of 61.5% to cariprazine. Only one paper reported on the efficacy of lumateperone in OCD. This was a single-case report on an adolescent patient with refractory OCD responding to lumateperone monotherapy. Conclusions: The current state of evidence supports the clinical utility of TGAs, particularly aripiprazole, in augmenting SRI treatment in patients with refractory OCD. Evidence regarding cariprazine and lumateperone is scarce, but still contributes to the discussion on the use of TGAs in OCD.

Objective: Diabetic kidney disease (DKD) is characterized by podocyte injury and impaired autophagy. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) exhibit therapeutic potential for DKD, yet their mechanisms remain unclear. This study investigated whether BMSC-Exos restore podocyte autophagy via the miR-143-3p/Bcl-2/Beclin1 axis to delay DKD progression. Methods: A high-glucose (HG)-induced podocyte injury model was established using mouse podocytes (MPC5). Autophagy-related proteins (Beclin1, Bcl-2, LC3) and the injury marker desmin were analyzed by Western blot and immunofluorescence (IF). High-throughput sequencing identified BMSC-Exos-enriched miRNAs, with the miR-143-3p/Bcl-2 targeting relationship validated by dual-luciferase reporter assays. BMSCs transfected with miR-143-3p mimic or inhibitor were used to assess exosomes effects on autophagy and podocin expression. In vivo, DKD mice received tail vein injections of modified BMSC-Exos, followed by evaluation of physiological parameters, biochemical indices, and renal histopathology. Results: BMSC-Exos were successfully isolated and characterized. Fluorescence microscopy confirmed exosomes internalization by HG-treated MPC5 cells. BMSC-Exos upregulated Beclin1 and LC3-II while downregulating Bcl-2 and desmin, indicating enhanced autophagy. High-throughput sequencing revealed miR-143-3p enrichment in BMSC-Exos, and Bcl-2 was confirmed as a direct target of miR-143-3p. Exosomes from miR-143-3p mimic-transfected BMSCs further promoted autophagy and podocin expression. In DKD mice, BMSC-Exos reduced blood glucose, urinary albumin-to-creatinine ratio (UACR), and ameliorated renal damage, whereas miR-143-3p inhibition attenuated these effects. Conclusions: BMSC-Exos deliver miR-143-3p to target Bcl-2, thereby activating Beclin1-mediated autophagy and ameliorating DKD. This study elucidates a novel autophagy regulatory mechanism supporting BMSC-Exos as a cell-free therapy for DKD.

Nickel allergy remains the most prevalent cause of allergic contact dermatitis worldwide, imposing a substantial socio-epidemiological and economic burden. Beyond its classical cutaneous presentation, systemic nickel allergy syndrome highlights the systemic dimension of Nickel hypersensitivity, wherein dietary nickel intake may provoke both gastrointestinal and cutaneous symptoms through mechanisms involving gut barrier impairment and mucosal immune priming. Recent evidence highlights the contribution of angiogenesis and lymph-angiogenesis to Nickel-induced allergic contact dermatitis, through crosstalk among keratinocytes, mast cells, endothelial cells, and pro-angiogenic mediators such as vascular endothelial growth factor. Against this background, we propose to revisit palmitoylethanolamide, an endogenous ALIAmide with well-documented anti-inflammatory, anti-angiogenic, and anti-allergic properties. Already studied in pain and inflammatory disorders and employed in veterinary dermatology, palmitoylethanolamide down-modulates mast cell degranulation, suppresses VEGF expression via PPAR-α/Akt/mTOR signaling, and enhances intestinal barrier integrity, acting as a promising "gatekeeper" molecule that reduces gut hyperpermeability characterizing systemic nickel allergy as well as other gut disorders with systemic consequences. This paper is presented as a viewpoint intended to highlight the untapped therapeutic potential of palmitoylethanolamide, suitable for both oral and topical administration, as a candidate to address the multifactorial pathophysiology of Nickel allergic contact dermatitis and systemic nickel allergy. Our purpose is not to provide definitive answers, but to stimulate scientific debate on its rational use within emerging gut-skin therapeutic strategies. We thus encourage future experimental and clinical studies to explore its potential integration within emerging gut-skin therapeutic paradigms.

Over the last decades, a significant improvement in cancer patient outcomes has occurred due to advances in cancer cell biology, systemic immunity, tumor-immune microenvironment (TIME) and precision cancer therapy. Despite this explosion of knowledge, its usefulness in clinical practice has been limited by the ability to translate multidimensional data into clinical care. Progress in artificial intelligence (AI) opens up a new frontier, with the promise of achieving synergistic and comprehensive integration. The classification of cancer biology and immunobiology into hallmarks of cancer by Hanahan and Weinberg provides a framework for organizing this information. This systematic classification has enabled the understanding of the interplay and cross-talk between its parts. Targeted cancer therapies and immunotherapies have achieved considerable success, yet their combinatorial potential is still being uncovered. Molecular diagnostics has worked hand-in-hand with precision oncology in deploying new therapies in a cancer-informed and patient-specific way. Harnessing the full power of the advances in these three fields with the aid of AI promises a transformation of molecular diagnostics. This review conceptualizes molecular diagnostics in the context of cancer hallmarks using nonsmall cell lung cancer (NSCLC) as a template, highlighting the potential of a new diagnostic science through the integrative power of AI.

Background/Objectives: Rapid and accurate diagnosis of acute appendicitis is crucial for patient health and management, and the diagnostic process can be prolonged due to varying clinical symptoms and limitations of diagnostic tools. This study aims to shorten the timeframe for these vital processes and increase accuracy by developing a quantum-inspired hybrid model to identify appendicitis types. Methods: The developed model initially selects the two most performing architectures using four convolutional neural networks (CNNs) and two Transformers (ViTs). Feature extraction is then performed from these architectures. Phase-based trigonometric embedding, low-order interactions, and norm-preserving principles are used to generate a Quantum Feature Map (QFM) from these extracted features. The generated feature map is then passed to the Multiple Head Attention (MHA) layer after undergoing Hadamard fusion. At the end of this stage, classification is performed using a multilayer perceptron (MLP) with a ReLU activation function, which allows for the identification of acute appendicitis types. The developed quantum-inspired hybrid model is also compared with six different CNN and ViT architectures recognized in the literature. Results: The proposed quantum-inspired hybrid model outperformed the other models used in the study for acute appendicitis detection. The accuracy achieved in the proposed model was 97.96%. Conclusions: While the performance metrics obtained from the quantum-inspired model will form the basis of deep learning architectures for quantum technologies in the future, it is thought that if 6G technology is used in medical remote interventions, it will form the basis for real-time medical interventions by taking advantage of quantum speed.

Background/Objectives: Obstructive sleep apnea (OSA) affects approximately 1 billion adults worldwide with extensive comorbidities, including cardiovascular disease, metabolic disorders, and cognitive decline, yet pharmacological therapies remain limited. Conventional bottom-up omics approaches identify numerous genes overlapping with other diseases, hindering therapeutic translation. This study introduces a top-down, comorbidity-driven approach to identify actionable molecular targets and develop rational dual kinase inhibitors for OSA management. Methods: We implemented a five-tier modeling workflow: (1) comorbidity network analysis, (2) disease module identification through NetworkAnalyst, (3) mechanistic pathway reconstruction of the CK1δ-(HIF1A)-PINK1 signaling cascade, (4) molecular docking analysis of Nigella sativa alkaloids and reference inhibitors (IC261, PF-670462) against CK1δ (PDB: 3UYS) and PINK1 (PDB: 5OAT) using AutoDock Vina, and (5) rational design and computational validation of novel dual inhibitors (ICL, PFL) integrating pharmacophoric features from natural alkaloids and established kinase inhibitors. Results: Extensive network analysis revealed a discrete OSA disease module centered on two interconnected protein kinases-CK1δ and PINK1-that mechanistically bridge circadian disruption and neurodegeneration. Among natural alkaloids, Nigellidine showed strongest CK1δ binding (-8.0 kcal/mol) and Nigellicine strongest PINK1 binding (-8.6 kcal/mol). Rationally designed dual inhibitors demonstrated superior binding: ICL (-7.2 kcal/mol PINK1, -8.9 kcal/mol CK1δ) and PFL (-10.8 kcal/mol CK1δ, -11.2 kcal/mol PINK1), representing -2.6-2.8 kcal/mol improvements over reference compounds. Conclusions: This study establishes a comorbidity-driven translational framework identifying the CK1δ-PINK1 axis as a therapeutic target in OSA. The rationally designed dual inhibitors represent third-generation precision therapeutics addressing OSA's multi-dimensional pathophysiology, while the five-tier workflow provides a generalizable template for drug discovery in complex multimorbid diseases.