International Journal of Medical Sciences最新文献

This first-in-human, open-label, dose-escalation study (NCT04097652) evaluates UMC119-06, a mesenchymal stem cell product derived from human umbilical cord, for the treatment of acute ischemic stroke (AIS). The study includes two dosing cohorts: 1×10^6 cells/kg and 5×10^6 cells/kg, with three participants enrolled in each cohort. The primary objective is to assess the safety, tolerability, and maximum feasible dose of UMC119-06 in AIS patients, while the secondary objective focuses on evaluating long-term safety and clinical efficacy following a single administration. The study conducted safety assessments across both dosing cohorts, demonstrating that UMC119-06 is well-tolerated, with no adverse events (AEs) classified as possibly, probably, or definitely related to the product. Despite the small sample size of six patients, trends toward positive outcomes were observed in the modified Rankin Scale, the National Institutes of Health Stroke Scale, the Barthel Index, and the infarct volume on brain magnetic resonance imaging. Additionally, changes in biomarkers such as IL-6, TNF-α, VEGF, and HGF suggest a potential impact of UMC119-06 on inflammation, angiogenesis, and tissue repair processes. This Phase I study provides preliminary evidence regarding the safety and potential efficacy of UMC119-06 in AIS patients. Larger-scale studies with control groups are warranted to validate these findings and further explore the therapeutic potential of UMC119-06 for AIS.

Purpose: Locoregional therapies, such as transarterial embolization (TAE) and transarterial chemoembolization (TACE), are central to the treatment of unresectable hepatocellular carcinoma (HCC), particularly at the intermediate stage. However, there have been few large-scale real-world data comparisons of their effectiveness with that of systemic therapies. This study aimed to assess the relationships between different treatment modalities and all-cause mortality in a nationwide HCC cohort. Patients and methods: We used the Taiwan National Health Insurance Research Database to recruit and identify 225,631 patients diagnosed with HCC between 2008 and 2021. The analyzed treatment modalities included hepatic resection, chemotherapy, targeted therapy, immunotherapy, TAE, and TACE. Cox proportional hazards models were applied to analyze the adjusted hazard ratios (HRs) for mortality. Results: Both TAE (HR: 0.17) and TACE (HR: 0.17) were independently associated with significantly reduced mortality (p < 0.0001). In contrast, targeted therapy (HR: 6.17) and immunotherapy (HR: 5.84) were associated with increased mortality, probably because the selected patients had more advanced diseases. Older age and male sex were also independently associated with worse outcomes. There was no significant association between chemotherapy and mortality. Conclusion: In this large, population-based, real-world cohort, TAE and TACE were significantly associated with better survival in patients with unresectable HCC, supporting their continued use as standard-of-care treatments in appropriately selected patients. The results highlight the need for multidisciplinary approaches to optimize advanced HCC outcomes.

Absorbable plates have become increasingly common in orthognathic surgery. Multiple plate types are available, including poly-L-lactic acid (PLLA) and PLLA/polyglycolic acid (PGA), the latter of which is expected to be absorbed more rapidly. However, the application of these materials in Le Fort I osteotomy is not clearly established. In this study, the strength and biomechanical properties of PLLA and PGA-co-PLLA absorbable plates were compared using an in vitro LeFort I osteotomy model. Basic physical strength was evaluated using tensile, bending, indentation, and handling test s. Biomechanical evaluations using the Le Fort I osteotomy model included anterior (with 0, 3, and 5 mm anterior movement) and occlusal (with a 2 mm downward vertical movement) indentation tests. In terms of basic physical properties, PLLA showed significantly higher strength than that of PGA-co-PLLA in tensile, bending, and indentation tests. In handling tests, PGA-co-PLLA demonstrated superior performance. In biomechanical evaluations, no significant differences were observed between PLLA and PGA-co-PLLA in anterior or occlusal indentation testing. Despite the greater basic physical strength of PLLA than PGA-co-PLLA, there were no significant differences between the two plate types in the biomechanical evaluation of Le Fort I osteotomy. These findings provide a basis for plate selection in clinical practice.

Outer Membrane Vesicles (OMVs) are spherical nanovesicles naturally secreted by Gram-negative bacteria, playing key roles in nutrient uptake, toxin delivery, and the transmission of drug resistance. Recent studies have increasingly focused on the clinical potential of OMVs. Due to their remarkable biocompatibility and immunogenic properties, OMVs offer wide-ranging applications in vaccine development and antigen/drug delivery, showing great promise in the treatment of tumors, autoimmune diseases, and infections. However, challenges remain in standardizing the production and modification of OMVs, limiting their broader application. This review consolidates research on OMV modification and application, aiming to provide valuable insights to advance the development of OMV-based therapeutic strategies and clinical implementations.

Background and Objective: Understanding living cell mechanisms and enabling intracellular monitoring requires advanced and often costly imaging technologies. Conventional fluorescence microscopy is widely used but suffers from resolution limitations, making it challenging to capture fine subcellular structures like mitochondria. While super-resolution microscopy may overcome these constraints, it introduces tradeoffs, including its limitation in intravital imaging fields and complexity in analyzing multiple cells simultaneously. To address these challenges, we developed a computational approach that enhances resolution and signal clarity without the need for specialized hardware, applicable for intravital imaging studies. Methods: We utilized Dendra2 transgenic mice to observe mitochondria in hepatocytes under normal physiological condition and in response to alcohol-induced liver stress. To achieve high-resolution in vivo imaging, we employed high-magnification objectives, ensuring precise visualization of subcellular structures. We implemented a trained self-supervised denoising model to suppress background noise and improve signal intensity, ensuring a clearer visualization of the mitochondria in hepatic cells. Additionally, enhanced super-resolution radial fluctuations (eSRRF) analysis was applied to image sequences to achieve subcellular resolution. Various numerical modifications and parameter optimizations were performed to refine the technique. The methodology was validated through computational analysis of different imaging conditions to assess its robustness and effectiveness. Results: Our approach successfully enhanced image resolution to the subcellular level, enabling the visualization of discrete mitochondrial structures and monitoring intracellular events in vivo. The denoising model effectively reduced background interference while preserving essential biological signals. Furthermore, the application of eSRRF significantly improved the clarity of cellular components, even when the original images exhibited poor lateral resolution, allowing for improved interpretation of intracellular structures. Conclusions: The proposed computational technique provides a cost-effective and accessible solution for achieving super-resolution live imaging without the need for high-end microscopy equipment. By reducing noise and enhancing resolution, this approach facilitates detailed intracellular analysis, suitable for live animal studies.

Background: Obsessive‒compulsive disorder is a chronic, disabling mental disorder. While repetitive transcranial magnetic stimulation has emerged as a promising neuromodulation intervention for psychiatric disorders, its efficacy in treatment-naïve obsessive‒compulsive disorder patients remains understudied. Objective: This study aimed to test the preliminary efficacy of low-frequency repetitive transcranial magnetic stimulation in treatment-naïve obsessive‒compulsive disorder patients. Methods: Treatment-naïve obsessive‒compulsive disorder patients (n = 41) were randomized to receive either standardized fluvoxamine therapy (150-200 mg/day) or daily low-frequency (1 Hz) repetitive transcranial magnetic stimulation targeting the supplementary motor area for 2 weeks. Clinical outcomes were longitudinally assessed via validated instruments, with a Yale-Brown Obsessive-Compulsive Scale score reduction rate ≥ 25% as the primary endpoint, supplemented by the Beck Depression Inventory and Beck Anxiety Inventory for comorbid symptom evaluation. Safety profiles were monitored throughout the trial. Results: The experimental results revealed that the difference in the response rate at the end of the intervention between the two groups was not statistically significant ( χ² = 0.183, p = 0.669), with 41.7% (5/12) in the repetitive transcranial magnetic stimulation group and 60% (6/10) in the fluvoxamine cohort. No severe adverse events were reported in either group. Conclusion: This trial revealed that low-frequency repetitive transcranial magnetic stimulation over the supplementary motor area might have preliminary positive outcomes for treatment-naïve patients with obsessive‒compulsive disorder. Our findings can be considered a good signal to promote further research in the form of randomized, double-blind, sham-controlled multicenter trials with extended follow-up periods.

Introduction: Lung cancer is a highly lethal disease characterized by a significant mortality rate. Cisplatin, a common drug used for lung cancer treatment, frequently develops resistance over time. Therefore, overcoming cisplatin resistance is crucial in the effective management of lung cancer. The ubiquitin-proteasome system (UPS) serves as a vital regulatory mechanism for maintaining protein homeostasis within cells. Recent studies have shown that manipulating deubiquitinating enzymes (DUBs) can overcome cisplatin resistance. This study aims to investigate the expression levels of DUBs under cisplatin treatment. Methods: Multiplex RT-PCR analysis was performed to identify potential biomarkers by comparing the differential expression patterns of DUBs, and their expression levels were analyzed by RT-qPCR. In addition, their protein expression levels were determined by western blot analysis. The bioinformatics tools including TCGA database and GEPIA website were used to validate potential as prognostic markers in lung cancer. Results: Multiplex RT-PCR analysis was performed to identify potential biomarkers by comparing the differential expression patterns of DUB genes. Multiplex RT-PCR showed distinct mRNA expression profiles of several DUB genes, including USP35, USP36, USP37, USP47, USP49, and OTUD6B in A549 lung cancer cells following exposure to cisplatin. In addition, RT-qPCR analysis revealed the downregulation of USP35, USP36, USP37, USP47, USP49, and OTUD6B, juxtaposed with the upregulation of USP47 under cisplatin treatment. Substantiating these findings, western blotting analysis confirmed the protein expression levels of USP35, USP36, USP37, USP47, USP49, and OTUD6B in cisplatin-treated lung cancer cells, mirroring the mRNA trends observed in non-treated counterparts except for OTUD6B. Bioinformatics analysis demonstrates that these DUBs except USP47 are upregulated and overall survival analysis indicates that lower expression of these DUBs, except USP37 and USP49, is correlated with improved overall survival in lung cancer patients. Conclusion: These findings strongly suggest that DUBs may play a crucial role in overcoming cisplatin resistance and improving the treatment efficacy for lung cancer.

Osteosarcoma is a highly malignant bone tumor affecting children and adolescents. Once metastasis occurs, the five-year survival rate drops to ~20%, emphasizing the need for new therapies. Fibroblast growth factor-23 (FGF-23), a bone-derived hormone, has been implicated in tumor progression, but its role in osteosarcoma remains unclear. Bioinformatics analysis using the R2 database revealed that elevated FGF-23 expression is associated with increased metastasis and reduced overall survival in osteosarcoma patients. Functional assays confirmed that FGF-23 enhances the migratory ability of osteosarcoma cells. Gene Expression Omnibus (GEO) analysis indicated that lysyl oxidase-like proteins-particularly LOXL1, LOXL2, and LOXL3-are overexpressed in osteosarcoma tissues compared to adjacent normal bone. In vitro experiments further showed that FGF-23 significantly upregulates LOXL2 expression in 143B and MG63 osteosarcoma cells, while LOXL2 knockdown via small interfering RNA (siRNA) markedly reduces cell migration. Moreover, pretreatment with ERK, p38, and JNK inhibitors or siRNAs targeting these pathways suppressed both FGF-23-induced LOXL2 expression and wound healing, indicating that FGF-23 promotes cell motility through ERK-, p38-, and JNK-dependent LOXL2 upregulation. FGF-23 stimulation also increased phosphorylation of ERK, p38, and JNK, and downregulated miR-4463. Inhibition of these pathways restored miR-4463 levels and suppressed LOXL2 expression. Taken together, these findings suggest that FGF-23 promotes osteosarcoma cell migration and may contribute to metastasis through coordinated regulation of the miR-4463/LOXL2 axis via ERK, p38, and JNK signaling. Targeting FGF-23 or its downstream signaling cascades may offer a promising therapeutic approach for metastatic osteosarcoma.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory condition that significantly impacts patients' quality of life, characterized by high recurrence rates and limited treatment efficacy. Standard therapies, including corticosteroid nasal sprays, saline irrigation, and endoscopic sinus surgery, often fail to provide sustained relief, highlighting the need for alternative therapeutic strategies. Glycyrrhiza glabra (G. glabra), a traditional herbal remedy with documented anti-inflammatory and immunomodulatory effects, has shown potential in modulating inflammation in various respiratory and inflammatory conditions. This study evaluates the efficacy and mechanism of a novel G. glabra-based nasal spray for CRSwNP treatment, focusing on its anti-inflammatory and epithelial-mesenchymal transition (EMT)-reversing effects. Methods: A total of 30 CRSwNP patients were enrolled and underwent a two-month single-regimen treatment with the G. glabra nasal spray without concomitant CRS medications, administered twice daily. Clinical outcomes were assessed via the Total Nasal Symptom Score (TNSS), Sinonasal Outcome Test-22 (SNOT-22), and nasal endoscopy. Histopathological evaluation was performed on nasal polyp biopsies from 15 patients pre- and post-treatment using immunohistochemistry (IHC) and immunofluorescence (IF) staining for mesenchymal and epithelial markers. Results: Results demonstrated significant improvement in TNSS and SNOT-22 scores, alongside visible reduction in polyp size. IHC and IF analyses revealed reduced expression of mesenchymal markers (α-SMA, vimentin, fibronectin) and increased expression of epithelial markers (E-cadherin, EpCAM), indicating EMT reversal. No adverse effects were reported. Conclusion: These findings suggest that G. glabra nasal spray may offer a safe and effective treatment option for CRSwNP, potentially acting through EMT modulation. Further studies with larger cohorts are recommended to refine patient stratification and explore the molecular basis of differential treatment responses.