Biomedicines最新文献

Background/Objectives: The underlying molecular mechanisms of deep vein thrombosis (DVT), which continues to be a major global public health concern, remain unclear. A key component of anticoagulant therapy, heparin (HP) interacts with heparin-binding growth factors including pleiotrophin (PTN) and midkine (MK), both of which have basic amino acid-rich domains that have a strong affinity for HP. The purpose of this study was to determine if changes in the levels of circulating HP, MK, and PTN are linked to the onset of acute DVT. Methods: Thirty patients diagnosed with acute DVT by venous Doppler ultrasonography (VDU) and 28 healthy controls with normal VDU findings were enrolled. Serum HP, MK, and PTN concentrations were measured using ELISA. In DVT patients, blood samples were obtained before and after routine subcutaneous low-molecular-weight heparin treatment; controls provided a single blood sample. ROC curve analysis was used to assess diagnostic performance. Results: Prior to treatment, patients with acute DVT exhibited significantly lower serum HP levels (p < 0.05) and significantly higher MK and PTN levels compared with healthy controls (both p < 0.05). Following heparin administration, serum HP levels increased significantly (p < 0.05), while MK and PTN levels showed a decreasing trend that did not reach statistical significance (p > 0.05). ROC curve analysis demonstrated limited diagnostic performance for HP (sensitivity 10.3%, specificity 68.8%), PTN (62.1%, 54.2%), and MK (82.8%, 35.4%). Conclusions: Decreased circulating HP and increased MK and PTN levels are characteristics of acute DVT that may indicate endogenous HP sequestration through binding to these growth factors. This imbalance could lead to less free HP being available, which would encourage the formation of thrombus. Therapeutic approaches that target MK- and PTN-mediated HP interactions may constitute a unique approach for the therapy of acute DVT, as evidenced by the partial normalization seen after exogenous heparin delivery.

Background/Objectives: Diabetic osteoporosis (DOP) is a metabolic bone disorder marked by reduced bone mass, impaired microarchitecture and elevated fracture risk arising from type 1 and type 2 diabetes. Understanding its pathophysiology is essential for developing effective interventions. Method: A broad literature search of Scopus and PubMed (2015-2025) using diabetic osteoporosis-related keywords identified relevant English in vivo studies, which were screened, extracted, and narratively summarised for this review. Results: In vivo models, including high-fat-diet (HFD), streptozotocin (STZ) and combined HFD + STZ protocols, are widely used to investigate DOP mechanisms. HFD models mimic obesity-induced insulin resistance, chronic hyperglycaemia and low-grade inflammation, leading to suppressed osteoblast activity, enhanced osteoclastogenesis and accumulation of advanced glycation end products (AGEs). Ultimately, they compromise bone microarchitecture and mechanical strength. STZ models replicate type 1 diabetes by inducing β-cell destruction, insulin deficiency, oxidative stress, osteoblast apoptosis and inflammatory pathways promoting bone resorption. The combined HFD + STZ model integrates insulin resistance and partial β-cell dysfunction, closely reflecting type 2 diabetes pathology, including trabecular bone loss, collagen glycation and disrupted osteoblast-osteoclast signalling. Mechanistically, DOP involves impaired insulin/IGF-I signalling, AGE-RAGE interactions, oxidative stress and inflammation, resulting in diminished bone formation and quality. These models provide robust platforms for exploring molecular mechanisms and evaluating potential therapies, including Wnt pathway modulators, antioxidants and ferroptosis inhibitors. Conclusions: Collectively, preclinical in vivo models are indispensable for understanding DOP pathophysiology and developing strategies to mitigate diabetic bone fragility.

Background/Objectives: Atezolizumab plus bevacizumab (Atz+Bev) is widely used for advanced hepatocellular carcinoma (HCC), yet predictors of post-progression survival (PPS), a clinically meaningful endpoint reflecting the feasibility of treatment sequencing, remain unclear. We aimed to identify determinants of PPS and factors associated with successful transition to subsequent therapy after progressive disease (PD) on Atz+Bev. Methods: We retrospectively analyzed 132 patients with HCC who initiated Atz+Bev with Child-Pugh A and Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1. PPS was defined as survival from radiological PD to death; tumor response was assessed by RECIST v1.1. Results: Among 132 patients treated with Atz+Bev, median progression-free and overall survival were 9.2 and 21.2 months. PD occurred in 97 patients, with a median PPS of 9.2 months. At PD, 76 patients (78.4%) maintained both Child-Pugh A and ECOG PS 0/1; 93.4% of these patients transitioned to subsequent therapy, compared with 38.0% of patients who did not maintain Child-Pugh A and ECOG PS 0/1. The median PPS values were 14.7 and 2.0 months, respectively (p < 0.0001). In this PD cohort, disease control achieved with subsequent therapy after radiological PD was associated with longer PPS (16.1 vs. 5.0 mosnths; p = 0.0002). ECOG PS 0, Child-Pugh A, absence of portal vein invasion, and AFP < 400 ng/mL at PD independently predicted prolonged PPS. A baseline Child-Pugh score of 5 independently predicted preservation of Child-Pugh A and ECOG PS 0/1 at PD. Conclusions: Initiating Atz+Bev under optimal liver function (Child-Pugh 5) and preserving hepatic reserve and performance status through progression are critical for enabling subsequent therapy and achieving longer PPS.

Triple-negative breast cancer (TNBC), which is characterized by a lack of the estrogen receptor, the progesterone receptor, and HER2 expression, is the most aggressive breast cancer subtype and has a poor prognosis and high recurrence rates because of frequent chemotherapy resistance. As a crucial epigenetic regulator, DNA methylation modulates gene expression through aberrant methylation patterns, contributing to tumor progression and therapeutic resistance. Early diagnosis and treatment of TNBC are vital for its prognosis. The development of DNA methylation testing technology and the application of liquid biopsy provide technological support for early diagnosis and treatment. Additionally, preclinical and early-phase clinical studies suggest that epigenetic therapies targeting DNA methylation may hold promise for TNBC treatment, pending larger clinical trials. Furthermore, research on DNA methylation-based prognostic models enables personalized precision treatment for patients, helping to reduce unnecessary therapies and improve overall survival. The emerging role of DNA methylation patterns in predicting the therapeutic response and overcoming drug resistance is highlighted. In this narrative review, we integrate current research findings and clinical perspectives. We propose that DNA methylation presents promising research prospects for the diagnosis, treatment and prognosis prediction of TNBC. Future efforts should focus on translating methylation-driven insights into clinically actionable strategies, ultimately advancing precision oncology for this challenging disease.

Background/Objectives: Dopamine agonists (DAs) are the first-line therapy for prolactinomas; however, a subset of patients exhibits resistance or incomplete response. Methods: This retrospective study included 85 of 125 eligible consecutive patients with prolactinoma who were treated with DA, followed for a median of 52.0 (31.5-86.8) months. Clinical, biochemical, and radiological parameters were analyzed at baseline and at 6 and 12 months. Resistance was defined as failure to normalize serum prolactin concentration (PRL) or achieve ≥ 30% reduction in tumor maximal diameter after standard DA therapy. Logistic regression analyses were performed to identify predictors of DA resistance and treatment response. Results: The cohort comprised 54 males (63.5%) and 31 females (36.1%), with a mean age of 41.5 ± 17.2 years. In total, 22.4% had giant prolactinomas. After 6 months of treatment, 24.7% achieved PRL normalization, and 29.4% demonstrated ≥ 50% reduction in tumor volume. At 12 months, PRL normalized in 40% of patients, and a ≥50% volume reduction was observed in 41.2%. DA-resistant patients, compared to DA-non-resistant, were predominantly men (80.0% vs. 56.7%, p = 0.042), with a higher proportion of giant adenomas (44.0% vs. 13.3%, p = 0.002) and significantly higher baseline PRL (2000.000 ng/mL vs. 478.985 ng/mL, p = 0.012). Early reduction in maximal tumor diameter at 6 months predicted a favorable therapeutic response at 12 months (aOR = 1.156; 95% CI = 1.001-1.335, p = 0.049). Conclusions: Male sex, higher baseline PRL, and larger tumor size can be predictors of DA resistance. On the other hand, early radiological tumor shrinkage may predict favorable treatment outcomes. However, new markers of DA resistance, particularly molecular ones, should be identified.

Background/Objectives: Optimizing routine neurointerventional workflow and minimizing exposure to ionizing radiation during coil-only endovascular treatment of intracranial aneurysms depend on operator experience, reduced frame rates during both fluoroscopy and digital subtraction angiography (DSA), and the use of advanced angiographic systems. The low-dose protocol implemented in this study used the lowest available fluoroscopy frame rate (3.125 frames per second [fps]) and a nominal acquisition rate of 2 fps (actual = 2.45 fps) for DSA, three-dimensional (3D) rotational angiography, two-dimensional (2D)/3D mapping, and roadmapping. Methods: This retrospective analysis encompassed 245 coil-only procedures performed at a single tertiary center from 2018 to 2024. Data collected for each procedure included dose-area product (DAP), reference air kerma (K_a,r), fluoroscopy time (FT), and the total number of DSA frames. Local diagnostic reference levels (DRLs; 75th percentile [P75]) and typical values (50th percentile [P50]) were determined and descriptively compared with values reported in the literature. Results: The P75 values, representing DRLs, were 22.4 Gy·cm² for DAP (literature range, 123-272.8 Gy·cm²), 268 mGy for K_a,r (1171-4240 mGy), 18 min 56 s for FT, and 285 DSA frames. The P50 values were 13.8 Gy·cm² for DAP (78.7-179.0 Gy·cm²), 196 mGy for K_a,r (801-2804 mGy), 13 min 25 s for FT, and 208 DSA frames. Conclusions: In this single-center cohort, dose metrics for coil-only intracranial aneurysm treatment were within the lower range of published values. Cross-study comparisons are descriptive and require cautious interpretation. The proposed local DRLs may support quality assurance, dose optimization, and patient safety in comparable clinical settings. Further multi-center and multi-operator studies are warranted to evaluate transferability and applicability beyond coil-only procedures.

Background: Visual dysfunction resulting from damage to the optic nerve and retinal neurons represents a significant concern in the postoperative management of childhood-onset craniopharyngioma (CP) survivors. The study aims to evaluate the influence of clinical parameters assessed in patients before and after neurosurgery of CP on peripapillary retinal nerve fiber layer (RNFL) thickness results, using optical coherence tomography (OCT) as early markers of compressive neuropathy. Methods: This study retrospectively examined 73 eyes from 38 individuals diagnosed with CP and 64 eyes from 32 healthy controls matched for age and sex. All patients in the study group underwent a complete endocrine examination before and after surgery. Moreover, all participants in both groups underwent a thorough ophthalmological examination and OCT imaging. The average RNFL thickness was analyzed, along with the RNFL in the superior and inferior sectors and in eight peripapillary sectors around the optic nerve. Clinical variables were analyzed to assess how they relate to alterations in RNFL thickness within specific sectors. Results: After surgery, the peripapillary RNFL thickness was much lower in the CP group than in the healthy control group. Preoperative factors significantly affecting RNFL reduction are as follows: age below 5 years at the time of diagnosis, birth in the country, optic disc oedema, delayed puberty, arginine vasopressin deficiency (AVD), growth hormone deficiency (GHD), hyperprolactinemia, and the degree of preoperative hypothalamic involvement. Moreover, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), as well as the end of AVD, memory disorder and hyperfagia after surgery, correlated with damage to RNFL. Conclusions: CP causes significant thinning of the RNFL, which demonstrates the tumor's impact on the visual pathway. Monitoring optic nerve damage and assessing outcomes after surgery can be performed effectively using OCT. Additionally, the relationship between RNFL thickness in specific areas and clinical indicators can provide vital information for diagnosing and monitoring. This highlights their usefulness in forecasting visual results. As a result, ongoing RNFL assessments should be part of the long-term management of CP patients to improve visual outlook and identify ongoing or remaining damage.

Background/Objectives: Neovascularization, defined as the sprouting of new blood vessels from pre-existing vasculature, is a critical pathological feature in ocular diseases such as pathological myopia and represents a leading cause of corneal vision loss. Vascular endothelial growth factor A (VEGFA) plays a pivotal role in endothelial cell proliferation, migration, survival by anti-apoptotic signaling, and vascular permeability. Dysregulation of VEGFA is closely linked to pathological neovascularization. Exosomes, nanosized phospholipid bilayer vesicles ranging from 30 to 150 nm, have emerged as promising gene delivery vehicles due to their intrinsic low immunogenicity, superior cellular uptake, and enhanced in vivo stability. This study aimed to investigate whether highly purified mesenchymal stem cell (MSC)-derived exosomes loaded with VEGFA siRNA labeled with FAM can effectively suppress pathological corneal neovascularization (CNV) via targeeted cellular transduction and VEGFA inhibition. Furthermore, we examined whether the therapeutic effect involves the modulation of the PI3K-Akt-Caspase-3 signaling axis. Methods: Exosomes purified by chromatography were characterized by electronmicroscopy, standard marker immunoblotting, and nanoparticle tracking analysis. In vitro, we assessed exosome uptake and cytoplasmic release, suppression of VEGFA mRNA/protein, cell viability, and apoptosis. In a mouse CNV model, we evaluated tissue reach and stromal retention after repeated intrastromal injections; anterior segment angiogenic indices; CD31/VEGFA immunofluorescence/immunoblotting; phosphorylated PI3K and Akt; cleaved caspase-3; histology (H&E); and systemic safety (liver, kidney, and spleen). Results: Exosomes were of high quality and showed peak efficacy at 48 h, with decreased VEGFA mRNA/protein, reduced viability, and increased apoptosis in vitro. In vivo, efficient delivery and stromal retention were observed, with accelerated inhibition of neovascularization after Day 14 and maximal effect on Days 17-19. Treatment reduced CD31 and VEGFA, decreased p-PI3K and p-Akt, and increased cleaved caspase-3. Histologically, concurrent reductions in neovascularization, inflammatory cell infiltration, and inflammatory epithelial thickening were observed, alongside a favorable systemic safety profile. Conclusions:VEGFA siRNA-loaded exosomes effectively reduce pathological CNV via a causal sequence of intracellular uptake, cytoplasmic release, targeted inhibition, and phenotypic suppression. Supported by consistent PI3K-Akt inhibition and caspase-3-mediated apoptosis induction, these exosomes represent a promising local gene therapy that can complement existing antibody-based treatments.

Background: Microsaccades are small fixational eye movements tightly linked to attention and oculomotor control. Although diabetes mellitus is associated with retinal and neural alterations that may impair visuomotor function, the influence of physical activity on microsaccade behaviour in individuals with type 2 diabetes mellitus (T2DM) remains unknown. This study investigated whether habitual physical activity modulates microsaccade characteristics during fixation under different optic flow stimuli. Given that optic flow engages motion processing and gaze stabilisation pathways that may be affected by diabetes-related microvascular/neural changes, it can reveal subtle visuomotor alterations during fixation. Methods: Twenty-eight adults with T2DM and no diagnosed retinopathy performed a fixation task while viewing optic flow stimuli made of moving dots. Eye movements were recorded using an EyeLink system. Physical activity behaviour was assessed at baseline and at a 6-month follow-up after a low-threshold aerobic circuit training programme. Classification as physically active (≥600 MET-min/week) or inactive (<600 MET-min/week) was based on the 6-month assessment. Microsaccade characteristics were analysed by repeated-measures ANOVA. Results: Microsaccade rate was modulated by optic flow (p = 0.044, η²p = 0.106) and showed a significant stimulus × group × sex interaction (p = 0.005, η²p = 0.163), indicating sex-dependent differences in how optic flow modulated microsaccade rate across physically active and inactive participants. A time × stimulus interaction effect was found in peak velocity (p = 0.03, η²p = 0.114) and amplitude (p = 0.02, η²p = 0.127), consistent with modest context-dependent changes over time. Conclusions: These findings suggest that physical activity modulates microsaccade generation and supports the potential of microsaccade metrics as sensitive indicators of oculomotor function in diabetes.

Background/Objectives: Nonunion bone healing results from a critical size defect that fails to bridge a bone injury to produce bony union. Novel approaches are critical for refining therapy in clinically challenging bone injuries, but the complex and coordinated nature of fracture callus tissue development requires study outside of the simple closed murine fracture model. Methods: We have utilized a three-dimensional printing approach to develop a scaffold construct with layers designed to sequentially release small molecule therapy within the tissues of a murine endochondral segmental defect to augment different mechanisms of fracture repair during critical stages of nonunion bone healing. Initially, a sonic hedgehog (SHH) agonist is released from a fibrin layer to promote chondrogenesis. A prolyl-hydroxylase domain (PHD)2 inhibitor is subsequently released from a β-tricalcium phosphate (β-TCP) layer to promote hypoxia-inducible factor (HIF)-1α regulation of angiogenesis. This sequential approach to therapy delivery is assisted by the inclusion of bone marrow stromal cells (BMSCs) to increase the cell substrate available for the small molecule therapy. Results: Immunohistochemistry of fracture callus tissue revealed increased expression of PTCH1 and HIF1α, targets of hedgehog and hypoxia signaling pathways, respectively, in the SAG21k/IOX2-treated mice compared to vehicle control. MicroCT and histology analyses showed increased bone in the fracture callus of mice that received therapy compared to control vehicle scaffolds. Conclusions: While our findings establish feasibility for the use of BMSCs and small molecules in the fibrin gel/β-TCP scaffolds to promote new bone formation for segmental defect healing, further optimization of these approaches is required to develop a fracture callus capable of completing bony union in a large defect.