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Neurofibromatosis type 1 (NF1) is associated with an increased risk of gastrointestinal stromal tumors (GISTs). Vasculopathy, such as aneurysms, is a recognized complication of NF1; however, it is little known among gastroenterologists. We report a 65-year-old woman with NF1 who developed hemorrhagic shock due to rupture of an intercostal artery aneurysm during sunitinib therapy. The patient underwent distal gastrectomy for duodenal GIST at age 49, but later developed hepatic and peritoneal recurrence. Because of failure of imatinib therapy and multiple transarterial embolization procedures, sunitinib therapy was initiated, stabilizing the disease for nine months. During treatment, she developed acute back pain with severe hypertension (220/106 mmHg) and was immediately admitted, where intravenous nicardipine was administered. Despite initial stabilization, the patient abruptly went into shock the following day. Dynamic computed tomography (CT) revealed a massive right hemothorax, posterior mediastinal hematoma, and contrast extravasation from a right intercostal artery aneurysm. Emergency angiography confirmed rupture of the ninth intercostal artery aneurysm measuring 18 mm. Embolization with microcoils achieved complete hemostasis. The patient recovered without sequelae and was discharged on day 34. Through a literature review, we identified 16 cases of intercostal artery aneurysm rupture in NF1. Of these, 11 were treated with embolization, although two experienced rebleeding. Sunitinib inhibits vascular endothelial growth factor signaling, which can induce hypertension and destabilize vascular integrity. Sunitinib therapy in NF1 patients requires strict blood pressure control. Additionally, pre-treatment vascular screening with CT angiography may be warranted.
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BACKGROUND/AIM: This study aimed to quantitatively analyze and compare aqueous humor concentrations of vascular endothelial growth factor-C (VEGF-C) in patients with primary open-angle glaucoma (POAG) versus non-glaucomatous controls while evaluating potential significant correlations. PATIENTS AND METHODS: We conducted an observational cross-sectional study. At surgery initiation, anterior chamber paracentesis was performed under sterile conditions, and 50-100 µl of aqueous humor samples were collected. VEGF-C quantification employed a multiplex magnetic bead immunoassay platform. RESULTS: The study involved the collection of aqueous humor samples from 76 participants: 39 samples were collected from the POAG group and 37 from the control group (age-related cataract). Quantitative analysis revealed mean VEGF-C concentrations of 26.41±26.016 pg/ml in POAG eyes compared to 16.70±8.60 pg/ml in controls (p=0.277), demonstrating no statistically significant difference. Receiver operating characteristic (ROC) curve analysis showed limited prognostic ability for POAG detection (AUC=0.60; p=0.278). CONCLUSION: This study represents the first large-scale evaluation of aqueous humor VEGF-C levels in patients with POAG. Our results provide evidence against VEGF-C up-regulation in POAG.
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Humor Acuoso , Glaucoma de Ángulo Abierto , Factor C de Crecimiento Endotelial Vascular , Humanos , Humor Acuoso/metabolismo , Glaucoma de Ángulo Abierto/metabolismo , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/patología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Factor C de Crecimiento Endotelial Vascular/metabolismo , Estudios Transversales , Curva ROC , BiomarcadoresRESUMEN
To evaluate the short-term outcomes and choroidal morphological changes after three monthly aflibercept injections for pachychoroid neovasculopathy (PNV). Twenty-nine treatment-naïve patients with PNV were enrolled in this prospective phase IV clinical trial. All patients received three monthly injections of aflibercept. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were measured at baseline and at week 12 (4 weeks after the third injection). Additionally, changes in the subfoveal choroidal thickness (SCT), largest choroidal vessel diameter, and area of the choriocapillaris-Sattler's and Haller's layers between baseline and week 12 were assessed. The BCVA improved from 67.5 ± 10.8 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline to 74.3 ± 10.7 letters at week 12. CRT decreased from 348.5 ± 77.4 µm at baseline to 254.3 ± 72.9 µm at week 12. Complete resolution of the retinal fluid was observed in 86.2% of cases at week 12. At baseline and 12 weeks, the SCT measured 388.3 ± 77.4 µm and 344.9 ± 91.9 µm, respectively, while the diameter of the largest choroidal vessel measured 280.3 ± 62.0 µm and 247.8 ± 57.6 µm, respectively. The areas of the choriocapillaris-Sattler's layer and Haller's layer at the corresponding time points were 0.56 ± 0.14 mm² and 0.57 ± 0.14 mm², and 1.56 ± 0.42 mm² and 1.40 ± 0.45 mm², respectively. Aflibercept loading injections for PNV resulted in both short-term visual and anatomical improvements. Notably, the reduction in the area of Haller's layer and choroidal vessel diameter after treatment suggests that aflibercept exerts an impact on this region of the choroid.
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Inhibidores de la Angiogénesis , Coroides , Neovascularización Coroidal , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Humanos , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Femenino , Masculino , Coroides/efectos de los fármacos , Coroides/patología , Coroides/irrigación sanguínea , Persona de Mediana Edad , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/patología , Anciano , Resultado del Tratamiento , Agudeza Visual/efectos de los fármacos , Tomografía de Coherencia Óptica , Estudios Prospectivos , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Inyecciones Intravítreas , Adulto , Retina/efectos de los fármacos , Retina/patologíaRESUMEN
INTRODUCTION: Non - clear cell renal cell carcinoma (nccRCC) encompasses a heterogeneous group of rare malignancies, representing approximately 20-25% of all renal cancers. Unlike clear cell RCC (ccRCC), these subtypes - papillary, chromophobe, collecting duct, translocation, molecularly defined variants and others - display distinct biological behaviors, genetic profiles, and therapeutic sensitivities, which preclude a uniform treatment approach. AREAS COVERED: This review provides an updated overview of systemic therapy for nccRCC, integrating evidence from prospective trials, retrospective series, and translational research. For most of these histologies, immune checkpoint inhibitor (ICI) - based combinations (e.g. pembrolizumab - lenvatinib, nivolumab - cabozantinib or nivolumab-ipilimumab) have demonstrated the best activity. In chromophobe RCC (chRCC), also mechanistic target of rapamycin (mTOR) inhibition appears particularly relevant, whereas in collecting duct carcinoma and renal medullary carcinoma platinum-based chemotherapy continue to have an important role, with cabozantinib showing encouraging results. Novel biomarker-driven approaches are emerging for selected molecular subsets. EXPERT OPINION: Although remarkable progress has been achieved, the optimal therapeutic strategy for nccRCC remains undefined. Future efforts should focus on histology- and biomarker-driven clinical trials, molecular stratification, to optimize efficacy across subtypes. International collaboration is crucial to overcome the challenges posed by the rarity and biological heterogeneity of these tumors.
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OBJECTIVE: Accumulating evidence demonstrates that exosomal microRNAs (miRNAs) play pivotal roles in multiple diseases, but little is known about their impacts on multi-organ failure in heat stroke. This study aimed to determine the functions of exosomal microRNAs in the development of heat stroke. METHODS: Human umbilical vein endothelial cell (HUVEC)-derived exosomes were collected after heat stress and assessed by microRNA sequencing. Differentially expressed exosome-encapsulated miRNAs were verified in exosome-enriched serum samples by qRT-PCR. Bioinformatics was used to identify the miRNA targets. HUVEC-derived exosomes after heat stress were administered to mice. Thrombotic factors were assessed in the mouse models and serum from heat stroke patients. RESULTS: In this study, miR-1-3p was significantly upregulated after heat stress. Heat-treated HUVEC exosomes impaired HUVEC proliferation, viability, and migration, while enhancing apoptosis; the inhibition of exosomal miR-1-3p expression partially alleviated the above effects. We found that exosomal miR-1-3p in 41 °C heat stress-treated HUVECs could remarkably increase the amounts of tissue factor (TF), von Willebrand factor (vWF), and PAI-1 (plasminogen activator inhibitor-1), and similar trends of changes were also seen in vivo experiments. Bioinformatics suggested VEGFα as a potential miR-1-3p target, which was verified by a dual-luciferase assay. miR-1-3p blockade induced VEGFα expression, while its upregulation suppressed VEGFα. Ectopic expression of VEGFα partially suppressed the impairing effects of heat-treated exosomes. In mice and humans, exosomal miR-1-3p seemed to regulate angiogenesis by targeting VEGFα. CONCLUSION: In a heat stroke model, exosomal miR-1-3p regulated HUVEC proliferation, viability, migration, and apoptosis by targeting VEGFα. Exosomal miR-1-3p may contribute to the diagnosis/treatment of heat stroke.
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Exosomas , Golpe de Calor , Células Endoteliales de la Vena Umbilical Humana , MicroARNs , Factor A de Crecimiento Endotelial Vascular , Humanos , Exosomas/metabolismo , Exosomas/genética , MicroARNs/genética , MicroARNs/metabolismo , Animales , Proliferación Celular , Apoptosis/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Golpe de Calor/genética , Golpe de Calor/metabolismo , Ratones , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Movimiento Celular , Células Cultivadas , Factor de von Willebrand/metabolismoRESUMEN
PURPOSE: This study aimed to investigate changes in choroidal thickness using widefield optical coherence tomography after anti-vascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (AMD). METHODS: We examined 69 patients with unilateral neovascular AMD. All patients underwent three monthly intravitreal injections of anti-VEGF agents. Widefield choroidal thickness within an 18-mm circular grid centered on the fovea, subdivided into nine areas, was evaluated at baseline and at 3 months. RESULTS: Forty-two and 27 patients were classified into the AMD and pachychoroid neovasculopathy (PNV) groups, respectively. At 3 months, the treated eyes in both groups showed significantly and extensively reduced choroidal thickness ( P < 0.01 for all areas). The untreated fellow eyes in the PNV group also showed decreased choroidal thickness at 3 months ( P < 0.05 for all areas). Complete retinal fluid resolution was significantly associated with a greater decrease ratio of choroidal thickness in the PNV group ( P < 0.05 for all areas). CONCLUSION: Anti-VEGF therapy for neovascular AMD led to extensively decreased choroidal thickness. In patients with PNV, a greater decrease in overall choroidal thickness appeared to be associated with more effective resolution of retinal fluid. Observation of widefield choroidal thickness may be important for the management of neovascular AMD.
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Inhibidores de la Angiogénesis , Coroides , Factor A de Crecimiento Endotelial Vascular , Degeneración Macular Húmeda , Humanos , Tomografía de Coherencia Óptica/métodos , Coroides/patología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Masculino , Femenino , Inyecciones Intravítreas , Anciano , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/diagnóstico , Ranibizumab/uso terapéutico , Agudeza Visual/fisiología , Anciano de 80 o más Años , Bevacizumab , Angiografía con Fluoresceína , Estudios Retrospectivos , Persona de Mediana Edad , Estudios de Seguimiento , Neovascularización Coroidal/tratamiento farmacológicoRESUMEN
Introduction: Metastatic papillary renal cell carcinoma (PRCC) is associated with a poor prognosis. Many patients with PRCC respond to first- and second-line systemic chemotherapy treatments; however, few respond to late-sequence treatment. We describe a case of a long-term response to fourth-line axitinib after the use of tyrosine kinase inhibitor therapy for metastatic papillary renal cell carcinoma. Case Presentation: A 37-year-old male presented with hematuria and left back pain. Following systemic examination, he was diagnosed with left renal cell carcinoma cT3aN0M1. He underwent left radical nephrectomy. The pathological diagnosis was PRCC type 2. After using sunitinib, cabozantinib, and nivolumab, axitinib was selected as fourth-line systemic therapy, resulting in a reduction in multiple liver metastases and 15 months of response. Conclusion: Late-sequence treatment with axitinib following prior use of tyrosine kinase inhibitor therapy resulted in a long-term response in a patient with metastatic papillary renal cell carcinoma.
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Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that western blot data appeared to have been assembled incorrectly in Fig. 4A on p. 6709. In this case, there was an apparent inversion of the pPI3K bands, and inclusion of one of these bands as a unique band (upside down) for the Control experiment in the pAkt row of data, purportedly showing the results of a different set of experiments. The authors were contacted by the Editorial Office to offer an explanation for this apparent anomaly in the presentation of the data in this paper; however, up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Molecular Medicine Reports 17: 6705-6710, 2018; DOI: 10.3892/mmr.2018.8678].
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Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , MicroARNs , Factor A de Crecimiento Endotelial Vascular , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Apoptosis/genética , Proliferación Celular/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Interferencia de ARNRESUMEN
This study developed a new type of sensor that integrates the bifunctional characteristics of nanozymes with surface-enhanced Raman scattering (SERS) technology for the efficient detection of vascular endothelial growth factor (VEGF) associated with diabetic retinopathy (DR). The sensor uses Au-coated Si nanopillar arrays (Au/SiNPA) as a substrate, whose high-density nanostructure can produce uniform SERS "hot spots", significantly improving signal stability. Additionally, Au@Pd nanorods (Au@Pd NRs) have both peroxidase (POD)-like activity and SERS enhancement effects, which can efficiently catalyze 3,3',5,5'-tetramethylbenzidine (TMB) to generate the characteristic Raman signal molecule oxTMB. This study employs a competitive recognition strategy, achieving VEGF detection through a simple sample addition reaction, thereby avoiding the complex labeling steps and invasive procedures associated with traditional methods. When VEGF in serum competitively displaces the probe, the oxTMB signal correspondingly weakens. By quantifying this signal change, rapid and highly sensitive detection can be achieved within 12 min, with a detection limit as low as 0.583 pg/mL. Validation using a DR rat model confirmed the sensor's accuracy, with results highly consistent with enzyme-linked immunosorbent assay (ELISA). This sensor offers a rapid, convenient, and highly sensitive solution for early screening of DR and dynamic monitoring of VEGF, demonstrating significant clinical application potential.
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Técnicas Biosensibles , Retinopatía Diabética , Espectrometría Raman , Factor A de Crecimiento Endotelial Vascular , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/análisis , Retinopatía Diabética/sangre , Retinopatía Diabética/diagnóstico , Animales , Oro/química , Espectrometría Raman/métodos , Catálisis , Ratas , Bencidinas/química , Paladio/química , Nanopartículas del Metal/química , Límite de Detección , Técnicas Biosensibles/métodos , Masculino , Nanotubos/química , Ratas Sprague-DawleyRESUMEN
PURPOSE: Retinopathy of prematurity (ROP) is a major cause of childhood blindness, and selecting the optimal treatment between anti-vascular endothelial growth factor (anti-VEGF) and laser therapy is crucial. Understanding their impact on key outcomes, particularly mortality, is essential for informed clinical decision-making. METHODS: A systematic literature search identified published studies comparing anti-VEGF and laser therapy for ROP up to December 31, 2024. Primary outcomes included mortality, retinal detachment, surgical interventions, myopia and neurodevelopmental outcomes. The risk of bias was assessed using the Cochrane Risk of Bias Tool and ROBINS-I. Data were synthesized using a random-effects model, with risk ratios (RR) and 95% confidence interval (CI). This review is registered in PROSPERO (CRD42024585336). RESULTS: A total of 12 randomized controlled trials (RCTs) and 58 observational studies, covering 10 516 infants, were included. Anti-VEGF therapy was associated with a higher mortality risk than laser therapy (RR: 1.68; 95% CI: 1.23-2.30), primarily in observational studies (1.85; 1.32-2.60), while RCTs showed no significant difference (1.02; 0.46-2.26). Anti-VEGF therapy was linked to lower risks of retinal detachment (0.36; 0.27-0.50), fewer surgical interventions (0.38; 0.22-0.65), and a lower risk of myopia (0.67; 0.54-0.82). No significant differences were found in neurodevelopmental outcomes (1.05; 0.96-1.15). CONCLUSIONS: Anti-VEGF therapy offers benefits over laser treatment, including reduced retinal detachment, fewer surgeries and lower myopia risk, with no observed increase in mortality or neurodevelopmental impairment. Future large-scale RCTs are needed to clarify mortality risks while minimising the impact of confounding factors.
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Inhibidores de la Angiogénesis , Coagulación con Láser , Terapia por Láser , Retinopatía de la Prematuridad , Factor A de Crecimiento Endotelial Vascular , Humanos , Retinopatía de la Prematuridad/mortalidad , Retinopatía de la Prematuridad/terapia , Retinopatía de la Prematuridad/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Coagulación con Láser/métodos , Recién Nacido , Inyecciones Intravítreas , Resultado del Tratamiento , Salud Global , Terapia por Láser/métodosRESUMEN
Intravitreal injections (IVI) are a common, effective therapy for multiple retinal diseases although can be associated with significant psychological effects that reduce adherence to treatment. We reviewed the psychological impacts of IVI to characterise their causes, consequences, and solutions. We searched the electronic databases PubMed, OVID Medline, OVID Embase, Google Scholar and Cochrane Reviews and retrieved 1252 peer-reviewed articles. Thirty-four articles were ultimately included and analysed. The majority of retrieved articles pertained to anxiety; however, other impacts were also identified with limited available evidence regarding depression. Pre-procedural anxiety was generally mild to moderate and reported in 17.3-85â¯% of patients undergoing IVI. Key contributing factors to anxiety included a lack of patient education, pain and discomfort during the procedure, and travel and waiting times. Potential strategies to reduce anxiety included person-centred education, alternatives to speculum use, reducing clinic wait times, and music or handholding during the procedure. Patients experience significant anxiety from IVI, owing to multiple factors, including lack of education about the procedure, lack of procedural familiarity, and pain, which require a patient-centred approach to addressing that considers individual needs and preferences. Little data pertain to non-anxiety effects of IVI, and thus further research may identify additional barriers to adherence and their solutions.
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Inhibidores de la Angiogénesis , Ansiedad , Inyecciones Intravítreas , Enfermedades de la Retina , Humanos , Inyecciones Intravítreas/psicología , Inyecciones Intravítreas/efectos adversos , Ansiedad/psicología , Ansiedad/etiología , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/psicología , Inhibidores de la Angiogénesis/administración & dosificaciónRESUMEN
BACKGROUND: Sex differences significantly affect many laboratory test results. However, sex differences in the serum and urine levels of the major vascular endothelial growth factor-A (VEGF-A) isoforms, VEGF-A121 and VEGF-A165, remain unclear. This study aimed to assess these sex-based profiles using a newly developed assay system. MATERIALS AND METHODS: We enrolled 780 age-matched subjects from Gifu University Hospital whose serum and urine samples were obtained simultaneously. Participants were not taking angiogenesis inhibitors, such as VEGF inhibitors. Total VEGF-A, VEGF-A121 and VEGF-A165 enzyme-linked immunosorbent assay were performed using an assay system developed by our group using isoform-specific monoclonal antibodies. RESULTS: Serum total VEGF-A and VEGF-A165 concentrations were not significantly different between the sexes; however, serum VEGF-A121 levels were significantly lower in females than in males (median [IQR] = 235.1 [156.0-366.3] pg/mL vs 223.0 [140.0-315.0] pg/mL, p = 0.0421). Conversely, the total urinary VEGF-A, VEGF-A121, and VEGF-A165 levels were significantly higher in females than in males (187.8 [115.3-325.1] ng/gCr vs 263.8 [161.1-446.0] ng/gCr, p < 0.0001, 123.2 [69.2-210.0] ng/gCr vs 173.1 [105.7-285.7] ng/gCr, p < 0.0001, and 13.3 [0.0-71.5] ng/gCr vs 33.2 [0.0-115.9] ng/gCr, p = 0.0091, respectively). Linear regression analysis revealed that total urinary VEGF-A, VEGF-A121, and VEGF-A165 levels were independently correlated with sex, regardless of renal function. CONCLUSIONS: These findings indicate clear sex-based differences in urinary excretion of VEGF-A isoforms, independent of serum levels. Sex-specific patterns should be considered when interpreting urinary VEGF-A as a clinical biomarker.
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Caracteres Sexuales , Factor A de Crecimiento Endotelial Vascular , Humanos , Femenino , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/orina , Masculino , Isoformas de Proteínas/orina , Isoformas de Proteínas/sangre , Persona de Mediana Edad , Ensayo de Inmunoadsorción Enzimática , Anciano , AdultoRESUMEN
While the transition from optical fiber to planar waveguide substrates in LMR-based sensors has allowed for the development of more robust, cost-effective, and easily manufactured platforms, it has also presented challenges in optimizing critical sensor parameters such as resolution and sensitivity in biosensing. In this work, we introduce the application of gold nanoparticles (AuNP) to enhance the sensitivity of a Lossy Mode Resonance (LMR)-based biosensor for the detection of vascular endothelial growth factor (VEGF) protein. The sensor was developed by depositing a nanometric TiO2 film on a planar waveguide, and its performance was assessed using three detection approaches: label-free, sandwich assay, and AuNP-labeled sandwich assay. The integration of AuNP significantly improved sensitivity, enabling detection at concentrations as low as 0.1 ng mL-1, surpassing the sensitivity of traditional label-free LMR-based sensors. These results demonstrate the potential of AuNP-enhanced LMR sensors for detecting low concentrations of biomarkers with high specificity and sensitivity, positioning them as promising tools for biosensing applications.
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Técnicas Biosensibles , Oro , Nanopartículas del Metal , Factor A de Crecimiento Endotelial Vascular , Oro/química , Nanopartículas del Metal/química , Técnicas Biosensibles/métodos , Factor A de Crecimiento Endotelial Vascular/análisis , Factor A de Crecimiento Endotelial Vascular/inmunología , Factor A de Crecimiento Endotelial Vascular/sangre , Humanos , Inmunoensayo/métodos , Límite de Detección , Titanio/químicaRESUMEN
Craniofacial fractures present intricate geometries that require defect-matched scaffolds for effective regeneration. Advanced 3D printing enables the fabrication of anatomically tailored structures, making it a powerful tool in bone tissue engineering. In this study, a novel 3D-printed scaffold integrating polyvinyl alcohol (PVA), hyaluronic acid (HA), fucoidan (Fc), and merwinite (Mr) nanoparticles with recombinant VEGF was developed as a multifunctional platform, with the aim of promoting both osteogenesis and angiogenesis in complex craniofacial defects. The HA.Fc.VEGF.Mr scaffold exhibited a compressive strength of 3.19 ± 0.11 MPa and an elastic modulus of 21.75 ± 3.32 MPa, making it suitable for craniofacial bone repair. After 28 days of immersion in PBS, the scaffold showed a degradation rate of 50.6 ± 4.6 %, while VEGF release reached 95.1 ± 5.1 % in a sustained, linear pattern by day 11. Bioactivity was validated through apatite-like deposition in SBF immersion for 28 days, alongside measurable release of Ca2+, Si4+, and Mg2+ ions. In vitro assessments demonstrated high cytocompatibility and enhanced osteogenic activity, confirmed by ALP levels, calcium deposition, and the upregulation of COL1, RUNX2, and osteocalcin. Angiogenic potential was further validated using the CAM assay, where the HA.Fc.VEGF.Mr scaffold exhibited superior neovascularization compared to other groups. These findings demonstrate the multifunctionality and regenerative potential of this scaffold for craniofacial bone repair.
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Ácido Hialurónico , Nanopartículas , Osteogénesis , Polisacáridos , Andamios del Tejido , Factor A de Crecimiento Endotelial Vascular , Ácido Hialurónico/química , Andamios del Tejido/química , Impresión Tridimensional , Osteogénesis/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/farmacología , Factor A de Crecimiento Endotelial Vascular/química , Nanopartículas/química , Ingeniería de Tejidos/métodos , Polisacáridos/química , Humanos , Animales , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Regeneración Ósea/efectos de los fármacos , Cráneo/efectos de los fármacos , Alcohol Polivinílico/químicaRESUMEN
BACKGROUND/AIM: Regorafenib, a multikinase inhibitor widely used to treat metastatic colorectal cancer (mCRC), is associated with elevations in pancreatic enzyme levels. However, clinical predictors of this adverse event have yet to be adequately defined. This study aimed to identify risk factors for regorafenib-induced enzyme elevation in routine clinical practice. PATIENTS AND METHODS: We retrospectively evaluated 47 patients with mCRC who received regorafenib between May 2013 and October 2024. Pancreatic enzyme elevation was defined as a Common Terminology Criteria for Adverse Events (CTCAE) grade ≥1 increase in serum lipase or amylase levels within 28 days of treatment initiation. Clinical data were extracted from medical records, and risk factors were assessed using univariate and multivariate logistic regression. Sensitivity analyses were performed to confirm the robustness of the findings. RESULTS: Lipase elevation occurred in 48.9% of patients, whereas amylase elevation was observed in 8.5% of patients. Severe enzyme elevation (CTCAE grade ≥3) was detected in 17.0% and exclusively involved lipase. The median onset time was 7 days, with no cases of acute pancreatitis reported. Multivariate analysis identified prior anti-vascular endothelial growth factor (VEGF) therapy lasting ≥300 days as an independent risk factor (adjusted odds ratio 5.99, 95% confidence interval 1.49-31.41, p=0.01). Sensitivity analyses supported this association. CONCLUSION: The elevation of pancreatic enzymes, predominantly lipase, is a frequent early adverse event associated with regorafenib treatment. A history of prolonged anti-VEGF therapy may predispose patients to toxicity, highlighting the need for close monitoring during the initial treatment phase. These findings provide novel insights that may help to optimize the safe clinical use of regorafenib.
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Amilasas , Antineoplásicos , Neoplasias Colorrectales , Lipasa , Páncreas , Compuestos de Fenilurea , Piridinas , Humanos , Masculino , Piridinas/efectos adversos , Piridinas/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Femenino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Persona de Mediana Edad , Anciano , Lipasa/sangre , Estudios Retrospectivos , Amilasas/sangre , Anciano de 80 o más Años , Adulto , Factores de Riesgo , Páncreas/enzimología , Páncreas/efectos de los fármacos , Metástasis de la Neoplasia , Antineoplásicos/efectos adversosRESUMEN
BACKGROUND/AIM: Bevacizumab (BV) is used in combination with paclitaxel to treat human epidermal growth factor receptor 2-negative advanced breast cancer. However, BV frequently causes hypertension. Because patients with advanced breast cancer already have an elevated cardiovascular risk, we investigated clinical factors associated with BV-induced severe hypertension in a real-world setting. PATIENTS AND METHODS: Patients with advanced breast cancer receiving BV with paclitaxel (n=67) were retrospectively evaluated. The primary endpoint was determination of factors for the occurrence of grade ≥3 severe hypertension, considering clinical significance. We also assessed the time to symptom onset and variation in blood pressure after treatment between specific patient groups. RESULTS: Hypertension occurred in 73.1% of the patients, with grades 2 and 3 severity in 20.9% and 52.2%, respectively. Multivariate logistic regression analysis suggested that pre-existing hypertension at baseline was an independent risk factor for grade ≥3 hypertension (adjusted hazard ratio=3.12; 95% confidence interval=1.30-7.87; p=0.01), resulting in similar results in a sensitive analysis. Additionally, median time to symptom onset was 70 days (range=56-119 days) in patients with pre-existing hypertension and 175 days (147 days-not available) in patients without pre-existing hypertension (p=0.004). No significant difference was noted in the range of fluctuations in systolic and diastolic blood pressure during treatment between patients with and without pre-existing hypertension. CONCLUSION: Pre-existing hypertension is a risk factor for BV-induced severe hypertension in patients with breast cancer.
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Antineoplásicos Inmunológicos , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias de la Mama , Hipertensión , Humanos , Bevacizumab/efectos adversos , Bevacizumab/administración & dosificación , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Hipertensión/inducido químicamente , Persona de Mediana Edad , Factores de Riesgo , Anciano , Estudios Retrospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Anciano de 80 o más Años , Presión Sanguínea/efectos de los fármacos , Antineoplásicos Inmunológicos/efectos adversosRESUMEN
Spine fusion devices fabricated from polyether ether ketone (PEEK) using traditional machining or with surface pores created by salt leaching result in a fibrous connective tissue interface. To overcome this limitation, we used fused strand deposition (FSD), which elevates fused filament fabrication (FFF) or fused deposition modeling (FDM) to generate a first-of-its-kind PEEK implant with an architecture designed to mimic trabecular bone. We examined the responses of human bone marrow stromal cells (MSCs) and macrophages isolated from the femurs of C57/Bl6 male mice to the additively manufactured porous PEEK (PP) and porous PEEK coated with HA (PP-HA) to determine if these modifications would improve cell response compared to solid PEEK (SP). PP and PP-HA constructs had similar 3D architectures but differed in hydrophilicity (PP-HA > PP). MSCs and macrophages were cultured on PP, PP-HA, and SP, and osteoblast differentiation and M1/M2 polarization were assessed. MSCs attached to the SP surface and the PP and PP-HA fibers, and synthesized osteoblast proteins in a surface-dependent manner. Notably, MSCs and macrophages produced VEGF mRNA and protein on PP-HA at levels higher than those on PP or SP. Macrophages grown on PP and PP-HA exhibited reduced expression of pro-inflammatory cytokines compared to cells on SP and increased levels of anti-inflammatory cytokines, but they did not exhibit a distinct M1 or M2 phenotype. These results show that additive manufacturing of a unique, fully porous PEEK implant using FSD, results in a surface that promotes MSC differentiation and decreases the pro-inflammatory response of macrophages to the surface, suggesting that PP and PP-HA implants will improve regeneration and eventually osseointegration in vivo. Importantly, the mechanisms involved are not the same as would be expected when testing Ti6Al4V substrates under the same experimental conditions and may have been obscured if the cells had been cultured using osteogenic media (OM). We correlated our in vitro findings with the clinical use of PP-HA implants in four patients, each of whom was treated with a different bone graft material; in all cases, fusion was achieved.
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Desarrollo Óseo , Inflamación , Cetonas , Células Madre Mesenquimatosas , Oseointegración , Polietilenglicoles , Benzofenonas , Animales , Cetonas/química , Cetonas/farmacología , Oseointegración/efectos de los fármacos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Humanos , Masculino , Polímeros , Ratones Endogámicos C57BL , Inflamación/prevención & control , Inflamación/patología , Ratones , Desarrollo Óseo/efectos de los fármacos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Prótesis e Implantes , Osteoblastos/citología , Osteogénesis/efectos de los fármacos , Células Cultivadas , PorosidadRESUMEN
OBJECTIVES: The aim of the present study was to assess the effect of dual growth factor release from collagen-based polyelectrolyte multilayer films (PEMs) on titanium implants on periimplant bone formation and angiogenetic activity in minipig mandibles. MATERIAL AND METHODS: Disc shaped Ti implants (5 × 7 × 1 mm) were coated with polyelectrolyte multilayer films and loaded with rhBMP-2, rhVEGF165, and a combination of both. Uncoated and unloaded Ti implants served as controls. The implants were inserted press-fit into 5 mm trephine cavities in minipig mandibles and evaluated after 4 and 13 weeks for bone formation, bone implant contact, and periimplant expression of CD31. RESULTS: After 4 weeks, there was no significant difference in periimplant bone formation nor bone-implant contact between the different surface conditions. CD31 expression was significantly increased around PEM coated implants loaded with VEGF and BMP each. After 13 weeks, bone implant contact and bone formation were significantly increased only around PEM coated implants with simultaneous release of BMP-2 and VEGF165. Expression of CD31 was significantly enhanced around all PEM coated implants loaded with growth factors regardless of the type or combination. CONCLUSION: It is concluded that simultaneous release of rhBMP-2 and rhVEGF165 may be required to achieve significant improvement of periimplant bone formation and bone implant contact. Angiogenesis as reflected by CD31 expression is enhanced by both rhVEGF165 and rhBMP-2 to a similar extent without an additive effect of simultaneous release.
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Proteína Morfogenética Ósea 2 , Colágeno , Implantes Dentales , Neovascularización Fisiológica , Osteogénesis , Titanio , Factor A de Crecimiento Endotelial Vascular , Animales , Porcinos , Porcinos Enanos , Proteína Morfogenética Ósea 2/farmacología , Proteína Morfogenética Ósea 2/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/farmacología , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Osteogénesis/efectos de los fármacos , Colágeno/farmacología , Mandíbula/cirugía , Propiedades de Superficie , Neovascularización Fisiológica/efectos de los fármacos , Materiales Biocompatibles Revestidos/farmacología , Proteínas Recombinantes/farmacología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismoRESUMEN
Nasopharyngeal carcinoma (NPC) is highly prevalent in Southeast Asia and southern China, with most patients diagnosed at advanced stages. Although epidermal growth factor receptor (EGFR)-targeted therapies have shown clinical promise, their long-term efficacy is limited. This study explores the regulatory role of AdipoR1 in EGFR-targeted therapy response and evaluates adiponectin as a potential strategy to overcome treatment resistance. NPC cell lines (5-8F and CNE1) were treated with nimotuzumab for short (24 h) and long (72 h) durations. mRNA and protein expression of vascular endothelial growth factor (VEGF), AdipoR1/R2, and other pathway components were assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. Adiponectin was applied to explore its regulatory role in VEGF expression and EGFR signaling. Prolonged treatment of NPC cells with nimotuzumab inhibited EGFR downstream signaling [protein kinase B, mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase], reduced cell invasion and migration initially, but invasive capacity gradually recovered over time. VEGF expression remained unchanged at 24â h but significantly increased after 72â h, promoting angiogenesis in cocultured HUVECs. Long-term nimotuzumab exposure downregulated AdipoR1 expression, while adiponectin restored AdipoR1 and VEGF levels with decreased mTOR expression, not EGFR, indicating that the mTOR pathway may mediate this regulation. In addition, nimotuzumab elevated the expression of lipid metabolism-related genes, FABP4 and CD36, which was mitigated by A-PN cotreatment. Prolonged EGFR-targeted therapy in NPC upregulates VEGF via AdipoR1 downregulation, reducing treatment efficacy. Adiponectin restores AdipoR1, suppresses VEGF, and reverses this effect, possibly through mTOR inhibition, suggesting a potential strategy to improve long-term therapeutic outcomes.
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Anticuerpos Monoclonales Humanizados , Resistencia a Antineoplásicos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Receptores de Adiponectina , Factor A de Crecimiento Endotelial Vascular , Humanos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Receptores de Adiponectina/metabolismo , Receptores de Adiponectina/genética , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Anticuerpos Monoclonales Humanizados/farmacología , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Adiponectina/farmacología , Adiponectina/metabolismo , Movimiento Celular/efectos de los fármacosRESUMEN
BACKGROUND: Cept1 is essential for de novo phopholipogenesis and is impacted by diabetes. We previously demonstrated that conditional knockdown of Cept1 in the endothelium leads to reduced tissue recovery. Therefore, we hypothesized that Cept1 overexpression may also be sufficient in promoting postischemic angiogenesis and recovery in the setting of diabetes. METHODS: CEPT1 (choline-ethanolamine phosphotransferase 1) content was evaluated in the peripheral arteries of human patients with peripheral artery disease and with or without diabetes. We also engineered a conditional endothelial cell (EC)-specific Cept1 overexpression mouse (Cept1fl/fl Cre+) in adult C57BL/6J (C57 black 6J) mice and performed unilateral hindlimb ischemia to assess the role of Cept1 in promoting angiogenesis. Murine aortae and ECs were harvested for single-cell RNA sequencing and molecular pathway analysis. RESULTS: In human arterial intima, CEPT1 was elevated in the setting of peripheral artery disease and diabetes, along with ACOX1 (acyl-coenzyme A oxidase 1), VEGF (vascular endothelial growth factor) R2, p-Akt (phosphorylated Akt), and p-eNOS (phosphorylated endothelial nitric oxide synthase). In mice, single-cell RNA sequencing demonstrated that ECs with Cept1 overexpression were enriched with wound healing, angiogenesis, sprouting, and cell migration pathways. Diabetic Cept1fl/flCre+ mice that underwent hindlimb ischemia demonstrated improved hindlimb perfusion and angiogenesis, and their aortic rings had increased ex vivo capillary sprouting. Cept1 overexpression in ECs significantly increased migration, tubule formation, and proliferation as predicted by single-cell RNA sequencing. Cept1 overexpression in ECs also led to increased expression of Pparα, Acox1, Vegfa, and Vegfr2. Similarly, treatment with siPparα and inhibitors for PPARα (peroxisome proliferator-activated receptor α; GW6471), VEGFR2 (ZM323881), Akt (LY294002), and eNOS (L-NAME [nitro-L-arginine methyl ester]) abrogated CEPT1-induced EC migration. CONCLUSIONS: Cept1 overexpression promotes EC function and postischemic recovery. The impact of CEPT1 on ECs is at least in part dependent on p-Akt/p-eNOS angiogenic signaling and PPARα. Because CEPT1 is elevated in diseased human peripheral arterial tissue, these findings suggest that CEPT1 may be playing an important compensatory role in vascular recovery and reperfusion following ischemic injury in the setting of diabetes.