Browsing by Subject "Vascular endothelial growth factor"
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Item A 6-month, subject-masked, randomized controlled study to assess efficacy of dexamethasone as an adjunct to bevacizumab compared with bevacizumab alone in the treatment of patients with macular edema due to central or branch retinal vein occlusion(Dove Press, 2014-06-03) Maturi, Raj K.; Chen, Vincent; Raghinaru, Dan; Bleau, Laurie; Stewart, Michael W.; Ophthalmology, School of MedicineAims: To determine if intravitreal bevacizumab combined with the dexamethasone intravitreal implant 0.7 mg improves visual acuity and macular thickness more than bevacizumab monotherapy in eyes with macular edema due to branch and central retinal vein occlusions. Methods: Thirty eyes were randomly assigned to receive either combination therapy or bevacizumab monotherapy. All patients received intravitreal bevacizumab at baseline, followed by dexamethasone implants or sham injections 1 week later. Monthly bevacizumab injections were given if the central subfield thickness (CST) was >250 μm, and the combined group received a second implant at month 4 or 5 if CST was >250 μm. Results: At 6 months, several secondary endpoints were met. Patients receiving combined therapy required fewer bevacizumab reinjections compared to those receiving monotherapy (two versus three; P=0.02), experienced greater mean reductions in CST from randomization (-56 μm versus +45 μm; P=0.01), and were more likely to have resolved all edema (CST <250 μm) (7/11 versus 2/14; P=0.02). The primary endpoint was not met since mean visual acuity changes from baseline were similar in the two groups (P=0.75). Conclusion: In patients with macular edema due to vein occlusions, bevacizumab with dexamethasone implants produces greater improvements in macular thickness compared to bevacizumab monotherapy, despite fewer bevacizumab injections.Item A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration(Dove Press, 2013) Kitchens, John W.; Kassem, Nawal; Wood, William; Stone, Thomas W.; Isernhagen, Rick; Wood, Edward; Hancock, Brad A.; Radovich, Milan; Waymire, Josh; Li, Lang; Schneider, Bryan P.; Medicine, School of MedicinePurpose: To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD). Methods: Patients with "wet" AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes. Results: 101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT. Conclusion: Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy.Item Biomarker Risk Score Algorithm and Preoperative Stratification of Patients with Pancreatic Cystic Lesions(Wolters Kluwer, 2021) Yip-Schneider, Michele T.; Wu, Huangbing; Allison, Hannah R.; Easler, Jeffrey J.; Sherman, Stuart; Al-Haddad, Mohammad A.; Dewitt, John M.; Schmidt, C. Max; Surgery, School of MedicineBackground: Pancreatic cysts are incidentally detected in up to 13% of patients undergoing radiographic imaging. Of the most frequently encountered types, mucin-producing (mucinous) pancreatic cystic lesions may develop into pancreatic cancer, while nonmucinous ones have little or no malignant potential. Accurate preoperative diagnosis is critical for optimal management, but has been difficult to achieve, resulting in unnecessary major surgery. Here, we aim to develop an algorithm based on biomarker risk scores to improve risk stratification. Study design: Patients undergoing surgery and/or surveillance for a pancreatic cystic lesion, with diagnostic imaging and banked pancreatic cyst fluid, were enrolled in the study after informed consent (n = 163 surgical, 67 surveillance). Cyst fluid biomarkers with high specificity for distinguishing nonmucinous from mucinous pancreatic cysts (vascular endothelial growth factor [VEGF], glucose, carcinoembryonic antigen [CEA], amylase, cytology, and DNA mutation) were selected. Biomarker risk scores were used to design an algorithm to predict preoperative diagnosis. Performance was tested using surgical (retrospective) and surveillance (prospective) cohorts. Results: In the surgical cohort, the biomarker algorithm outperformed the preoperative clinical diagnosis in correctly predicting the final pathologic diagnosis (91% vs 73%; p < 0.000001). Specifically, nonmucinous serous cystic neoplasms (SCN) and mucinous cystic neoplasms (MCN) were correctly classified more frequently by the algorithm than clinical diagnosis (96% vs 30%; p < 0.000008 and 92% vs 69%; p = 0.04, respectively). In the surveillance cohort, the algorithm predicted a preoperative diagnosis with high confidence based on a high biomarker score and/or consistency with imaging from ≥1 follow-up visits. Conclusions: A biomarker risk score-based algorithm was able to correctly classify pancreatic cysts preoperatively. Importantly, this tool may improve initial and dynamic risk stratification, reducing overdiagnosis and underdiagnosis.Item Diabetic Retinopathy in the Aging Population: A Perspective of Pathogenesis and Treatment(Dovepress, 2021-07-15) Leley, Sameer P.; Ciulla, Thomas A.; Bhatwadekar, Ashay D.; Ophthalmology, School of MedicineThe elderly population in the United States is projected to almost double by the year 2050. In addition, the numbers of diabetics are rising, along with its most common complication, diabetic retinopathy (DR). To effectively treat DR within the elderly population, it is essential first to consider the retinal changes that occur due to aging, such as decreased blood flow, retinal thinning, and microglial changes, and understand that these changes can render the retina more vulnerable to oxidative and ischemic damage. Given these considerations, as well as the pathogenesis of DR, specific pathways could play a heightened role in DR progression in elderly patients, such as the polyol pathway and the vascular endothelial growth factor (VEGF) axis. Current ocular treatments include intravitreal corticosteroids, intravitreal anti-VEGF agents, laser photocoagulation and surgical interventions, in addition to better control of underlying diabetes with an expanding range of systemic treatments. While using therapeutics, it is also essential to consider how pharmacokinetics and pharmacodynamics change with aging; oral drug absorption can decrease, and ocular drug metabolism might affect the dosing and delivery methods. Also, elderly patients may more likely be nonadherent to their medication regimen or appointments than younger patients, and undertreatment with anti-VEGF drugs often leads to suboptimal outcomes. With a rising number of elderly DR patients, understanding how aging affects disease progression, pharmacological metabolism, and adherence are crucial to ensuring that this population receives adequate care.Item Double-Masked, Randomized, Phase 2 Evaluation of Abicipar Pegol (an Anti-VEGF DARPin Therapeutic) in Neovascular Age-Related Macular Degeneration(Mary Ann Liebert, 2018-11-09) Callanan, David; Kunimoto, Derek; Maturi, Raj K.; Patel, Sunil S.; Staurenghi, Giovanni; Wolf, Sebastian; Cheetham, Janet K.; Hohman, Thomas C.; Kim, Kimmie; López, Francisco J.; Schneider, Susan; Ophthalmology, School of MedicinePURPOSE: To evaluate safety and efficacy of the vascular endothelial growth factor binding protein abicipar pegol (abicipar) versus ranibizumab for neovascular age-related macular degeneration. METHODS: Phase 2, multicenter, randomized, double-masked comparison (REACH study, stage 3). Patients (n = 64) received intravitreal injections of abicipar 1 mg or 2 mg at baseline, week 4, and week 8 (3 injections) or ranibizumab 0.5 mg at baseline and monthly (5 injections). RESULTS: In the abicipar 1 mg (n = 25), abicipar 2 mg (n = 23), and ranibizumab (n = 16) arms, respectively, least-squares mean best-corrected visual acuity (BCVA) change from baseline was +6.2, +8.3, and +5.6 letters at week 16 (primary endpoint) and +8.2, +10.0, and +5.3 letters at week 20. Least-squares mean central retinal thickness (CRT) reduction from baseline was 134, 113, and 131 μm at week 16 and 116, 103, and 138 μm at week 20. Intraocular inflammation adverse events (AEs), reported in 5/48 (10.4%) abicipar-treated patients, resolved without sustained vision loss or other sequelae. CONCLUSIONS: Abicipar demonstrated durability of effect: BCVA and CRT improvements were similar between abicipar and ranibizumab at weeks 16 and 20 (8 and 12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection). No serious AEs were reported.Item Increased lung volume in infants and toddlers at high compared to low altitude(Wiley, 2013-12) Llapur, Conrado J.; Martínez, Myriam R.; Caram, María Marta; Bonilla, Federico; Cabana, Celia; Yu, Zhansheng; Tepper, Robert S.; Biostatistics, School of MedicineChildren and adults residing at high altitude (HA) compared to low altitude (LA) have larger lung volumes; however, it is unknown whether this response to chronic hypoxia begins early in life. Our objective was to determine whether infants and toddlers at HA have larger lung volumes compared to infants and toddlers at LA. Oxygen saturation (SaO2 ), functional residual capacity (FRC), as well as serum levels of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) were measured in infants and toddlers from HA (N = 50; 3,440 m) and LA (N = 35; 440 m). There were no significant differences in somatic size for HA and LA subjects; however, HA subjects had significantly lower SaO2 (88.5% vs. 96.7%; P < 0.0001). Subjects at HA had significantly greater FRC compared to subjects at LA (group mean: 209 and 157 ml; P < 0.0001), adjusting for body length. Male infants at HA had a significantly greater FRC compared to males at LA (57 ml; P-value < 0.001); however, the increase in FRC for females at HA compared to LA was not significant (20 ml; P-value = 0.101). VEGF and EPO were significantly higher for subjects at HA compared to LA with no gender differences. In summary, infants and toddlers at HA have lower oxygen saturations, higher serum levels of VEGF and EPO, and higher FRC compared to subjects at LA; however, chronic hypoxia appears to generate a more robust response in lung growth in male compared to female infants early in life.Item Regulation of Bone Marrow Angiogenesis by Osteoblasts during Bone Development and Homeostasis(Frontiers Media, 2013-07-10) Schipani, Ernestina; Wu, Collen; Rankin, Erinn B.; Giaccia, Amato J.; Medicine, School of MedicineBone marrow is a highly heterogeneous and vascularized tissue. The various cell types populating the bone marrow extensively communicate with each other, and cell-to-cell cross talk is likely to be essential for proper bone development and homeostasis. In particular, the existence of osteogenesis and angiogenesis coupling has been recently proposed. Despite its high degree of vascularization, a gradient of oxygenation is present in the bone marrow, and the endosteal surface of cortical bone appears to be among the most hypoxic areas in the body. Oxygen (O2) is both an essential metabolic substrate and a regulatory signal that is in charge of a specific genetic program. An important component of this program is the family of transcription factors known as hypoxia-inducible factors (HIFs). In this Perspective, we will summarize our current knowledge about the role of the HIF signaling pathway in controlling bone development and homeostasis, and especially in regulating the crosstalk between osteoblasts, progenitor cells, and bone marrow blood vessels.Item Stimulation of sphingosine 1-phosphate signaling as an alveolar cell survival strategy in emphysema(American Thoracic Society, 2010-02-15) Diab, Khalil J.; Adamowicz, Jeremy J.; Kamocki, Krzysztof; Rush, Natalia I.; Garrison, Jana; Gu, Yuan; Schweitzer, Kelly S.; Skobeleva, Anastasia; Rajashekhar, Gangaraju; Hubbard, Walter C.; Berdyshev, Evgeny V.; Petrache, Irina; Medicine, School of MedicineRATIONALE: Vascular endothelial growth factor receptor (VEGFR) inhibition increases ceramides in lung structural cells of the alveolus, initiating apoptosis and alveolar destruction morphologically resembling emphysema. The effects of increased endogenous ceramides could be offset by sphingosine 1-phosphate (S1P), a prosurvival by-product of ceramide metabolism. OBJECTIVES: The aims of our work were to investigate the sphingosine-S1P-S1P receptor axis in the VEGFR inhibition model of emphysema and to determine whether stimulation of S1P signaling is sufficient to functionally antagonize alveolar space enlargement. METHODS: Concurrent to VEGFR blockade in mice, S1P signaling augmentation was achieved via treatment with the S1P precursor sphingosine, S1P agonist FTY720, or S1P receptor-1 (S1PR1) agonist SEW2871. Outcomes included sphingosine kinase-1 RNA expression and activity, sphingolipid measurements by combined liquid chromatography-tandem mass spectrometry, immunoblotting for prosurvival signaling pathways, caspase-3 activity and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays, and airspace morphometry. MEASUREMENTS AND MAIN RESULTS: Consistent with previously reported de novo activation of ceramide synthesis, VEGFR inhibition triggered increases in lung ceramides, dihydroceramides, and dihydrosphingosine, but did not alter sphingosine kinase activity or S1P levels. Administration of sphingosine decreased the ceramide-to-S1P ratio in the lung and inhibited alveolar space enlargement, along with activation of prosurvival signaling pathways and decreased lung parenchyma cell apoptosis. Sphingosine significantly opposed ceramide-induced apoptosis in cultured lung endothelial cells, but not epithelial cells. FTY720 or SEW2871 recapitulated the protective effects of sphingosine on airspace enlargement concomitant with attenuation of VEGFR inhibitor-induced lung apoptosis. CONCLUSIONS: Strategies aimed at augmenting the S1P-S1PR1 signaling may be effective in ameliorating the apoptotic mechanisms of emphysema development.Item The Effects of Two rhPDGF-BB Applications on Periodontal Ligament Cell’s Proliferation and VEGF Expression(2024) Velgis, Raziel; Windsor, L. Jack; John, Vanchit; Batra, Chadni; Batra, Chandni; John, Vanchit; Batra, Chandni; Windsor, JackBackground: Platelet derived growth factor (PDGF) has been shown since the late 1980s to play a major role in periodontal regeneration. PDGF has five isoforms and the isoform PDGF-BB has been found to be the most effective. Animal studies evaluating release kinetics of purified recombinant human platelet-derived growth factor (rh-PDGF-BB), demonstrated that 90% of rh-PDGF-BB was depleted from sites within 72 hours after implantation. Thus, the aim of this in-vitro study was to evaluate the effects of two rhPDGF-BB applications on periodontal ligament fibroblasts proliferation and VEGF expression. Materials & Methods: Periodontal ligament (PDL) cells were seeded in multiple 6 well plates and split into 3 groups. Group 1 served as a control that received no rh-PDGF-BB. Group 2 was given an initial dose of 10 ng/ml rhPDGF-BB on day 1 and none on day 3. Group 3 received a dose of 10 ng/ml rhPDGF-BB on day 1 and a second dose on day 3. On day 3, half of the plates were stopped and media collected was used for LDH, WST-1 and VEGF ELISA analysis for evaluation of VEGF expression, cellular proliferation and cytotoxicity. Plain media was then added to groups 1 and 2 while group 3 received media with rh-PDGF-BB. On day 6, the collected media was used for ELISA, WST-1 and LDH assays. Results: PDL cell proliferation was not significantly different between any group studied (p=0.689). VEGF expression was increased in group 2 and 3 on day 3 compared to group 1 (p=0.005). There was no difference between groups 1 and 2 on day 6 (p=0.977). Conclusion: The addition of rhPDGF-BB to PDL cells did not increase proliferation at any time point. A single application of rhPDGF-BB increased the expression of VEGF from PDL cells; however, an additional application did not significantly increase the expression of VEGF.Item The evolving therapeutic landscape of diabetic retinopathy(Taylor & Francis, 2023) Shughoury, Aumer; Bhatwadekar, Ashay; Jusufbegovic, Denis; Hajrasouliha, Amir; Ciulla, Thomas A.; Ophthalmology, School of MedicineIntroduction: Diabetic retinopathy (DR) is a leading cause of blindness worldwide. Recent decades have seen rapid progress in the management of diabetic eye disease, evolving from pituitary ablation to photocoagulation and intravitreal pharmacotherapy. The advent of effective intravitreal drugs inhibiting vascular endothelial growth factor (VEGF) marked a new era in DR therapy. Sustained innovation has since produced several promising biologics targeting angiogenesis, inflammation, oxidative stress, and neurodegeneration. Areas covered: This review surveys traditional, contemporary, and emerging therapeutics for DR, with an emphasis on anti-VEGF therapies, receptor tyrosine kinase inhibitors, angiopoietin-Tie2 pathway inhibitors, integrin pathway inhibitors, gene therapy 'biofactory' approaches, and novel systemic therapies. Some of these investigational therapies are being delivered intravitreally via sustained release technologies for extended durability. Other investigational agents are being delivered non-invasively via topical and systemic routes. These strategies hold promise for early and long-lasting treatment of DR. Expert opinion: The evolving therapeutic landscape of DR is rapidly expanding our toolkit for the effective and durable treatment of blinding eye disease. However, further research is required to validate the efficacy of novel therapeutics and characterize real world outcomes.