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Effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in patients with moderate to severe COVID-19.
Fernandes, AL, Murai, IH, Reis, BZ, Sales, LP, Santos, MD, Pinto, AJ, Goessler, KF, Duran, CSC, Silva, CBR, Franco, AS, et al
The American journal of clinical nutrition. 2022;(3):790-798
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Abstract
BACKGROUND The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. OBJECTIVES We aimed to investigate the effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. METHODS This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1β, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1β (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. RESULTS The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m2, of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group difference at postintervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. CONCLUSIONS The findings do not support the use of a single dose of 200,000 IU vitamin D3, compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19.This trial was registered at clinicaltrials.gov as NCT04449718.
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Calcium hydroxybenesulfonate improves vascular proliferation in patients with diabetic retinopathy via reducing VEGF, CAM-1 and MMP-9.
Yao, L, Li, Y, Zhao, Z
Minerva medica. 2021;(5):668-670
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Prognostic Significance of VEGF and HIF-1 α in Hepatocellular Carcinoma Patients Receiving Sorafenib Versus Metformin Sorafenib Combination.
El Shorbagy, S, abuTaleb, F, Labib, HA, Ebian, H, Harb, OA, Mohammed, MS, Rashied, HA, Elbana, KA, Haggag, R
Journal of gastrointestinal cancer. 2021;(1):269-279
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major health problem. HCC burden has been increasing in Egypt in the past 10 years. Most HCC cases are diagnosed at an advanced stage with limited treatment options. Sorafenib is the standard therapy for advanced HCC, but the effectiveness is not satisfied. Metformin may decrease the risk of HCC development in diabetic patients, reduces tumor invasion, and augments sensitivity to sorafenib; however, safety and efficacy of combined treatment are still unclear. As HCC is characterized by high vascularity, and vascular endothelial growth factor (VEGF) plays an important role in vascularization, many studies questioned if VEGF and HIF-1 α could offer information about HCC response to sorafenib. We conducted this study to assess the benefits from adding metformin to HCC treatment, and appraise the role of VEGF and HIF-1 α in HCC prognosis. METHOD This was a prospective, randomized study in which 80 advanced measurable patients consecutively treated with sorafenib plus metformin (arm A) or sorafenib alone (arm B), prognostic value of plasma, and tissue levels of VEGF and HIF-1 α were evaluated. RESULTS We enrolled 61 men and 19 women with a median age of 60 years (range 49-68 years). Fifty-seven patients had Child-Pugh A while 23 had early B, the most common etiology of liver disease was hepatitis C (86%). Sixty percent of patients were diabetic. No significant difference was detected between arm A and arm B regarding response to treatment (p = 0.5), time to disease progression (p = 0.3), or overall survival (p = 0.6). Low VEGF and HIF-1 α plasma levels were significantly associated with better treatment response (p < 0.001 for both), and higher OS (p < 0.001). Patients with high expressions of VEGF and HIF in HCC tissue had significantly poor treatment outcome (p < 0.001, p = 0.03, respectively), and poor OS (p < 0.001, p < 0.001, respectively). CONCLUSIONS No superior efficacy of adding metformin to sorafenib in HCC treatment. VEGF and HIF-1 α had promising prognostic value in HCC.
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A randomized single-blinded, parallel-arm group feasibility trial evaluating role of pectoral nerve block on serum vascular endothelial growth factor levels in patients undergoing unilateral modified radical mastectomy.
Govil, N, Naithani, M, Ravi, B, Sharda, P, Tripathi, M, Bhardwaj, BB
Medical gas research. 2020;(4):179-184
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Abstract
Metastatic breast cancer cells carry adult and neonatal variants of NaV1.5 voltage-gated activated Na+ channels involved in cell invasion. We hypothesize that instilling lignocaine near the surgical field to anesthetize the pectoral nerves for analgesia will decrease angiogenesis by blocking voltage-gated activated Na+ channels. Twenty patients undergoing unilateral modified radical mastectomy were randomized in a single-blinded, parallel-arm group feasibility pilot study in two groups. In Group I a catheter was placed between the pectoralis major and minor muscle under direct vision before skin closure. Ten milliliters of 2% lignocaine was given as an initial bolus followed by 10 mL of 2% lignocaine every 8 hours up to 24 hours. Group II did not receive any regional block. Primary measure outcomes were pre and postoperative changes in levels of vascular endothelial growth factor. Secondary outcomes were postoperative pain scores and total rescue analgesia used. Nine patients in each group were analyzed. Baseline demographic data of all females were similar with respect to age, body mass, height and duration of anesthesia. Postoperative mean serum levels of vascular endothelial growth factor were decreased by 46.60% from baseline in Group I, while were increased by 84.27% as compared to preoperative values in Group II. Postoperative average pain scores were less in Group I. Postoperative rescue analgesia in 24 hours in Group I was lower than that in Group II. There was no postoperative adverse event related to catheter or lignocaine administration at given doses. Instilling lignocaine to block pectoral nerves provides better postoperative analgesia and decreases a marker of angiogenesis. The study protocol was approved by the Institutional Ethical Committee of the Tertiary Centre (All India Institute of Medical Sciences Rishikesh India) (No. AIIMS/IEC/19/1002) on August 9, 2019, and the larger expansion trial was prospectively registered on Clinical Trial Registry India (No. CTRI/2020/01/022784) on January 15, 2020.
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Impact of Prior Bevacizumab Treatment on VEGF-A and PlGF Levels and Outcome Following Second-Line Aflibercept Treatment: Biomarker Post Hoc Analysis of the VELOUR Trial.
Van Cutsem, E, Paccard, C, Chiron, M, Tabernero, J
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;(3):717-725
Abstract
PURPOSE Aflibercept is a targeted anti-VEGF therapy used to treat patients with metastatic colorectal cancer (mCRC) following progression on oxaliplatin-based regimens. This post hoc study evaluated the effect of prior bevacizumab treatment and growth factor levels on patient outcomes associated with aflibercept in the VELOUR phase III trial. EXPERIMENTAL DESIGN Baseline biomarker plasma concentrations were measured using a bead-based multiplex assay. Patients were grouped according to prior bevacizumab treatment, second-line treatment, and serum biomarker concentrations, and analyzed for overall survival (OS) and progression-free survival (PFS). RESULTS Plasma samples were available for 553 patients (placebo n = 265; aflibercept n = 288), of which 169 had received prior bevacizumab. Nine biomarkers implicated in angiogenesis or bevacizumab resistance correlated with prior bevacizumab therapy. VEGF-A and placental growth factor (PlGF) were the most significantly increased in patients who had received prior bevacizumab compared with those who had not received prior bevacizumab. In the placebo group, patients with high VEGF-A (>144 pg/mL) levels at baseline had worse OS and PFS compared with patients with lower levels at baseline (9.6 vs. 12.9 months). This was also seen in patients who received placebo and had high baseline PlGF (>8 pg/mL; 9.7 vs. 11.7 months). In the aflibercept group, prolonged OS and PFS were observed regardless of baseline VEGF-A or PlGF levels. CONCLUSIONS High VEGF-A and PlGF serum levels may underlie development of resistance to bevacizumab in patients with mCRC. Aflibercept retains its activity regardless of baseline VEGF-A and PlGF levels and may be an effective second-line treatment for patients with bevacizumab-induced resistance.
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Effects of cholecalciferol supplementation on serum angiogenic biomarkers in breast cancer patients treated with tamoxifen: A controlled randomized clinical trial.
Shahvegharasl, Z, Pirouzpanah, S, Mahboob, SA, Montazeri, V, Adili, A, Asvadi, I, Sanaat, Z, Esfehani, A, Pirouzpanah, SS, Mesgari, M
Nutrition (Burbank, Los Angeles County, Calif.). 2020;:110656
Abstract
OBJECTIVE The aim of this study was to investigate the effects of cholecalciferol supplementation on serum levels of angiogenic parameters in patients with breast cancer (BC) who were treated with tamoxifen. METHODS This was a pilot-based, randomized, triple-blind, placebo-controlled clinical trial with 52 patients with BC randomly assigned to either an intervention group receiving weekly 50 000 IU cholecalciferol or a placebo group for 8 wk. At baseline and at end of study, serum levels of angiogenic growth factors such as vascular endothelial growth factor (VEGF)-A, angiopoietin (Ang)-2, hypoxia-inducible factor (Hif)-1, and high-sensitivity C-reactive protein were measured by enzyme-linked immunosorbent assay. Every 4 wk, a completed 3-d, 24-h dietary record and daily sunlight exposure checklist were collected and anthropometric variables were measured. RESULTS The ultimate number of participants in each arm was 22 for analyses. For premenopausal women, cholecalciferol supplementation resulted in a significant decrease in serum levels of Ang-2 and VEGF-A after 8 wk of treatment (P < 0.05). In the absence of vascular invasion, supplementation led to a significant decrease in Ang-2 levels compared with the placebo group (P < 0.05). Supplementation caused significant increases in Hif-1 in patients diagnosed with the infiltration of tumors into vascular or lymphatic vessels (P < 0.05). CONCLUSION Cholecalciferol supplementation achieved sufficient efficacy among patients with BC taking tamoxifen and could be effective in the reduction of angiogenic biomarkers particularly dependent on the infiltration status of the tumor to vessels. Further studies with larger subgroups should be investigated.
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The Effects of Selenium Supplementation on Clinical Symptoms and Gene Expression Related to Inflammation and Vascular Endothelial Growth Factor in Infertile Women Candidate for In Vitro Fertilization.
Heidar, Z, Hamzepour, N, Zadeh Modarres, S, Mirzamoradi, M, Aghadavod, E, Pourhanifeh, MH, Asemi, Z
Biological trace element research. 2020;(2):319-325
Abstract
This study was performed to determine the effects of selenium supplementation on clinical symptoms and gene expression related to inflammatory markers in infertile women with polycystic ovary syndrome (PCOS) who were candidate for in vitro fertilization (IVF). Thirty-six women candidate for IVF were recruited in this randomized double-blinded, placebo-controlled trial. They (n = 18/group) were randomly assigned into intervention groups to take either 200 μg/day of selenium or placebo for 8 weeks. RT-PCR findings indicated that selenium supplementation downregulated gene expression of interleukin-1 (IL-1) (P < 0.004) and tumor necrosis factor alpha (TNF-α) (P = 0.02) in lymphocytes of patients with PCOS compared with the placebo. In addition, selenium supplementation upregulated gene expression of vascular endothelial growth factor (VEGF) (P = 0.001) in lymphocytes of patients with PCOS compared with the placebo. Selenium supplementation had no significant effect on clinical symptoms and gene expression of IL-8 (P = 0.10) and transforming growth factor beta (TGF-β) (P = 0.63). Overall, our findings documented that selenium supplementation for 8 weeks to infertile women candidate for IVF improved IL-1, TNF-α, and VEGF gene expression, though selenium had no effect on clinical symptoms and, IL-8 and TGF-β gene expression. Clinical trial registration number: http://www.irct.ir: IRCT20170513033941N23.
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Vitamin D suppresses proangiogenic factors in patients with ulcerative colitis: A randomized double blind placebo controlled clinical trial.
Emami, MR, Sharifi, A, Yaseri, M, Derakhshanian, H, Hosseinzadeh-Attar, MJ
Complementary therapies in clinical practice. 2020;:101086
Abstract
BACKGROUND Angiogenesis and inflammation are involved in the pathogenesis of ulcerative colitis (UC). This study aimed to assess the effect of vitamin D on serum levels of proangiogenic factors, visfatin and vascular endothelial growth factor (VEGF), in patients with UC. MATERIALS AND METHODS Ninety patients were randomized to receive either a single intramuscular injection of 300,000 IU vitamin D or normal saline. Visfatin, VEGF, and 25-hydroxyvitamin D [25(OH)D] concentrations were assessed before and 90 days after the intervention. RESULTS There were no significant differences in visfatin and VEGF levels between the two groups following supplementation. In patients with vitamin D insufficiency, visfatin increase was significantly lower in the intervention versus placebo group. There was an inverse correlation between serum 25(OH)D and visfatin in the subgroup with vitamin D insufficiency. CONCLUSION Vitamin D might be beneficial in decreasing proangiogenic factors such as visfatin in UC patients with low 25(OH)D levels.
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Evaluation of Month-24 Efficacy and Safety of Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration: The MERLOT Randomized Clinical Trial.
Jackson, TL, Soare, C, Petrarca, C, Simpson, A, Neffendorf, JE, Petrarca, R, Muldrew, A, Peto, T, Chakravarthy, U, Membrey, L, et al
JAMA ophthalmology. 2020;(8):835-842
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Abstract
IMPORTANCE Although anti-vascular endothelial growth factor (VEGF) treatment offers better outcomes than the natural history of neovascular age-related macular degeneration (ARMD), a less burdensome, less expensive, and more durable treatment is needed. OBJECTIVE To assess the efficacy and safety of epimacular brachytherapy (EMB) for chronic, active, neovascular ARMD. DESIGN, SETTING, AND PARTICIPANTS The Macular Epiretinal Brachytherapy vs Ranibizumab (Lucentis) Only Treatment (MERLOT) pivotal device trial was conducted at 24 National Health Service hospitals across the UK. Patients who had neovascular ARMD and received intravitreal ranibizumab were enrolled between November 10, 2009, and January 30, 2012. Eligible patients were randomized 2:1 and were stratified by lens status and angiographic lesion type to receive either EMB plus as-needed ranibizumab or as-needed ranibizumab monotherapy. Participants were followed up monthly for 24 months and then assessed at a final visit at month 36. Masking of participants and clinicians was not possible, but best-corrected visual acuity (BCVA) and imaging were analyzed by masked assessors. Analysis followed the intent-to-treat approach. INTERVENTIONS Pars plana vitrectomy with 24 Gy EMB plus as-needed ranibizumab vs as-needed ranibizumab monotherapy. MAIN OUTCOMES AND MEASURES Coprimary outcomes were the number of as-needed ranibizumab injections and the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA with a noninferiority margin of -5 ETDRS letters. Secondary outcomes were the percentage of participants losing fewer than 15 ETDRS letters and gaining 0 or more or 15 or more ETDRS letters and the mean change in angiographic total lesion size, choroidal neovascularization size, and foveal thickness on optical coherence tomography. RESULTS Of 363 participants, 329 (90.6%) completed 24 months of follow-up (222 participants in the EMB group and 107 in the ranibizumab group). The mean (SD) age of the combined groups was 76.5 (7.4) years. The mean (SD) number of ranibizumab injections was 9.3 (6.7) in the EMB group and 8.3 (4.5) in the ranibizumab group, with a difference of 1.0 injection (95% CI, -0.3 to 2.3; P = .13). The mean (SD) BCVA change was -11.2 (15.7) ETDRS letters in the EMB group and -1.4 (10.9) ETDRS letters in the ranibizumab group, with a difference of 9.8 ETDRS letters (95% CI, -6.7 to -12.9). In the EMB group, 65.6% of participants (160 of 244) lost fewer than 15 ETDRS letters vs 86.6% (103 of 119) in the ranibizumab group, with a difference of 21% (95% CI, 12.4%-29.5%; P < .001). Microvascular abnormalities occurred in 20 of 207 eyes (9.7%) in the EMB group and 1 of 97 eyes (1.0%) in the ranibizumab group. These abnormalities occurred outside the foveal center, and there were no unexpected safety concerns. CONCLUSIONS AND RELEVANCE The MERLOT trial found that despite the acceptable safety of EMB, it did not reduce the number of ranibizumab injections and was associated with worse visual acuity than anti-VEGF treatment alone; these results do not support EMB use as an adjunct treatment for chronic, active neovascular ARMD. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01006538.
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Intravitreal Conbercept Injection as an Adjuvant in Vitrectomy with Silicone Oil Infusion for Severe Proliferative Diabetic Retinopathy.
Gao, S, Lin, Z, Chen, Y, Xu, J, Zhang, Q, Chen, J, Shen, X
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics. 2020;(5):304-310
Abstract
Purpose: To assess the clinical effects of preoperative, intraoperative, or preoperative combined with intraoperative intravitreal conbercept (IVC) injection in vitrectomy with silicone oil tamponade for severe proliferative diabetic retinopathy (PDR). Methods: Ninety-eight eyes of 98 severe PDR patients undergoing vitrectomy with silicone oil tamponade were randomly assigned to 3 groups: Group 1 (34 eyes) received IVC injections 3 to 5 days before surgery; Group 2 (35 eyes) received IVC injections at the end of surgery; and Group 3 (29 eyes) received IVC injections 3 to 5 days before and at the end of operation. Follow-up examinations were performed for 6 months. Results: The incidence and severity of intraoperative bleeding were not significantly different (P = 0.233). However, the duration of surgery was significantly shorter in Group 1 and Group 3 compared with Group 2 (P < 0.001). The incidences of early and late recurrent vitreous hemorrhage (VH) were 32.35%, 28.57%, and 13.80%, respectively. At 6-month follow-up, mean best-corrected visual acuity had significantly increased to 1.25 ± 0.45 logMAR in Group 1, 1.29 ± 0.46 logMAR in Group 2, 1.16 ± 0.44 logMAR in Group 3 (all P < 0.001). The incidence of postoperative VH, neovascular glaucoma, and retinal detachment in Group 3 was slightly lower, however, no significant differences were observed (all P > 0.05). In young patients, similar results were observed and Group 3 had better visual improvements (P = 0.037). Conclusions: Preoperative IVC injection could be a safe and effective adjunct in pars plana vitrectomy with silicone oil tamponade for severe PDR. Preoperative combined with intraoperative IVC are promising, especially in young patients.