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Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.
Imel, EA, Glorieux, FH, Whyte, MP, Munns, CF, Ward, LM, Nilsson, O, Simmons, JH, Padidela, R, Namba, N, Cheong, HI, et al
Lancet (London, England). 2019;(10189):2416-2427
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Abstract
BACKGROUND X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING Ultragenyx Pharmaceutical and Kyowa Kirin International.
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A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection.
Lachmann, R, Bevan, MA, Kim, S, Patel, N, Hawrylowicz, C, Vyakarnam, A, Peters, BS
AIDS (London, England). 2015;(10):1127-35
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Abstract
OBJECTIVES To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity. DESIGN This was a pilot, open-label, three-arm prospective phase 1 study. METHODS We recruited 28 patients with low plasma vitamin D (<50 nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200 000 IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4 T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation. RESULTS One month of vitamin D supplementation restored plasma levels to sufficiency (>75 nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1β - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1β, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced. CONCLUSION Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy.
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Preoperative standard oral nutrition supplements vs immunonutrition: results of a systematic review and meta-analysis.
Hegazi, RA, Hustead, DS, Evans, DC
Journal of the American College of Surgeons. 2014;(5):1078-87
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Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: a population-based cohort study.
Pinart, M, Benet, M, Annesi-Maesano, I, von Berg, A, Berdel, D, Carlsen, KC, Carlsen, KH, Bindslev-Jensen, C, Eller, E, Fantini, MP, et al
The Lancet. Respiratory medicine. 2014;(2):131-40
Abstract
BACKGROUND Eczema, rhinitis, and asthma often coexist (comorbidity) in children, but the proportion of comorbidity not attributable to either chance or the role of IgE sensitisation is unknown. We assessed these factors in children aged 4-8 years. METHODS In this prospective cohort study, we assessed children from 12 ongoing European birth cohort studies participating in MeDALL (Mechanisms of the Development of ALLergy). We recorded current eczema, rhinitis, and asthma from questionnaires and serum-specific IgE to six allergens. Comorbidity of eczema, rhinitis, and asthma was defined as coexistence of two or three diseases in the same child. We estimated relative and absolute excess comorbidity by comparing observed and expected occurrence of diseases at 4 years and 8 years. We did a longitudinal analysis using log-linear models of the relation between disease at age 4 years and comorbidity at age 8 years. FINDINGS We assessed 16 147 children aged 4 years and 11 080 aged 8 years in cross-sectional analyses. The absolute excess of any comorbidity was 1·6% for children aged 4 years and 2·2% for children aged 8 years; 44% of the observed comorbidity at age 4 years and 50·0% at age 8 years was not a result of chance. Children with comorbidities at 4 years had an increased risk of having comorbidity at 8 years. The relative risk of any cormorbidity at age 8 years ranged from 36·2 (95% CI 26·8-48·8) for children with rhinitis and eczema at age 4 years to 63·5 (95% CI 51·7-78·1) for children with asthma, rhinitis, and eczema at age 4 years. We did longitudinal assessment of 10 107 children with data at both ages. Children with comorbidities at 4 years without IgE sensitisation had higher relative risks of comorbidity at 8 years than did children who were sensitised to IgE. For children without comorbidity at age 4 years, 38% of the comorbidity at age 8 years was attributable to the presence of IgE sensitisation at age 4 years. INTERPRETATION Coexistence of eczema, rhinitis, and asthma in the same child is more common than expected by chance alone-both in the presence and absence of IgE sensitisation-suggesting that these diseases share causal mechanisms. Although IgE sensitisation is independently associated with excess comorbidity of eczema, rhinitis, and asthma, its presence accounted only for 38% of comorbidity, suggesting that IgE sensitisation can no longer be considered the dominant causal mechanism of comorbidity for these diseases.
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Comparison of in vitro tests for antioxidant and immunomodulatory capacities of compounds.
Becker, K, Schroecksnadel, S, Gostner, J, Zaknun, C, Schennach, H, Uberall, F, Fuchs, D
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2014;(2):164-71
Abstract
Oxidative stress is considered to be critically involved in the normal aging process but also in the development and progression of various human pathologies like cardiovascular and neurodegenerative diseases, as well as of infections and malignant tumors. These pathological conditions involve an overwhelming production of reactive oxygen species (ROS), which are released as part of an anti-proliferative strategy during pro-inflammatory immune responses. Moreover, ROS themselves are autocrine forward regulators of the immune response. Most of the beneficial effects of antioxidants are considered to derive from their influence on the immune system. Due to their antioxidant and/or radical scavenging nature, phytochemicals, botanicals and herbal preparations can be of great importance to prevent oxidation processes and to counteract the activation of redox-regulated signaling pathways. Antioxidants can antagonize the activation of T-cells and macrophages during the immune response and this anti-inflammatory activity could be of utmost importance for the treatment of above-mentioned disorders and for the development of immunotolerance. Herein, we provide an overview of in vitro assays for the measurement of antioxidant and anti-inflammatory activities of plant-derived substances and extracts, by discussing possibilities and limitations of these methods. To determine the capacity of antioxidants, the oxygen radical absorbance capacity (ORAC) assay and the cell-based antioxidant activity (CAA) assay are widely applied. To examine the influence of compounds on the human immune response more closely, the model of mitogen stimulated human peripheral blood mononuclear (PBMC) cells can be applied, and the production of the inflammatory marker neopterin as well as the breakdown of the amino acid tryptophan in culture supernatants can be used as readout to indicate an immunomodulatory potential of the tested compound. These two biomarkers of immune system activation are robust and correlate with the course of cardiovascular, neurodegenerative and malignant tumor diseases, but also with the normal aging process, and they are strongly predictive. Thus, while the simpler ORAC and CAA assays provide insight into one peculiar chemical aspect, namely the neutralization of peroxyl radicals, the more complex PBMC assay is closer to the in vivo conditions as the assay comprehensively enlights several properties of immunomodulatory test compounds.
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1α,25-Dihydroxyvitamin D3 and its analogs as modulators of human dendritic cells: a comparison dose-titration study.
Ferreira, GB, Overbergh, L, Verstuyf, A, Mathieu, C
The Journal of steroid biochemistry and molecular biology. 2013;:160-5
Abstract
The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), presents pronounced immunomodulatory effects, mainly mediated through its actions on different immune cells such as dendritic cells (DC) and T lymphocytes. Because of the high concentrations needed to obtain immune effects, a major limitation in using 1α,25(OH)2D3 in clinical immune therapy is its calcemic side effects. TX527 (19-nor-14,20-bis-epi-23-yne-1α,25(OH)2D3) is a structural 1α,25(OH)2D3 analog showing reduced calcemic activity with maintained immunomodulatory effects in vitro and in vivo. The aim of the present study was to establish the relative potency of TX527 versus the parent molecule as an immunomodulator in vitro. In this regard, we evaluated the morphology, surface marker expression and reactive oxygen species (ROS) production in in vitro-generated human DCs treated with TX527 or 1α,25(OH)2D3 at different concentrations. Human CD14(+) monocytes were differentiated toward immature DCs, in the presence or absence of 1α,25(OH)2D3 or TX527 in a dose range from 10(-7)M to 10(-10)M. Mature DCs (mDC) were obtained after exposure of cells to LPS/interferon (IFN) γ or cluster of differentiation (CD) 40 ligand (L). Both compounds potently inhibited down-regulation of the monocytic marker CD14 in mDCs. Interestingly, CD80 and HLA-DR were down-regulated after TX527 treatment, whereas this effect was lost when using 1α,25(OH)2D3 at the lowest concentration (10(-10)M). ROS production was especially induced in TX527-treated DCs, without any adverse effects on cell survival. Finally, this altered DC surface phenotype was accompanied by typical morphological features, with control cells forming large clusters of non-adherent cells, whereas TX527 and, to a lesser extent, 1α,25(OH)2D3-modulated cells yielding small clusters of mostly adherent spindle-shaped cells. This more pronounced immune potential in vitro combined with the previously shown decreased side effects on calcium and bone metabolism, makes TX527 a promising 1α,25(OH)2D3 analog for in vivo applications in autoimmune diseases and transplantation. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
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Enteral immunonutrition versus standard enteral nutrition for patients undergoing oesophagogastric resection for cancer.
Mabvuure, NT, Roman, A, Khan, OA
International journal of surgery (London, England). 2013;(2):122-7
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Abstract
A best evidence topic in surgery was written according to a structured protocol. The question addressed was "In cancer patients undergoing oesophageal or gastric resection for cancer and requiring postoperative nutritional support, does enteral immunonutrition confer additional clinical benefits as compared to standard enteral nutrition? Two hundred and fifty-eight papers were identified by a search of the MEDLINE and EMBASE databases, of which six randomized controlled trials represented the best evidence to answer this clinical question. The authors, journal, date and country of publication, patient group, study group, relevant outcomes and results of these papers were tabulated. All six of these randomised controlled trials compared the clinical benefits of standard enteral nutrition with those of enteral nutrition supplemented with a variety of immune-modulating substances. The studies failed to demonstrate consistent differences in patients' postoperative clinical course, complications, length of hospital stay and inflammatory marker levels. Hence although there is reasonable evidence to suggest that immunonutrition improves humoral immunity as opposed to cellular immunity, this improvement does not result in reductions in infection rates or reduced hospital stay. There is currently not enough evidence to recommend routine immunonutrition in all patients undergoing oesophageal or gastric resection for cancer.
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A clinico-biochemical evaluation of the role of a herbal (Ayurvedic) immunomodulator in chronic periodontal disease: a pilot study.
Shetty, S, Bose, A, Sridharan, S, Satyanarayana, A, Rahul, A
Oral health and dental management. 2013;(2):95-104
Abstract
BACKGROUND Host modulation is fast gaining popularity as a preferred therapeutic modality for periodontal disease. Recent research in the medical field into herbal immunomodulators such as Septilin® has spurred an interest in evaluating its efficacy in periodontitis for the first time. AIM: The aim of the study was to assess the immunomodulatory effects of the herbal immunomodulator Septilin® (Himalaya Drug Company, Bangalore, India) when used as an adjunct to scaling and root planing in chronic periodontal disease. METHODS Forty systemically healthy patients aged between 25 and 55 years of age and with chronic periodontitis were randomly divided into two groups. The test group was administered Septilin® tablets for two weeks following scaling and root planing whereas the control group was treated by scaling and root planing alone. Changes in gingival index (GI), gingival bleeding index (GBI), serum C-reactive protein (CRP) levels and salivary tumour necrosis factor-alpha (TNF-α) levels were assessed at day 0, at two weeks, and at three and six months. RESULTS The GI and GBI showed a statistically significant reduction at two weeks, three months and six months (P<0.001) in both groups. Salivary TNF-α level reduction was significant in the test group only (P<0.001). No significant change was found in serum CRP levels in both groups (P>0.05). CONCLUSION In this pilot evaluation, Septilin® was found to be a safe and effective immunomodulator as an adjunct to routine periodontal therapy. Further long-term studies to test Septilin® on larger sections of the population are recommended.
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Ascorbic acid has superior ex vivo antiproliferative, cell death-inducing and immunomodulatory effects over IFN-α in HTLV-1-associated myelopathy.
Moens, B, Decanine, D, Menezes, SM, Khouri, R, Silva-Santos, G, Lopez, G, Alvarez, C, Talledo, M, Gotuzzo, E, de Almeida Kruschewsky, R, et al
PLoS neglected tropical diseases. 2012;(7):e1729
Abstract
BACKGROUND Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP. PRINCIPAL FINDINGS Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes. CONCLUSIONS In comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.
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Evidence of immunomodulatory effects of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486.
You, J, Yaqoob, P
FEMS immunology and medical microbiology. 2012;(3):353-62
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Abstract
Bifidobacterium longum bv. infantis CCUG 52486 was originally isolated from healthy elderly subjects and demonstrated to have particular ecological fitness and anti-pathogenic effects. Bifidobacteria are commonly associated with immuno-modulatory properties, especially in older people, but this strain has not been investigated for effects on immune function. This study aimed to explore the immunomodulatory effects of this novel probiotic, compared with three commercial strains, B. longum SP 07/3, Lactobacillus rhamnosus GG (L.GG) and Lactobacillus casei Shirota (LcS). Human peripheral blood mononuclear cells (PBMCs) were isolated from fasting blood of young or older volunteers and exposed to probiotic strains or Con A. NK activity and activation, and cytokine release was enhanced by all probiotics with strain specificities. The effect of B. infantis on NK activity was influenced by ageing. Except for L.GG, probiotics increased IFN-γ production to a much greater degree in young subjects and increased IL-6 production to a much greater degree in older subjects. Based on IL-10/IL-12 ratios, B. infantis resulted in the most anti-inflammatory profile of all of the probiotics. These results suggest that B. infantis CCUG 52486 has strong immunomodulatory potential compared with well-known commercial strains and that the immune response to probiotics may be influenced by ageing.