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Schlicher, L., P. Kulig, M. Murphy, and M. Keller. "AB0024 IN VITRO CHARACTERIZATION OF CENERIMOD, A POTENT AND SELECTIVE SPHINGOSINE 1-PHOSPHATE RECEPTOR 1 (S1P1) MODULATOR IN PREVENTING MIGRATION OF NON-ACTIVATED AND ACTIVATED PRIMARY HUMAN B CELLS IN THE PRESENCE OR ABSENCE OF GLUCOCORTICOIDS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1046.1–1046. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2482.
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Background:Cenerimod is a potent, selective, and orally active sphingosine 1-phosphate receptor 1 (S1P1) modulator that is currently being evaluated in a Phase 2b study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P1 receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including B lymphocytes) in the blood stream and in inflamed tissues. Extensive clinical experience has become available for the nonselective S1P receptor modulator fingolimod in relapsing forms of multiple sclerosis, supporting this therapeutic concept for the treatment of autoimmune disorders.Objectives:Although the effect of S1P-receptor modulators in reducing peripheral B cells is well documented1,2, the role of the S1P1 receptor on this cell type is only incompletely understood. In this study, the mode of action of cenerimod on primary human B cells was investigated in a series of in vitro experiments, including S1P1 receptor cell surface expression and chemotaxis towards S1P. Moreover, S1P1 expression following B cell activation in vitro was studied. As glucocorticoids (GC) are frequently used in the treatment of patients with autoimmune disorders including SLE, the potential influence of GC on the mode of action of cenerimod was evaluated.Methods:Primary human B lymphocytes from healthy donors were isolated from whole blood. In one set of experiments, cells were treated with different concentrations of cenerimod to measure S1P1 receptor internalization by flow cytometry. In a second set of experiments, isolated B cells were activated using different stimuli or left untreated. Cells were then analysed for S1P1 and CD69 cell surface expression and tested in a novel real-time S1P-mediated migration assay. In addition, the effect of physiological concentrations of GCs (prednisolone and prednisone) on cenerimod activity in preventing S1P mediated migration was tested.Results:In vitro, cenerimod led to a dose-dependent internalization of the S1P1 receptor on primary human B lymphocytes. Cenerimod also blocked migration of nonactivated and activated B lymphocytes towards S1P in a concentration-dependent manner, which is in line with the retention of lymphocytes in the lymph node and the reduction of circulating lymphocytes observed in the clinical setting. Upon B cell activation, which was monitored by CD69 upregulation, a simultaneous downregulation of S1P1 expression was detected, leading to less efficient S1P-directed cell migration. Importantly, physiological concentrations of GC did not affect the inhibitory activity of cenerimod on B cell migration.Conclusion:These results show that cenerimod, by modulating S1P1, blocks B lymphocyte migration towards its natural chemoattractant S1P and demonstrate compatibility of cenerimod with GC. These results are consistent with results of comparable experiments done previously using primary human T lymphocytes.References:[1]Nakamura M et al., Mult Scler. 2014 Sep; 20(10):1371-80.[2]Strasser DS et al., RMD Open 2020;6:e001261.Disclosure of Interests:None declared
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Flygare, Johan, Violeta Rayon Estrada, Chanseok Shin, Sumeet Gupta, and Harvey Lodish. "Stress Erythropoiesis: HIF-1 Alpha Synergizes with Glucocorticoids to Induce BFU-E Progenitor Self-Renewal." Blood 116, no. 21 (November 19, 2010): 814. http://dx.doi.org/10.1182/blood.v116.21.814.814.
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Abstract Abstract 814 The goal of this study was to find small molecules that stimulate erythropoiesis at an earlier stage than erythropoietin (Epo). We therefore studied the mechanisms by which glucocorticoids (GCs) promote erythroblast formation during stress erythropoiesis (SE). Since the target cell of GCs in SE was not known we first established a FACS-based method to purify burst-forming unit erythroid (BFU-E) and colony-forming unit of erythroid lineage (CFU-E) cells from mouse fetal liver. BFU-E and CFU-E cells were resolved by differences in CD71 or CD24a expression (BFU-E = CD71/CD24a10% low; CFU-E = CD71/CD24a20% high) from a population of cells positive for Kit, and negative for the cell surface markers Ter119, B220, Mac-1, CD3, Gr-1, Sca-1, FcGR, CD41 and CD34. Purified “BFU-E” cells formed 94% BFU-E colonies and “CFU-E” cells formed 95% CFU-E colonies at cloning efficiencies of 55–70%. Using pure CFU-E and BFU-E progenitors we demonstrated that while 100nM Dexamethasone (Dex) does not increase proliferation or self-renewal of CFU-E cells, Dex stimulates the earlier BFU-E progenitors to undergo limited self-renewal, which increases formation of CFU-E cells and erythroblasts >20-fold. After identifying BFU-E progenitors as the target cells of GCs during SE, we next determined how DEX changes miRNA and mRNA expression in BFU-Es by next generation sequencing. No miRNAs changed the level of expression more than 50%. Of the 10,000 most expressed mRNAs 83 were up-regulated and 112 mRNAs down-regulated more than 2-fold in response to Dex. Since previous studies show that dimerization (trans activation) of the GC receptor is necessary for GCs to induce erythroblast production, the most important GC target genes are likely up- rather than down-regulated. We hypothesized that other molecules that are able to enhance the expression of the 83 up-regulated genes could enhance or replace the stimulatory effect of Dex. We therefore computationally analyzed the promoter regions of the up-regulated genes using motif enrichment analysis. We found that Dex induces expression of genes in BFU-E cells that contain promoter regions highly enriched for hypoxia-induced factor 1 alpha (HIF1a) binding sites (p-value = 1e–27). Analysis of six published gene expression datasets, where the effect of GCs on gene expression had been determined in cell types other than BFU-E cells, showed very low or no enrichment of HIF1a targets among genes up-regulated by Dex. We confirmed the suggested overlapping effects of HIF1a and GCs on gene expression in BFU-E cells by comparing the effect of Dex with that of pharmacological HIF1a activation by the prolyl hydroxylase inhibitor (PHI) Dimethyloxalylglycine (DMOG). As determined by next generation mRNA sequencing, DMOG increased expression of 98 genes more than 50%, of which 28 were among 109 genes up-regulated >50% by Dex (p-value for overlap = 1e–26). Importantly the overlap in effects on gene expression also resulted in overlapping biological effects. Similar to Dex, DMOG had little effect on CFU-E cells (Figure A). In contrast DMOG synergized with Dexamethasone to promote BFU-E self-renewal and prevent BFU-E cell exhaustion, enhancing the production of CFU-E cells 170-fold and maximum erythroblast production 300-fold (Figure B). DMOG thus enhanced the stimulatory effect of 100nM Dex on erythroblast production 7-fold. In similar experiments where BFU-E cells were cultured in GCs levels corresponding to physiological cortisol levels (1 nM Dex), DMOG enhanced erythroblast production 10-fold. We further showed that DMOG and Dex also synergistically enhance proliferation of adult mouse and human erythroid progenitors. Our results support a physiological model of SE where increased systemic levels of free cortisol, in combination with local anoxia, induce BFU-E self-renewal and increase erythroblast production. This suggests that the therapeutic potential for PHIs in treatment for anemia goes beyond replacing recombinant Epo. Here we show that in addition to enhancing Epo production from the kidneys, PHIs have an intrinsic stimulatory effect on BFU-E progenitors, leading to increased production of Epo-responsive CFU-E cells. Thus PHIs provide a new window for treating Epo-resistant anemia. The synergistic effect of GCs and PHIs further suggests that PHIs may enhance or replace the effect of Prednisone in the treatment of Diamond-Blackfan Anemia and other bone marrow failure syndromes. Disclosures: No relevant conflicts of interest to declare.
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Filaretova, Ludmila, Tatiana Podvigina, and Natalia Yarushkina. "Physiological and Pharmacological Effects of Glucocorticoids on the Gastrointestinal Tract." Current Pharmaceutical Design 26, no. 25 (August 4, 2020): 2962–70. http://dx.doi.org/10.2174/1381612826666200521142746.
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The review considers the data on the physiological and pharmacological effects of glucocorticoids on the gastric mucosa and focuses on the gastroprotective role of stress-produced glucocorticoids as well as on the transformation of physiological gastroprotective effects of glucocorticoids to pathological proulcerogenic consequences. The results of experimental studies on the re-evaluation of the traditional notion that stress-produced glucocorticoids are ulcerogenic led us to the opposite conclusion suggested that these hormones play an important role in the maintenance of the gastric mucosal integrity. Exogenous glucocorticoids may exert both gastroprotective and proulcerogenic effects. Initially, gastroprotective effect of dexamethasone but not corticosterone, cortisol or prednisolone can be transformed into proulcerogenic one. The most significant factor for the transformation is the prolongation of its action rather the dose. Gastrointestinal injury can be accompanied by changes in somatic pain sensitivity and glucocorticoids contribute to these changes playing a physiological and pathological role.
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Saxenhofer, Hermann, Martin Angst, Peter Weidmann, Sidney G. Shaw, and Claudia Ferrier. "Corticosteroid-induced stimulation of atrial natriuretic peptide in man." Acta Endocrinologica 118, no. 2 (June 1988): 179–86. http://dx.doi.org/10.1530/acta.0.1180179.
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Abstract. Previously, we reported elevated plasma immunoreactive ANP (irANP) levels from the 2nd to the 9th day of administering either prednisone, 50 mg/day, or 9α-fludrocortisone acetate (9αF), 0.6 mg/day, to normal humans. To investigate the course of plasma irANP levels during the first 48 h of corticosteroid adminstration, 9 healthy men (mean age ± sem, 24 ± 1 years) received in randomised sequence A) a 4-h iv infusion of prednisolone sodium tetrahydrophthalate followed by oral administration of prednisone for 2 days; or B) a 4-h infusion of aldosterone followed by oral administration of 9αF for 2 days. Basal supine plasma irANP levels averaged 32 ± 5 ng/l in study A and 30 ± 6 ng/l in study B; they were unchanged or even deceased up to 24 h of glucocorticoid or mineralocorticoid administration, but rose (P < 0.01) to 56 ± 9 and 62 ± 12 ng/l at 48 h, respectively, of the two interventions. During glucocorticoid treatment, blood pressure (BP) and indices of the sodium-fluid volume state were unchanged after 48 h. During 9αF administration, body weight increased (1.1 ± 0.3%, P < 0.001), whereas urinary sodium excretion (63 ±7%, P < 0.001), hematocrit (4.1 ± 1.1%, P < 0.001), and plasma renin activity (38 ± 4%, P < 0.001) decreased. Conclusions: The increase in circulating irANP at 48 h of administration of either a glucocorticoid or a mineralocorticoid demonstrates a distinct but slow response of the ANP system to these corticosteroids in normal humans. ANP may play a potential role in mediating and/or modulating physiological and pathophysiological effects of corticosteroids.
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Mullier, François, Severine Robert, Philippe Devel, Lutfiye Alpan, Nicolas Lufin, Bernard Chatelain, and Jean-Michel Dogné. "Pharmacological Study of Antimyeloma Agents on Hemostasis." Blood 116, no. 21 (November 19, 2010): 3175. http://dx.doi.org/10.1182/blood.v116.21.3175.3175.
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Abstract Abstract 3175 Introduction: Patients with multiple myeloma (MM) have an increasing risk of developing venous thromboembolism (VTE). The use of thalidomide or lenalidomide, two antimyeloma agents has been associated with an increased risk of VTE especially when associated with dexamethasone or melphalan-prednisone. This increased risk in less pronounced with the proteasome inhibitor bortezomib. The pharmacological effects of thalidomide, lenalidomide and bortezomib have never been studied on platelet aggregation or coagulation. These preliminary data are necessary to understand the differential effects of these drugs on thrombotic events. Aims: The aim of our study is to investigate the pharmacological effects of these drugs on primary hemostasis by light transmission agregometry (LTA) and on secondary hemostasis using thrombin generation test (TGT). Methods: LTA was performed with a Chrono-Log aggregometer (Kordia). Platelet-rich plasma (PRP) of healthy blood donors (n=3 to 10) was adjusted to 300,000 platelets/μl. Platelet-poor plasma (PPP) and PRP were used respectively to adjust the photometric measurement to the minimum and maximum optical density. The platelet reactivity of the healthy donors was previously checked by LTA. Thalidomide (racemic, enantiomer (+) and enantiomer (-)), lenalidomide and bortezomib were spiked at final concentration of 200 μM in PRP except for studying the influence of thalidomide on ADP-induced platelet aggregation where the maximal concentration usable was 100 μM. LTA was performed without (spontaneous aggregation) and with addition of 5μM ADP, 190μg/ml collagen, 600μM arachidonic acid (AA) and 10 μM PAR1-AP (final concentrations). Negative controls (physiological saline and DMSO at concentrations used to dissolve the drugs) were also included. TGT was performed both on PPP (from normal pool plasma (NPP)) and on PRP. We first validated the method on NPP and PRP with two anticoagulants: a thrombin direct inhibitor (i.e. argatroban) and a FXa direct inhibitor (i.e. ZK-807834). Thalidomide ((+/−), (+) and (-)), lenalidomide and bortezomid were tested at the final concentrations of 5, 10, 50, 100 and 200 μM. For the experiments on NPP, PPP reagent (5 pM TF + 4 μM PL in the final assays), PPP reagent low (1 pM TF + 4 μM PL in the final assays) and MP reagent (4 μM PL in the final assays) were used whereas for the experiments on PRP, PRP reagent (1 pM TF in the final assays) was used. Results: LTA Both three drugs did not induce spontaneous aggregation until 200 μM. Lenalidomide and bortezomib showed no effect on induced platelet aggregation until 200 μM, whatever the agonist used. On the contrary, for racemic thalidomide, platelet aggregation was reduced at 50 and 100 μM with 5 μM ADP and at 150 and 200 μM with 600 μM AA. These effects were more pronounced with thalidomide (+) than with thalidomide (-). So, the half maximal inhibitory concentrations (IC50) for platelet aggregation induced by 600 μM AA were 127, 143 and 221 μM for racemic, enantiomer (+) and enantiomer (-), respectively. When 190μg/ml collagen or 10 μM PAR1-AP were used as agonists, no effect was observed on platelet aggregation until 200 μM thalidomide. TGT. With argatroban and ZK-807834, we observed a concentration-dependent decrease and delay of the thrombin activity profiles in PRP and NPP, whatever the inducer used. No significant effect on thrombin activity in NPP or PRP has been observed for antimyeloma drugs at all concentrations tested, whatever the inducer used. Conclusions: Lenalidomide, thalidomide and bortezomid do not induce spontaneous platelet aggregation and do not affect platelet aggregation induced by collagen or PAR1-AP. Conversely to lenalidomide and bortezomib, thalidomide, and especially its enantiomer (+), moderately inhibits platelet aggregation induced by ADP and AA. Moreover, these antimyeloma agents have no effect on thrombin generation. The increased risk of VTE by thalidomide or lenalidomide in patients with multiple myeloma is thus not mediated by a direct impact on primary or secondary hemostasis at therapeutic concentrations. Disclosures: No relevant conflicts of interest to declare.
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Kirimi, E., O. Tuncer, M. Kösem, E. Ceylan, A. Tas, I. Tasal, R. Balahoroğlu, and H. Caksen. "The Effects of Prednisolone and Serum Malondialdehyde Levels in Puppies with Experimentally Induced Meconium Aspiration Syndrome." Journal of International Medical Research 31, no. 2 (April 2003): 113–22. http://dx.doi.org/10.1177/147323000303100207.
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The aim of this study was to investigate the effect of different doses of prednisolone in puppies experimentally induced with meconium aspiration syndrome (MAS). Meconium was collected from human babies in the first day of life and was released into the trachea of 11 newborn puppies to induce MAS. Puppies were treated with 2 mg/kg prednisolone (standard dose), 30 mg/kg prednisolone (megadose) or 0.9% saline, all administered intravenously. The study ended 20 h after meconium aspiration and the lungs were then scored for histopathology. Animals not treated with prednisolone deteriorated after 8 h while respiration rate, oxygenation, pH and partial pressure of carbon dioxide values were better in the prednisolone-treated groups. Histopathology scores were better in the treatment groups compared with the control group, with megadose giving the best result. At the end of the study, serum malondialdehyde levels were significantly higher in the megadose prednisolone group compared with the other two groups. In conclusion, we determined that prednisolone reduced physiological and histological changes in puppies with MAS and that a 30 mg/kg dose was more effective than 2 mg/kg.
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Walker, John WT, Lai Xu, Michael Smylie, and Shokrollah Elahi. "Effect of high-dose corticosteroids on CD4+ or CD8+ lymphocyte proliferation or IL-2 production after stimulation with pembrolizumab." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e14587-e14587. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14587.
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e14587 Background: Immune checkpoint inhibitor (ICI) therapy has improved survival of patients with melanoma and other types of cancers. The effect of immunosuppresive corticosteroids on ICI efficacy is unknown, however treatment of immune-related adverse events with high-dose steroid therapy impairs neither efficacy nor time to failure of ICI. In certain clinical circumstances (for instance in the treatment of patients with symptomatic brain metastases) it may be advantageous to begin ICI therapy despite a requirement for steroid therapy. This study examined the effect of high-dose steroid therapy on lymphocyte proliferation/functionality after stimulation with anti-CD3 in the presence of pembrolizumab (PD-1 inhibitor) ex vivo. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from patients with either chronic hepatitis C infection or active malignant melanoma. CD4+ and CD8+ T cells were isolated and subjected to flow cytometry stating for the expression of PD-1. Isolated PBMCs were then pre-treated with prednisone (1 nM - 1 mM) before anti-CD3 stimulation. Anti-CD3-stimulated cells were then incubated with pembrolizumab (5 µg/mL) and their proliferative capacity and IL-2 secretion ability were measured by carboxyfluorescein succinimidyl ester (CFSE) staining and ELISA, respectively. Results: A dose-dependent inhibition of both lymphocyte proliferation and IL-2 production was observed, but at physiologically relevant nanomolar prednisone concentration the steroid effect was negligible. Millimolar prednisone concentrations resulted in > 50% relative reduction in lymphocyte proliferation, however even at this steroid concentration treatment with pembrolizumab was able to further stimulate proliferation and IL-2 secretion versus anti-CD3stimulation alone. Conclusions: Despite heavily immunosuppressive treatment, CD4+ and CD8+ lymphocytes demonstrate proliferative capacity and immunological activity following treatment with pembrolizumab. This suggests that treatment with pembrolizumab may be efficacious despite a requirement for steroid therapy, a scenario often encountered in patients with brain metastases.
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HAYAKAWA, TARO, NOBUHITO SHIBATA, NOBUO HOSHINO, TOKUZO MINOUCHI, AKIRA YAMAJI, KANJI TAKADA, HAJIME ABE, MASASHI KODAMA, KYUN IL PARK, and TADAO TOMOYOSHI. "Effects of Prednisolone on the Physiological Factors Regulating Cyclosporin A Blood Distribution in Renal Transplant Patients." Japanese Journal of Hospital Pharmacy 23, no. 4 (1997): 289–96. http://dx.doi.org/10.5649/jjphcs1975.23.289.
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Frey, Kathrin R., Tina Kienitz, Julia Schulz, Manfred Ventz, Kathrin Zopf, and Marcus Quinkler. "Prednisolone is associated with a worse bone mineral density in primary adrenal insufficiency." Endocrine Connections 7, no. 6 (June 2018): 811–18. http://dx.doi.org/10.1530/ec-18-0160.
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Context Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) receive life-long glucocorticoid (GC) therapy. Daily GC doses are often above the physiological cortisol production rate and can cause long-term morbidities such as osteoporosis. No prospective trial has investigated the long-term effect of different GC therapies on bone mineral density (BMD) in those patients. Objectives To determine if patients on hydrocortisone (HC) or prednisolone show changes in BMD after follow-up of 5.5 years. To investigate if BMD is altered after switching from immediate- to modified-release HC. Design and patients Prospective, observational, longitudinal study with evaluation of BMD by DXA at visit1, after 2.2 ± 0.4 (visit2) and after 5.5 ± 0.8 years (visit3) included 36 PAI and 8 CAH patients. Thirteen patients received prednisolone (age 52.5 ± 14.8 years; 8 women) and 31 patients received immediate-release HC (age 48.9 ± 15.8 years; 22 women). Twelve patients on immediate-release switched to modified-release HC at visit2. Results Prednisolone showed significantly lower Z-scores compared to HC at femoral neck (−0.85 ± 0.80 vs −0.25 ± 1.16, P < 0.05), trochanter (−0.96 ± 0.62 vs 0.51 ± 1.07, P < 0.05) and total hip (−0.78 ± 0.55 vs 0.36 ± 1.04, P < 0.05), but not at lumbar spine, throughout the study. Prednisolone dose decreased by 8% over study time, but no significant effect was seen on BMD. BMD did not change significantly after switching from immediate- to modified-release HC. Conclusions The use of prednisolone as hormone replacement therapy results in significantly lower BMD compared to HC. Patients on low-dose HC replacement therapy showed unchanged Z-scores within the normal reference range during the study period.
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Kang, Seong Soo, Sok Cheon Pak, and Seok Hwa Choi. "The Effect of Whole Bee Venom on Arthritis." American Journal of Chinese Medicine 30, no. 01 (January 2002): 73–80. http://dx.doi.org/10.1142/s0192415x02000089.
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This study was performed to assess the clincotherapeutic effect of whole venom of honeybee (Apis mellifera) in adjuvant-induced arthritic rat. Ninety Sprague-Dawley male rats were injected with complete Freund's adjuvant (CFA). Adjuvant arthritis was produced by a single subcutaneous injection of 1 mg Mycobacterium butyricum suspended in 0.1 ml paraffin oil into the right hind paw. Righting reflex was uniformly lost and considered to be the point of arthritis development on day 14 after CFA injection. The experiments were divided into three groups. When arthritis was developed in the rat, tested groups were administered with prednisolone (10 mg/kg, p.o.) or honeybee venom (one bee, s.c.) every other day for another 14 days. Control group was injected with 0.1 ml of physiological saline solution subcutaneously. Clinical and hematological values with histopathological findings were observed during the drug administration. In treatment groups, the development of inflammatory edema and polyarthritis was suppressed. No significant differences of hind paw edema volume and lameness score between prednisolone and honeybee venom groups were observed during treatment. White blood cell counts of control group showed leucocytosis that was significantly different from the two treatment groups (p < 0.01). Erosions of articular cartilage and inflammatory cell infiltrations into interphalangeal joint were effectively suppressed in treated groups. In conclusion, whole honeybee venom was found to suppress arthritic inflammation in the rat. This may be an alternative treatment of arthritic agony in humans.
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McNeil, Paul L., Carolina Nebot, and Katherine A. Sloman. "Physiological and Behavioral Effects of Exposure to Environmentally Relevant Concentrations of Prednisolone During Zebrafish (Danio rerio) Embryogenesis." Environmental Science & Technology 50, no. 10 (April 28, 2016): 5294–304. http://dx.doi.org/10.1021/acs.est.6b00276.
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Kox, Corinne, Svenja Leible, Stephen Breit, Martin Stanulla, Martin Schrappe, Martina Ulrike Muckenthaler, and Andreas Kulozik. "Notch Pathway Activation by a Combination of Activating NOTCH1-Receptor and Inactivating FBXW7 Mutations Robustly Predicts Excellent Early Treatment Response in Pediatric T-ALL." Blood 112, no. 11 (November 16, 2008): 1493. http://dx.doi.org/10.1182/blood.v112.11.1493.1493.
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Abstract In contrast to pre B-ALL, robust DNA-based biomarkers with prognostic and predictive value are not available in T-ALL. We have previously shown that common activating mutations of the NOTCH1 receptor predict good early treatment response and excellent long term outcome in T-ALL (Breit et al., Blood 2006). We now aimed at analyzing if recently described inactivating mutations of FBXW7, the E3 ubiquitin ligase of NOTCH, contribute to the predictive power of the Notch1 pathway activation in pediatric T-ALL. Figure Figure We genotyped FBXW7 in 137 T-ALL and found inactivating mutations in 22 patients. We next analyzed the influence of this mutation on treatment response and found that most patients with FBXW7 mutations showed a prednisone good response (PGR; 19/22), whereas PGR was observed in only 58/115 with no FBWX7 mutation (p=0.0006). This beneficial effect of FBXW7 inactivating mutations is enhanced when the NOTCH1 mutational status was considered. Among 17 patients with NOTCH1 and FBXW7 mutations, only 1 showed a prednisone poor response (PPR; p=0.0003). These results suggest a synergistic effect of NOTCH1 and FBXW7 mutations in early treatment response in pediatric T-ALL. Notably, FBXW7 mutations occur in the group of leukemias with NOTCH1 heterodimerisation (HD) domain mutations only and do not occur in those with truncations of the PEST domain, where FBXW7 physiologically targets NOTCH for degradation. One might thus predict that patients with NOTCH1-HD/PEST double mutations would be biologically similar to those with NOTCH1-HD/FBXW7 double mutations. A comparison of early treatment response between these groups indeed showed PGR in 10/13 patients with NOTCH1-HD/PEST and 16/17 with NOTCH1-HD/FBXW7 status. Furthermore, these groups taken together exhibit a significantly better prednisone response than both, the patients with single mutations in either NOTCH1 or in FBXW7 or those with detectable mutations in neither NOTCH1 nor FBWX7 (see bar diagram). These data indicate that activation of the Notch1 pathway by a combination of receptor gain of function mutations and inactivating mutations of its E3 ubiquitin ligase has a strong favorable effect on in-vivo prednisone sensitivity. Notch pathway activation may thus define a novel group of biomarkers that predict early treatment response and thus help to stratify risk of children and adolescents with T-ALL.
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Van Der Zwet, Jordy C. G., Jessica G. C. A. M. Buijs-Gladdines, Valentina Cordo', Donna Debets, Willem K. Smits, Zhongli Chen, Jelle Dylus, et al. "The Central Role of MAPK-ERK Signaling in IL7-Dependent and IL7-Independent Steroid Resistance Reveals a Broad Application of MEK-Inhibitors Compared to JAK1/2-Inhibition in T-ALL." Blood 136, Supplement 1 (November 5, 2020): 20. http://dx.doi.org/10.1182/blood-2020-139305.
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Introduction Poor prednisolone response in the induction phase of treatment is a risk-stratification marker in the current Dutch DCOG ALL-11 treatment protocol. Physiological or mutational activation of the IL7-receptor (IL7R) provokes steroid resistance in T-ALL. Moreover, relapsed T-ALL patients that harbor IL7R or RAS mutations are considered as an ultra-high-risk group with extremely poor outcome. Aim We studied the contribution of two key IL7R downstream pathways (STAT5B and MAPK-ERK respectively) to steroid resistance in order to optimize future treatment regimens. Results To date, IL7-dependent steroid resistance has been proposed to depend on IL7-induced JAK-STAT signaling and subsequent BCL2 upregulation. Here, we demonstrate that the transforming STATBN642H mutation does not impair steroid sensitivity despite a paradoxical upregulation of BCL2 and BCLXL following steroid treatment. We therefore hypothesized that other pathways contribute to IL7-dependent steroid resistance in T-ALL. By studying T-ALL PDX samples, we observed that physiological IL7-signaling can activate the MAPK-ERK pathway in IL7-dependent and IL7-independent steroid resistant PDX cells. Similar to mutational-driven MAPK-ERK signaling (e.g. by activating IL7R, JAK1 or NRAS mutations), IL7-induced MAPK-ERK signaling leads to the inactivation of the pro-apoptotic protein BIM by inhibitory phosphorylation of both BIM-EL and BIM-L isoforms. By mass spectrometry, we observe that phosphorylated BIM specifically decreases its physical interaction with Aurora kinase A and Bcl-2 family members BMF, BCL2, BCLXL and MCL1, which alters the apoptotic threshold and effectuates steroid resistance. The JAK1/2-inhibitor ruxolitinib and MEK-inhibitor selumetinib are considered for future basket-treatment protocols in IL7R/JAK-STAT-activated or MAPK-ERK-activated leukemias respectively. We demonstrate that both ruxolitinib and selumetinib prevent IL7-induced MAPK-ERK signaling in T-ALL PDX cells. Moreover, ruxolitinib and selumetinib abolish BIM phosphorylation in mutant JAK1-overexpressing SUPT-1 cells, which restores the binding of BIM to BCL2, BCLXL and MCL1. Only selumetinib restores the function of BIM in wild type or mutant NRAS overexpressing SUPT-1 cells, indicating that ruxolitinib only blocks MAPK-ERK signaling in the context of 'upstream' (e.g. mutant IL7R/JAK1 or IL7-induced) pathway activation. Surprisingly, none of our 46 PDX samples respond to ruxolitinib treatment in the absence of IL7, while the majority of these samples demonstrate a robust response towards MEK-inhibition. IL7-dependent steroid resistant PDX samples do respond to ruxolitinib treatment in the presence of IL7, while IL7 exposed IL7-independent steroid resistant PDX samples remain unresponsive to ruxolitinib. We therefore conclude that the therapeutic effect of ruxolitinib is dependent on an IL7-protective effect, limiting its therapeutic application to a selective subset of T-ALL patients. When we combine prednisolone treatment with selumetinib or ruxolitinib, we observe that ruxolitinib only synergizes with prednisolone in IL7-dependent steroid resistant PDX samples in the presence of IL7. Importantly, combination treatment with prednisolone and selumetinib acts highly synergistic in IL7-dependent and IL7-independent steroid resistant samples in the presence and absence of IL7. Conclusion and clinical relevance In addition to described JAK-STAT and PI3K-AKT signaling, our study demonstrates that IL7-induced signaling activates the MAPK-ERK signaling pathway, which actively contributes to IL7-dependent steroid resistance. We demonstrate the central importance of MAPK-ERK signaling in T-ALL, whereas all T-ALL PDX samples tested highly benefit from combined prednisolone and selumetinib treatment. Ruxolitinib only acts synergistically with steroids in the context of IL7-dependent steroid resistance. Moreover, our data proposes that this synergistic effect may (in part) depend on the anti-MAPK-ERK effect downstream of JAK1/2-inhibition. Combined, our study strongly supports the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507), and contributes to the optimization and stratification of newly designed T-ALL treatment regimens. Disclosures Bourquin: Servier: Other: Travel Support. Vormoor:AstraZeneca: Research Funding.
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Tarnopolsky, M. A., J. M. Bourgeois, R. Snow, S. Keys, B. D. Roy, J. M. Kwiecien, and J. Turnbull. "Histological assessment of intermediate- and long-term creatine monohydrate supplementation in mice and rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 285, no. 4 (October 2003): R762—R769. http://dx.doi.org/10.1152/ajpregu.00270.2003.
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Creatine monohydrate (CrM) supplementation appears to be relatively safe based on data from short-term and intermediate-term human studies and results from several therapeutic trials. The purpose of the current study was to characterize pathological changes after intermediate-term and long-term CrM supplementation in mice [healthy control and SOD1 (G93A) transgenic] and rats (prednisolone and nonprednisolone treated). Histological assessment (18-20 organs/tissues) was performed on G93A mice after 159 days, and in Sprague-Dawley rats after 365 days, of CrM supplementation (2% wt/wt) compared with control feed. Liver histology was also evaluated in CD-1 mice after 300 days of low-dose CrM supplementation (0.025 and 0.05 g · kg-1 · day-1) and in Sprague-Dawley rats after 52 days of CrM supplementation (2% wt/wt) with and without prednisolone. Areas of hepatitis were observed in the livers of the CrM-supplemented G93A mice ( P < 0.05), with no significant inflammatory lesions in any of the other 18-20 tissues/organs that were evaluated. The CD-1 mice also showed significant hepatic inflammatory lesions ( P < 0.05), yet there was no negative effect of CrM on liver histology in the Sprague-Dawley rats after intermediate-term or long-term supplementation nor was inflammation seen in any other tissues/organs ( P = not significant). Dietary CrM supplementation can induce inflammatory changes in the liver of mice, but not rats. The observed inflammatory changes in the murine liver must be considered in the evaluation of hepatic metabolism in CrM-supplemented mice. Species differences must be considered in the evaluation of toxicological and physiological studies.
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Akahoshi, T., J. J. Oppenheim, and K. Matsushima. "Induction of high-affinity interleukin 1 receptor on human peripheral blood lymphocytes by glucocorticoid hormones." Journal of Experimental Medicine 167, no. 3 (March 1, 1988): 924–36. http://dx.doi.org/10.1084/jem.167.3.924.
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The in vitro effect of glucocorticoids (GCs) on IL-1-R expression of human PBMCs was investigated. Both physiological and pharmacological concentration ranges of GC increased the specific binding of 125I-labeled human rIL-1 alpha to PBMCs. This enhancement was specific for GC, since other steroid hormones, such as progesterone, 17 beta-estradiol, and testosterone failed to elevate the binding of 125I-IL-1 alpha to PBMCs. The effect was time dependent with maximal effect occurring 6 h after treatment and dose dependent with half-maximal effect elicited by 100 nM prednisolone. Scatchard plot analysis indicated that 125I-IL-1 alpha binding increased from approximately 100 IL-1-R per cell to 2 X 10(3) receptors per cell without a major change in affinity (Kd = 2.6 X 10(-10) M). The subpopulation of PBMCs induced by GC to express higher levels of IL-1-R consisted predominantly of B lymphocytes, but not T lymphocytes, large granular lymphocytes, or monocytes. GCs also induced the expression of IL-1-R on some other cell types, including normal human dermal fibroblasts and the human large granular lymphocyte cell line YT. Since cycloheximide and actinomycin D inhibited the induction of IL-1-R by GC, synthesis of both new RNA and protein seems to be required for IL-1-R induction. This study presents the first evidence of upregulation of the receptors for IL-1 by GC, and may account for the reported enhancement of in vitro and in vivo humoral immune responses by GCs.
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Ma, Yun, Jeffry S. Nyman, Huan Tao, Heather H. Moss, Xiangli Yang, and Florent Elefteriou. "β2-Adrenergic Receptor Signaling in Osteoblasts Contributes to the Catabolic Effect of Glucocorticoids on Bone." Endocrinology 152, no. 4 (January 25, 2011): 1412–22. http://dx.doi.org/10.1210/en.2010-0881.
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Abstract The sympathetic nervous system is a physiological regulator of bone homeostasis. Autonomic nerves are indeed present in bone, bone cells express the β2-adrenergic receptors (β2AR), and pharmacological or genetic disruption of sympathetic outflow to bone induces bone gain in rodents. These recent findings implied that conditions that affect β2AR signaling in osteoblasts and/or sympathetic drive to bone may contribute to bone diseases. In this study, we show that dexamethasone stimulates the expression of the β2AR in differentiated primary calvarial osteoblasts, as measured by an increase in Adrβ2 mRNA and β2AR protein level after short-term dexamethasone treatment. Isoproterenol-induced cAMP accumulation and the expression of the β2AR target gene Rankl were also significantly increased after dexamethasone pretreatment, indicating that dexamethasone promotes the responsiveness of differentiated osteoblasts to adrenergic stimulation. These in vitro results led to the hypothesis that glucocorticoid-induced bone loss, provoked by increased endogenous or high-dose exogenous glucocorticoids given for the treatment of inflammatory diseases, might, at least in part, be mediated by increased sensitivity of bone-forming cells to the tonic inhibitory effect of sympathetic nerves on bone formation or their stimulatory effect on bone resorption. Supporting this hypothesis, both pharmacological and genetic β2AR blockade in mice significantly reduced the bone catabolic effect of high-dose prednisolone in vivo. This study emphasizes the importance of sympathetic nerves in the regulation of bone homeostasis and indicates that this neuroskeletal signaling axis can be modulated by hormones or drugs and contribute to enhance pathological bone loss.
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Loef, M., T. Faquih, J. Von Hegedus, M. Ghorasaini, A. Ioan-Facsinay, F. Kroon, M. Giera, and M. Kloppenburg. "POS1087 USING LIPIDOMICS TO PREDICT PREDNISOLONE TREATMENT RESPONSE IN PATIENTS WITH INFLAMMATORY HAND OSTEOARTHRITIS: THE HOPE STUDY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 822.1–823. http://dx.doi.org/10.1136/annrheumdis-2021-eular.19.
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Background:Lipidomics analysis has become a valuable technology for understanding patho-physiological mechanisms and may aid the identification of biomarkers of therapeutic responsiveness.Objectives:To explore the use of lipidomics for prediction of prednisolone treatment response in patients with inflammatory hand osteoarthritis.Methods:The Hand Osteoarthritis Prednisolone Efficacy (HOPE) study is a blinded, randomized placebo-controlled trial, that investigated the effect of prednisolone treatment in patients with painful, inflammatory hand OA, fulfilling the American College of Rheumatology criteria. The present analyses comprised only patients randomized to daily 10 mg prednisolone treatment for six weeks. Response to prednisolone treatment was defined according to the OARSI-OMERACT responder criteria at six weeks. Baseline blood samples were obtained non-fasted. Lipid species were quantified in erythrocytes with the LipidyzerTM platform (Sciex). After pre-processing of the data, 286 lipids species were available for further analyses (nmol/mL). In addition, we used an in-house LC-MS/MS platform to analyse oxylipins in plasma, identifying 25 oxylipins (area ratios). Elastic net regularized regression was used to predict prednisolone treatment response. A 10-fold cross-validation (CV) was performed for selection of the optimal tuning parameters based on the smallest CV mean prediction error. First, a model was fit with commonly assessed patient characteristics and patient reported outcomes, measured at baseline (model 1). Second, we fitted model 2 by adding the LipidyzerTM platform lipids to model 1. Third, we fitted model 3 by adding the oxylipins to model 1. The discriminatory accuracy of the model was estimated by receiver operating characteristic (ROC) analyses. The area under the curve (AUC) and corresponding 95% confidence intervals (CI) were calculated using 1,000 bootstrap replications.Results:Among the 40 patients included, 31 (78%) fulfilled the OARSI-OMERACT responder criteria. From the included general patient characteristics (Table 1), elastic net selected baseline hand function as only predictor of treatment response, with an AUC of 0.78 (95% CI 0.60;0.96) (Figure 1). In model 2, we added the 286 LipidyzerTM platform variables to model 1. In addition to hand function, two lipids were selected: diacylglycerol(DAG)(16:0/16:0) and phosphatidylethanolamine(PE)(O-18:0/20:4), which improved the discriminatory accuracy to an AUC of 0.92 (0.83;1.02). Lastly, model 3 was fit with patient characteristics as well as oxylipins, resulting in selection of AUSCAN function and three oxylipin predictors: 9-hydroxy-octadecatrienoic acid (HOTrE), 5-hydroxy-eicosapentaenoic acid (HEPE) and 10-hydroxy-docosahexaenoic acid (HDHA), with an AUC of 0.85 (0.69;1.02).Conclusion:The patients’ lipid profile improved the discriminative accuracy of the prediction of prednisolone treatment response in patients with inflammatory hand osteoarthritis compared to prediction by commonly measured patient characteristics alone. This exploratory study suggests that lipidomics is a promising field for biomarker discovery for prediction of anti-inflammatory treatment response.Table 1.Baseline characteristicsAll prednisolone treatedn = 40Respondersn = 31 (78%)Non-respondersn = 9 (23%)General characteristicsAge, year62.4 (9.3)62.9 (9.4)60.8 (9.4)Sex, % women858489BMI, kg/m227.4 (4.4)27.8 (4.2)26.2 (5.0)Education, % high464256Disease duration6.7 (7.1)7.2 (7.4)4.9 (5.8)Erosive OA, %717456Kellgren-Lawrence sum score, 0-12035.1 (16.4)34.1 (16.5)37.5 (14.7)Ultrasound synovitis sum score, 0-9016.2 (6.6)15.5 (6.4)18.7 (7.2)VAS global assessment, 0-10052.3 (20.6)54.2 (16.8)45.6 (30.8)AUSCAN pain, 0-2011.0 (3.3)11.3 (2.4)10 (5.4)AUSCAN function, 0-3617.7 (7.6)19.6 (6.6)11 (7.5)Numbers represent mean (SD) unless otherwise specified. AUSCAN = Australian/Canadian Hand Osteoarthritis Index, BMI = body mass index, VAS = visual analogue scaleDisclosure of Interests:Marieke Loef: None declared, Tariq Faquih: None declared, Johannes von Hegedus: None declared, Mohan Ghorasaini: None declared, Andreea Ioan-Facsinay: None declared, Féline Kroon: None declared, Martin Giera Shareholder of: Pfizer, Consultant of: Boehringer Ingelheim Pharma, Margreet Kloppenburg: None declared.
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Ohlsson, Claes, Karin H. Nilsson, Petra Henning, Jianyao Wu, Karin L. Gustafsson, Matti Poutanen, Ulf H. Lerner, and Sofia Movérare-Skrtic. "WNT16 overexpression partly protects against glucocorticoid-induced bone loss." American Journal of Physiology-Endocrinology and Metabolism 314, no. 6 (June 1, 2018): E597—E604. http://dx.doi.org/10.1152/ajpendo.00292.2017.
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Therapeutic use of glucocorticoids (GCs) is a major cause of secondary osteoporosis, but the molecular mechanisms responsible for the deleterious effects of GCs in bone are only partially understood. WNT16 is a crucial physiological regulator of bone mass and fracture susceptibility, and we hypothesize that disturbed WNT16 activity might be involved in the deleterious effects of GC in bone. Twelve-week-old female Obl-Wnt16 mice (WNT16 expression driven by the rat procollagen type I α1 promoter) and wild-type (WT) littermates were treated with prednisolone (7.6 mg·kg−1·day−1) or vehicle for 4 wk. We first observed that GC treatment decreased the Wnt16 mRNA levels in bone of female mice (−56.4 ± 6.1% compared with vehicle, P < 0.001). We next evaluated if WNT16 overexpression protects against GC-induced bone loss. Dual-energy X-ray absorptiometry analyses revealed that GC treatment decreased total body bone mineral density in WT mice (−3.9 ± 1.2%, P = 0.028) but not in Obl-Wnt16 mice (+1.3 ± 1.4%, nonsignificant). Microcomputed tomography analyses showed that GC treatment decreased trabecular bone volume fraction (BV/TV) of the femur in WT mice ( P = 0.019) but not in Obl-Wnt16 mice. Serum levels of the bone formation marker procollagen type I N-terminal propeptide were substantially reduced by GC treatment in WT mice (−50.3 ± 7.0%, P = 0.008) but not in Obl-Wnt16 mice (−3.8 ± 21.2%, nonsignificant). However, the cortical bone thickness in femur was reduced by GC treatment in both WT mice and Obl-Wnt16 mice. In conclusion, GC treatment decreases Wnt16 mRNA levels in bone and WNT16 overexpression partly protects against GC-induced bone loss.
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Danielsen, Erik Hvid, P. Dimming, F. Andersen, D. Bender, T. Brevig, L. Falborg, A. Gee, et al. "The DaNeX Study of Embryonic Mesencephalic, Dopaminergic Tissue Grafted to a Minipig Model of Parkinson's Disease: Preliminary Findings of Effect of MPTP Poisoning on Striatal Dopaminergic Markers." Cell Transplantation 9, no. 2 (March 2000): 247–59. http://dx.doi.org/10.1177/096368970000900210.
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A multicenter study is under way to investigate the efficacy of allografting of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Göttingen minipigs. We are now using positron emission tomography (PET) methods for testing the physiological responses to MPTP intoxication and the time course of the response to several treatment strategies. We now report preliminary results obtained in 11 pigs employed in the initial phase of the study; the completed study shall ultimately include 30 pigs. Animals were randomly assigned to one of five groups: 1) Control, 2) MPTP intoxication, 3) MPTP intoxication followed by allograft, 4) MPTP intoxication followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete glia cell line-derived neurotrophic factor (GDNF) (≈2 ng GDNF/h/105 cells). MPTP was administered (1 mg/kg/day, SC) for 7–10 days until the pigs had developed mild parkinsonian symptoms of muscle rigidity, hypokinesia, and impaired coordination, especially of the hind limbs. Approximately 2 weeks after the last MPTP dose, animals received a T1-weighted magnetic resonance imaging (MRI) scan, and a series of dynamic PET recordings. After the first series of PET scans, four grafts of porcine embryonic mesencephalic tissue (E28 days) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-based stereotactic techniques. Immunosuppression of some animals with cyclosporin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last scans, pigs were killed and the brains were perfused for unbiased stereological examination of cytological and histochemical markers in striatum and substantial nigra. The behavioral impairment of the animals (the “Parkinson's score”) had been evaluated throughout the 8-month period. Kinetic analysis of the first set of PET scans has indicated that the rate constant for the decarboxylation of FDOPA in catecholamine fibers was reduced by 33% in striatum of the mildly parkinsonian pigs. The rate of association of [11C]NS-2214 to catecholamine uptake sites was reduced by 62% in the same groups of pigs. No significant difference was found in the binding potential of [11C]raclopride to the dopamine D2-like receptors in striatum of the MPTP-intoxicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially denervated pig striatum.
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Floisand, Yngvar, Knut Lundin, Vladimir Lazarevic, Jorn Dehli Kristiansen, Liv T. N. Osnes, Geir E. Tjonnfjord, Henrik Mikael Reims, and Tobias Gedde-Dahl. "Targeting Integrin a4b7-Expressing T-Cells in Steroid Refractory Intestinal GvHD." Blood 126, no. 23 (December 3, 2015): 3137. http://dx.doi.org/10.1182/blood.v126.23.3137.3137.
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Abstract Introduction Grade III-IV GvHD is associated with poor outcome. Severe steroid refractory (SR) intestinal manifestations are difficult to treat, and current treatment modalities augment the immunodeficiency and often lead to opportunistic infections, multiorgan failure (MOF) and death. 2nd and 3rd line treatments are less than optimally documented and often with erratic responses. Vedolizumab (Vedo), a monoclonal antibody targeting the homing of T-cells to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM, is effective in inflammatory bowel disease (IBD) refractory to TNF-a inhibitors. Encouraged by the responses reported in IBD, we used Vedo in six patients with intestinal SR GvHD. Methods Patient characteristics are provided in table 1. Patients 1 and 2 had been through 2nd and 3rd line therapy without response or resolution of the GvHD. Patients 3 to 6 were given Vedo as second line therapy after steroid failure. Patient 4 already had MOF with gastrointestinal GvHD before receiveing Vedo, and died of MOF. Vedo was delivered as prescribed in IBD; 300 mg iv without premedication week 0, 2 and 6, followed by infusions every 8 weeks on clinical indication. Results All patients exhibited clinical responses within 7 - 10 days after start of treatment with decrease in abdominal pain and watery diarrhoea. Serial endoscopies were performed in patients 1,2,3,5 and 6. These revealed gradual macroscopic and histologic improvement; the upper GI-tract showing a more rapid improvement than the colon. Figure 1 shows colon histology before (a, b, c) and after 3 doses of Vedo (d, e, f) in patient 1, 2 and 3. After 3 doses of Vedo, most patients could taper systemic corticosteroid therapy. All patients, except patient 4, were on oral medication including immunosuppressants. Concomitant immunosuppressive therapy was administered as oral cyclosporine or MMF. There were no or sparse clinical symptoms of acute intestinal GvHD Patient 1 is in continued clinical remission of GvHD 8 months after start of therapy. Patient 2 was asymptomatic for 5 months, then a molecular relapse of acute promyelocytic leukemia was diagnosed and intestinal GvHD recurred when all immunosuppression was stopped. In patient 3, the intestinal GvHD resolved after three doses of Vedo, but he developed skin GvHD after cessation of IS and died of an opportunistic infection following treatment with high dose methyl-prednisolone. Patient 4 had MOF prior to start of treatment with Vedo and died in MOF. Patient 5 and 6 have no clinical signs of intestinal GvHD after 2 and 3 doses of Vedo. Five out of six patients could be discharged from hospital after treatment with Vedo. Immunophenotyping of peripheral blood revealed high levels of CD25+ Treg cells in 4 out of 5 evaluable patients prior to treatment and the numbers decreased to normal levels after start of therapy and with signs of clinical effect. Patient 2 stopped IS after a molecular relapse of APL and had a recurrence of GvHD. This recurrence coincided with an increase in Treg percentage. Discussion This case series provides the first proof of concept that targeting integrin a4b7 T-cells is feasible, safe and may provide clinical improvement in intestinal SR GvHD. The mechanism of action is not known, but may be due to the inhibition of the homing of a4b7 expressing allo-reactive T-cells to recipient MadCAM expressing intestinal endothelial cells. The mechanism behind the Treg patterns is unclear. One might speculate that the initial high levels of Tregs are part of the physiologic reaction to the alloreactive inflammation in the intestinal epithelium and that the subsequent normalization occurs as the inflammation subsides. Table 1. Patient 1 2 3 4 5 6 Diagnosis AML AML NHL AML NHL AML Sex male male male female male male Age at transplant 46 58 42 44 50 62 Lines of therapy after steroid refractoriness 2 1 0 0 0 0 Other manifestations 1 2,3,4 1 Steroid dose (mg) at last FU N/A N/A 2 mg/kg 1,7 mg/kg 10 0 Number of Vedolizumab doses at last FU 5 5 3 1 2 3 Immunosuppression at last FU No CyA CyA + steroids MMF + steroids CyA + steroids No watery stools at last FU No Yes No No No No Treg % before start of Vedo (reference: 2,5 - 5,8) 10,2 29,6 4 1,7 33 6,5 Treg % follow up 1 5,7 15 2,1 13,3 13 Treg % follow up 2 6,2 6 Treg % follow up 3 4,6 6,6 Treg % follow up 4 4,9 Treg % follow up 5 8,5* *IS cessation due to molecular relapse followed by relapse of GvHD 1 CMV 2 renal failure 3 hepatic failure 4 multi-organ GvHD Figure 1. Figure 1. Disclosures Off Label Use: Vedolizumab is approved for the treatment of inflammatory bowel disease. The present study describes its effect on steroid-refractory acute intestinal GvHD. Lundin:Takeda: Consultancy, Honoraria.
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Janyst, Michał, Beata Kaleta, Karolina Janyst, Radosław Zagożdżon, Ewa Kozlowska, and Witold Lasek. "Comparative Study of Immunomodulatory Agents to Induce Human T Regulatory (Treg) Cells: Preferential Treg-Stimulatory Effect of Prednisolone and Rapamycin." Archivum Immunologiae et Therapiae Experimentalis 68, no. 4 (June 12, 2020). http://dx.doi.org/10.1007/s00005-020-00582-6.
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Abstract T regulatory (Treg) cells play a critical role in the maintenance of self-tolerance, as well as in inhibition of inflammation and exaggerated immune response against exogenous antigens. They develop in the thymus (tTreg cells) but also may be generated at the peripheral tissues, including tumor microenvironment (pTreg cells), or induced in vitro in the presence of transforming growth factor (TGF)-β (iTreg cells). Since tTreg cells constitute a minor fraction of peripheral blood lymphocytes in physiological conditions, an alternative way to obtain high number of functional Treg cells for therapeutic purposes is their generation in vitro from conventional T cells. In our studies, we compared effectiveness of several pharmacological agents with suggested immunomodulatory effects on Treg development (rapamycin, prednisolone, inosine pranobex, glatiramer acetate, sodium butyrate, and atorvastatin) to optimize Treg-inducing protocols. All but one (atorvastatin) immunomodulators augmented induction of polyclonal Treg cells in cultures. They were effective both in increasing the number of CD4+CD25highFoxp3high cells and Foxp3 expression. Rapamycin and prednisolone were found the most effective. Both drugs prolonged also phenotypic stability of Treg cells and induced fully active Treg cells in a functional assay. In the assay, prednisolone appeared superior versus rapamycin. The results, on the one hand, may be helpful in planning optimal protocols for generation of Treg cells for clinical application and, on the other hand, shed some light on mechanisms of the immunomodulatory activity of some tested agents observed in vivo.
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Carnovali, Marta, Giuseppe Banfi, and Massimo Mariotti. "Age-dependent modulation of bone metabolism in zebrafish scales as new model of male osteoporosis in lower vertebrates." GeroScience, September 30, 2020. http://dx.doi.org/10.1007/s11357-020-00267-0.
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Abstract After middle age, in human bone, the resorption usually exceeds formation resulting in bone loss and increased risk of fractures in the aged population. Only few in vivo models in higher vertebrates are available for pathogenic and therapeutic studies about bone aging. Among these, male Danio rerio (zebrafish) can be successfully used as low vertebrate model to study degenerative alterations that affect the skeleton during aging, reducing the role of sex hormones. In this paper, we investigated the early bone aging mechanisms in male zebrafish (3, 6, 9 months old) scales evaluating the physiological changes and the effects of prednisolone, a pro-osteoporotic drug. The results evidentiated an age-dependent reduction of the mineralization rate in the fish scales, as highlighted by growing circle measurements. Indeed, the osteoblastic ALP activity at the matrix deposition site was found progressively downregulated. The higher TRAP activity was found in 63% of 9-month-old fish scales associated with resorption lacunae along the scale border. Gene expression analysis evidentiated that an increase of the tnfrsf1b (homolog of human rank) in aging scales may be responsible for resorption stimulation. Interestingly, prednisolone inhibited the physiological growth of the scale and induced in aged scales a more significant bone resorption compared with untreated fish (3.8% vs 1.02%). Bone markers analysis shown a significant reduction of ALP/TRAP ratio due to a prednisolone-dependent stimulation of tnfsf11 (homolog of human rankl) in scales of older fish. The results evidentiated for the first time the presence of a senile male osteoporosis in lower vertebrate. This new model could be helpful to identify the early mechanisms of bone aging and new therapeutic strategies to prevent age-related bone alterations in humans.
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Gürsu, Alper Hazim, Emine Azak, Eda Mengen, Sevim Ünal, and İbrahim İlker Çetin. "A Rare Side Effect of Diazoxide Therapy: Pulmonary Hipertension." Journal of Dr. Behcet Uz Children s Hospital, 2020. http://dx.doi.org/10.5222/buchd.2020.94547.
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We present a newborn diagnosed with Beckwith-Wiedemann syndrome and hypoglycemia, and developed pulmonary hypertension due to initiated diazoxide treatment because of these indications. Beckwith-Wiedemann syndrome was considered due to abdominal wall defect, macrosomia, macroglossia and hypoglycemia in a 34 week newborn with respiratory distress, hypoglycemia and syndromic appearance. Blood glucose level was measured as 1 mg/dL. Oral feeding, glucose infusion, prednisolone and then diazoxide treatment were started. At the first admission transthoracic echocardiographic examination, ventricular and atrial septal defects were detected. Control echocardiography performed under diazoxide treatment, showed development of enlarged right heart chambers, severe tricuspid regurgitation, and pulmonary hypertension. The development of pulmonary hypertension was thought to be related to diazoxide treatment. Diazoxide was discontinued after the patient became normoglycemic during follow--up period. Subsequently performed echocardiography revealed that the systolic pulmonary artery pressure regressed to 20 mmHg, and cardiac chambers returned to their physiologic balance. The patient without any problem during monitorization was discharged with the recommendation to attend further controls visits. In this case report, it was aimed to be reminded that pulmonary hypertension can develop due to diazoxide treatment, and it can regress with discontinuation of diazoxide. Besides, transthoracic ECHO should be performed to check for the development of pulmonary hypertension in newborns treated with diazoxide.
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Meyer, Emily Jane, David J. Torpy, Anastasia Chernykh, Morten Thaysen-Anderson, Marni Anne Nenke, John Lewis, Wayne Rankin, and Steven Polyak. "OR19-05 Steroid:Corticosteroid-Binding Globulin Interactions; Effects of Neutrophil Elastase Cleavage, Pyrexia and Acidosis." Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.109.
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Abstract Context Corticosteroid-binding globulin (CBG) transports cortisol and other steroid hormones1,2. High-affinity CBG (haCBG) undergoes proteolysis of the reactive centre loop (RCL) by neutrophil elastase (NE) at inflammatory sites, liberating immunomodulatory cortisol and altering conformation to low-affinity CBG (laCBG). Pyrexia reduces CBG:cortisol binding affinity, an interaction at the RCL is speculated3. Objective To measure the equilibrium binding constants of a panel of steroids to glycosylated haCBG and laCBG over temperature and pH ranges mimicking the pathophysiological conditions of septic shock. Design Surface plasmon resonance was used to determine the binding profiles of 19 steroid ligands to haCBG and laCBG at temperatures 25°C, 37°C and 39°C and pH 7.4 and 7.0. The RCL-recognizing 9G12 antibody was used to assess cleavage and epitope availability of the RCL across conditions. Results A 4–8 fold reduction in affinity for cortisol, cortisone, corticosterone, 11-deoxycortisol, progesterone, 17-hydroxyprogesterone and prednisolone occurred with NE-mediated haCBG-to-laCBG conversion, cortisol expectedly displayed the highest binding affinity. Binding affinity consistently decreased at higher temperatures and at acidic pH for both haCBG and laCBG. 9G12 antibody RCL binding was preserved for haCBG across temperatures. Conclusions These studies reveal that steroid binding to CBG is selective and in all cases reduced upon NE-mediated haCBG-to-laCBG transition. Moreover, reduced CBG:cortisol binding affinity at elevated temperature occurs with an intact and accessible RCL epitope, suggesting a non-RCL mechanism for the delivery of anti-inflammatory cortisol in pyrexia. Synergy of NE cleavage and pyrexia/acidosis may serve for local inflammatory site cortisol delivery and increase free cortisol. These findings demonstrate the modifiable hormone binding characteristics of CBG in (patho-)physiological conditions, supporting its significance in cortisol delivery in obviating systemic inflammation and multiorgan-organ failure in patients with septic shock and its association with mortality4. 1. Pemberton PA, Stein PE, Pepys MB, et al. Hormone binding globulins undergo serpin conformational change in inflammation. Nature. 1988;336(6196):257–258. 2. Pugeat MM, Dunn JF, Nisula BC. Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53(1):69–75. 3. Cameron A, Henley D, Carrell R, et al. Temperature-responsive release of cortisol from its binding globulin: a protein thermocouple. J Clin Endocrinol Metab. 2010;95(10):4689–4695. 4. Meyer EJ, Nenke MA, Rankin W, et al. Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality. Clin Endocrinol (Oxf). 2019;90(1):232–240.