A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance

Background: Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for improved alternatives to classic steroids. We sought to unravel how two glucocorticoid receptor-activating compounds, dexamethasone and Compound A, influence glucocorticoid receptor levels and how this can be correlated to their gene regulatory potential. Methods: Compound A and dexamethasone were applied in a short-term and long-term treatment protocol. By quantitative PCR analysis in fibroblast-like synoviocytes (FLS) the gene regulatory potential of both compounds in the two experimental conditions was analysed. A parallel Western blot assay revealed the glucocorticoid receptor protein levels in both conditions (ex vivo). In addition, this study examined the effect of systemic administration of dexamethasone and Compound A, in concentrations effective to inhibit collagen-induced arthritis, in DBA/1 mice on glucocorticoid receptor levels (in vivo). Results: Compound A does not induce a homologous downregulation of glucocorticoid receptor in vivo and ex vivo, thereby retaining its anti-inflammatory effects after prolonged treatment in FLS. This is in sharp contrast to dexamethasone, showing a direct link between prolonged dexamethasone treatment, decreasing glucocorticoid receptor levels, and the abolishment of inflammatory gene repression in FLS. It was also observed that the acquired low receptor levels after prolonged dexamethasone treatment are still sufficient to sustain the transactivation of endogenous glucocorticoid-responsive element-driven genes in FLS, a mechanism partly held accountable for the metabolic side-effects. Conclusion: Compound A is less likely to evoke therapy resistance, as it does not lead to homologous glucocorticoid receptor downregulation, which is in contrast to classic glucocorticoids

Omineca Herald, May, 23, 1924

Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse

Pirfenidone in idiopathic pulmonary fibrosis:expert panel discussion on the management of drug-related adverse events

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.Correction in: Advances in Therapy, Volume 31, Issue 5, pp 575-576 , doi: 10.1007/s12325-014-0118-8</p

Variability of the immune response in freshwater sponges

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Small bowel endoscopy and Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant inherited disease. It is clinically characterized by the development of gastrointestinal hamartomas, mainly located in the small bowel. These hamartomas are prone to complications such as intussus-ceptions, abdominal complaints and anaemia. Furthermore, patients are at increased risk for developing small bowel cancer. Therefore, regular surveillance of the small bowel is indicated. However, the optimal strategy for surveillance has not been determined yet. This review gives an overview of the different techniques that have been described to examine the small bowel of PJS patients. First, a number of radiologic and endoscopic imaging modalities with diagnostic value are discussed. Secondly, recently developed advanced endoscopy techniques are described that can serve both as a diagnostic and therapeutic tool in the surveillance of the small bowel. Finally, a recommendation is given how to apply these individual techniques for small bowel surveillance in a step-up approach. (C) 2012 Elsevier Ltd. All rights reserved

Behandeling van patiënten met ernstige glucocorticoïd-refractaire colitis ulcerosa: ciclosporine of infliximab?

Cyclosporine and infliximab are so-called 'rescue-therapies' as last resort for the treatment of patients with severe glucocorticoid-refractory ulcerative colitis. A recent study found that cyclosporine and infliximab are similar in terms of efficacy in the treatment of patients with severe ulcerative colitis. Cyclosporine may be prescribed as a bridge to treatment with thiopurines; infliximab may be prescribed when a patient is intolerant or refractory to thiopurines. Preoperative treatment with cyclosporine or infliximab does not affect the number of postoperative complication