A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies.

Purpose Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.Patients and methods Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5-3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.Results DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.Conclusions Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL

To be understood: Transitioning to adult life for people with Autism Spectrum Disorder

Introduction: The purpose of this study was to explore the viewpoints of parents of young people with Autism Spectrum Disorder (ASD) in relation to their child's transition to adulthood. Methods: Data were collected during four structured focus groups with 19 parents of young people with ASD with average to high intellectual capacities. Condensed meaning units were identified and checked during focus groups, and were subsequently linked to the International Classification of Functioning, Disability and Health (ICF). Results: Three major themes emerged: to be understood, to understand the world and to succeed. The ICF domains of activity and participation and environmental factors emerged as having the greatest potential to influence transition outcomes. Conclusions: Policies and services should focus on strengths to maximise participation in higher education, employment and independent living amongst young people with ASD. Interventions targeting environmental factors could be effective in improving participation in adult life. Person-centred and individualised approaches could further complement this approach supporting the transition to adulthood for people with ASD, ultimately improving outcomes in adulthood

Occurrence of L-iduronic acid and putative D-glucuronyl C5-epimerases in prokaryotes

Glycosaminoglycans (GAGs) are polysaccharides that are typically present in a wide diversity of animal tissue. Most common GAGs are well-characterized and pharmaceutical applications exist for many of these compounds, e.g. heparin and hyaluronan. In addition, also bacterial glycosaminoglycan-like structures exist. Some of these bacterial GAGs have been characterized, but until now no bacterial GAG has been found that possesses the modifications that are characteristic for many of the animal GAGs such as sulfation and C5-epimerization. Nevertheless, the latter conversion may also occur in bacterial and archaeal GAGs, as some prokaryotic polysaccharides have been demonstrated to contain L-iduronic acid. However, experimental evidence for the enzymatic synthesis of L-iduronic acid in prokaryotes is as yet lacking. We therefore performed an in silico screen for D-glucuronyl C5-epimerases in prokaryotes. Multiple candidate C5-epimerases were found, suggesting that many more microorganisms are likely to exist possessing an L-iduronic acid residue as constituent of their cell wall polysaccharides