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// Wiem Chaabane 1 , Malin Lindqvist Appell 1 1 Division of Drug Research, Department of Medical and Health Sciences, Linkoping University, SE-58183 Linkoping, Sweden Correspondence to: Malin Lindqvist Appell, email: Malin.lindqvist.appell@liu.se Wiem Chaabane, email: wiemchaabane27@hotmail.fr Keywords: 6-thioguanine, 6-mercaptopurine, azathioprine, autophagy, apoptosis Received: May 26, 2016 Accepted: September 15, 2016 Published: September 28, 2016 ABSTRACT Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are a class of genotoxic drugs extensively used in the treatment of various illnesses including leukemia. Their underlying molecular mechanism of action involves the activation of apoptosis and autophagy but remains widely unclear. Here we present evidence that autophagy induction by thiopurines is a survival mechanism that antagonizes apoptosis and is involved in degrading damaged mitochondria through mitophagy. On the other hand, apoptosis is the main cell death mechanism by thiopurines as its inhibition prohibited cell death. Thus a tight interplay between apoptosis and autophagy controls cell fate in response to thiopurine treatment. Moreover, thiopurines disrupt mitochondrial function and induce a loss of the mitochondrial transmembrane potential. The involvement of the mitochondrial pathway in thiopurine-induced apoptosis was further confirmed by increased formation of reactive oxygen species (ROS). Inhibiting oxidative stress protected the cells from thiopurine-induced cell death and ROS scavenging prohibited autophagy induction by thiopurines. Our data indicate that the anticarcinogenic effects of thiopurines are mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy.

Background: One way to facilitate the translation of research into the occupational health service practice is through clinical practice guidelines. To increase the implementability of guidelines it is important to include the end-users in the development, for example by a community of practice approach. This paper describes the development of an occupational health practice guideline aimed at the management of non-specific low back pain (LBP) by using a community of practice approach. The paper also includes a process evaluation of the development providing insight into the feasibility of the process. Methods: A multidisciplinary community of practice group (n = 16) consisting of occupational nurses, occupational physicians, ergonomists/physical therapists, health and safety engineers, health educators, psychologists and researchers from different types of occupational health services and geographical regions within Sweden met eleven times (June 2012-December 2013) to develop the practice guideline following recommendations of guideline development handbooks. Process-outcomes recruitment, reach, context, satisfaction, feasibility and fidelity were assessed by questionnaire, observations and administrative data. Results: Group members attended on average 7.5 out of 11 meetings. Half experienced support from their workplace for their involvement. Feasibility was rated as good, except for time-scheduling. Most group members were satisfied with the structure of the process (e.g. presentations, multidisciplinary group). Fidelity was rated as fairly high. Conclusions: The described development process is a feasible process for guideline development. For future guideline development expectations of the work involved should be more clearly communicated, as well as the purpose and tasks of the CoP-group. Moreover, possibilities to improve support from managers and colleagues should be explored. This paper has important implications for future guideline development; it provides valuable information on how practitioners can be included in the development process, with the aim of increasing the implementability of the developed guidelines. Funding Agencies|Swedish Council for Working Life and Social Research [130153, 2010-1572, 2012-1785]; AFA insurance, Sweden