Permanent embryo arrest: molecular and cellular concepts

Developmental arrest is one of the mechanisms responsible for the elevated levels of embryo demise during the first week of in vitro development. Approximately 10–15% of IVF embryos permanently arrest in mitosis at the 2- to 4-cell cleavage stage showing no indication of apoptosis. Reactive oxygen species (ROS) are implicated in this process and must be controlled in order to optimize embryo production. A stress sensor that can provide a key understanding of permanent cell cycle arrest and link ROS with cellular signaling pathway(s) is p66Shc, an adaptor protein for apoptotic-response to oxidative stress. Deletion of the p66Shc gene in mice results in extended lifespan, which is linked to their enhanced resistance to oxidative stress and reduced levels of apoptosis. p66Shc has been shown to generate mitochondrial H2O2 to trigger apoptosis, but may also serve as an integration point for many signaling pathways that affect mitochondrial function. We have detected elevated levels of p66Shc and ROS within arrested embryos and believe that p66Shc plays a central role in regulating permanent embryo arrest. In this paper, we review the cellular and molecular aspects of permanent embryo arrest and speculate on the mechanism(s) and etiology of this method of embryo demise

Optimizing cancer pain management in resource-limited settings

Purpose: Adequate cancer pain management (CPM) is challenging in resource-limited settings, where current international guideline recommendations are difficult to implement owing to constraints such as inadequate availability and accessibility of opioids, limited awareness of appropriate opioid use among patients and clinicians, and lack of guidance on how to translate the best evidence into clinical practice. The multinational and multidisciplinary CAncer Pain managEment in Resource-limited settings (CAPER) Working Group proposes a two-step initiative to bridge clinical practice gaps in CPM in resource-limited settings. Methods: A thorough review of the literature, a steering committee meeting in February 2017, and post-meeting teleconference discussions contributed to the development of this initiative. As a first step, we developed practical evidence-based CPM algorithms to support healthcare providers (HCPs) in tailoring treatment according to availability of and access to resources. The second part of the initiative proposes a framework to support an effective implementation of the CPM algorithms that includes an educational program, a pilot implementation, and an advocacy plan. Results: We developed CPM algorithms for first-line use, breakthrough cancer pain, opioid rotation, and refractory cancer pain based on the National Comprehensive Cancer Network guidelines and expert consensus. Our proposed educational program emphasizes the practical elements and illustrates how HCPs can provide optimal CPM according to evidence-based guidelines despite varied resource limitations. Pilot studies are proposed to demonstrate the effectiveness of the algorithms and the educational program, as well as for providing evidence to support a draft advocacy document, to lobby policymakers to improve availability and accessibility of analgesics in resource-limited settings. Conoclusions: These practical evidence-informed algorithms and the implementation framework represent the first multinational step towards achieving optimal CPM in resource-limited settings.Sam H. Ahmedzai, Mary Jocylyn Bautista, Kamel Bouzid, Rachel Gibson, Yuddi Gumara, Azza Adel Ibrahim Hassan, Seiji Hattori, Dorothy Keefe, Durval Campos Kraychete, Dae Ho Lee, Kazuo Tamura, Jie Jun Wang (CAncer Pain management in Resource-limited settings (CAPER) Working Group