Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation

Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes occurring within the extracellular environment that are specific to GBM motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of in vitro and in vivo models. In this study, the upregulation of Cx43 in C6 glioma cells induced morphological changes and the secretion of proteins associated with cell motility. Demonstrating the selective engagement of ECM remodeling networks, secretome analysis revealed the near-binary increase of osteopontin and matrix metalloproteinase-3 (MMP3), with gelatinase and NFF-3 assays confirming the proteolytic activities. Informatic analysis of interactome and secretome downstream of Cx43 identifies networks of glioma motility that appear to be synergistically engaged. The data presented here implicate ECM remodeling and matrikine signals downstream of Cx43/MMP3/osteopontin and ARK1B10 inhibition as possible avenues to inhibit GBM

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

Ongoing harlequin toad declines suggest the amphibian extinction crisis is still an emergency

Biodiversity loss is extreme in amphibians. Despite ongoing conservation action, it is difficult to determine where we stand in overcoming their extinction crisis. Among the most threatened amphibians are the 131 Neotropical harlequin toads. Many of them declined since the 1980s with several considered possibly extinct. Recently, more than 30 species have been rediscovered, raising hope for a reversing trend in the amphibian extinction crisis. We use past and present data available for harlequin toads (Atelopus), to examine whether the amphibian extinction crisis is still in an emergency state. Since 2004 no species has improved its population status, suggesting that recovery efforts have not been successful. Threats include habitat change, pathogen spread and climate change. More mitigation strategies need implementation, especially habitat protection and disease management, combined with captive conservation breeding. With harlequin toads serving as a model, it is clear that the amphibian extinction crisis is still underway. The status of the harlequin toads has not improved since 2004 despite species rediscoveries accompanied by increasing conservation efforts, and habitat destruction and degradation continue to threaten them today, according to an analysis of population status records over the period 2004-2022

Implementing stakeholder engagement to explore alternative models of consent: An example from the PREP-IT trials

Introduction: Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent. Methods: The PREP-IT program consists of two multi-center cluster randomized crossover trials that engaged patient advisors to determine an optimal model of consent. Patient advisors and stakeholders met regularly and reached consensus on decisions related to the trial design including the model for consent. Patient advisors provided valuable insight on how key decisions on trial design and conduct would be received by participants and the impact these decisions will have. Results: Patient advisors, together with stakeholders, reviewed the pros and cons and the requirements for the traditional model of consent, deferred consent, and waiver of consent. Collectively, they agreed upon a deferred consent model, in which patients may be approached for consent after their fracture surgery and prior to data collection. The consent rate in PREP-IT is 80.7%, and 0.67% of participants have withdrawn consent for participation. Discussion: Involvement of patient advisors in the development of an optimal model of consent has been successful. Engagement of patient advisors is recommended for other large trials where the traditional model of consent may not be optimal