Pharmacology of a Potent and Novel Inhibitor of the NOD-Like Receptor Pyrin Domain-Containing Protein 3 (NLRP3) Inflammasome that Attenuates Development of Nonalcoholic Steatohepatitis and Liver Fibrosis.

The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex and component of the innate immune system that is activated by exogenous and endogenous danger signals to promote activation of caspase-1 and the maturation and release of the proinflammatory cytokines interleukin (IL)-1ß and IL-18. Inappropriate activation of NLRP3 has been implicated in the pathophysiology of multiple inflammatory and autoimmune diseases, including cardiovascular disease, neurodegenerative diseases, and nonalcoholic steatohepatitis (NASH), thus increasing the clinical interest of this target. We describe in this study the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel and highly specific NLRP3 inhibitor, JT001 (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonylurea). In cell-based assays, JT001 potently and selectively inhibited NLRP3 inflammasome assembly, resulting in the inhibition of cytokine release and the prevention of pyroptosis, a form of inflammatory cell death triggered by active caspase-1. Oral administration of JT001 to mice inhibited IL-1ß production in peritoneal lavage fluid at plasma concentrations that correlated with mouse in vitro whole blood potency. Orally administered JT001 was effective in reducing hepatic inflammation in three different murine models, including the Nlrp3A350V /+CreT model of Muckle-Wells syndrome (MWS), a diet-induced obesity NASH model, and a choline-deficient diet-induced NASH model. Significant reductions in hepatic fibrosis and cell damage were also observed in the MWS and choline-deficient models. Our findings demonstrate that blockade of NLRP3 attenuates hepatic inflammation and fibrosis and support the use of JT001 to investigate the role of NLRP3 in other inflammatory disease models. SIGNIFICANCE STATEMENT: Persistent inflammasome activation is the consequence of inherited mutations of NLRP3 and results in the development of cryopyrin-associated periodic syndromes associated with severe systemic inflammation. NLRP3 is also upregulated in nonalcoholic steatohepatitis, a metabolic chronic liver disease currently missing a cure. Selective and potent inhibitors of NLRP3 hold great promise and have the potential to overcome an urgent unmet need.

Exploring smoking cessation experiences among persons with spinal cord injury: Informing theory-based recommendations for interventions.

STUDY DESIGN: Qualitative study. OBJECTIVE: Use an integrated knowledge translation (IKT) and theory-based approach, to (1) explore factors influencing smoking cessation behaviour among people with SCI, and (2) explore the preferred intervention and implementation options for smoking cessation interventions for persons with SCI. SETTING: Community. METHODS: Aligned with an IKT approach, an SCI organization was meaningfully engaged throughout the research process. Semi-structured interviews were conducted with people with SCI who have quit or tried to quit smoking. Barriers and facilitators to smoking cessation were extracted and deductively coded using the Theoretical Domains Framework (TDF) and inductively analysed. To identify intervention options, a behavioural analysis was conducted using the Behaviour Change Wheel. To identify implementation options, modes of delivery and intervention messengers were extracted. Modes of delivery were deductively coded, and themes relating to intervention messengers were constructed. RESULTS: Among the 12 participants (7 males; 6 with tetraplegia), seven had quit and five had relapsed. Across the 12 interviews, 130 barriers and 218 facilitators were coded to the TDF. The prominent TDF domains were beliefs about consequences, social influences, environmental context and resources, and behavioural regulation, and served as themes in the inductive analysis. Multiple modes of delivery and intervention messengers were considered important for the delivery of smoking cessation interventions. CONCLUSION: This study is the first to use IKT and theory-based approaches to explore factors influencing smoking cessation among persons with SCI. Findings from this study resulted in the co-development of practical recommendations for future SCI-specific smoking cessation interventions.

Participation of people living with disabilities in physical activity: a global perspective.

Approximately 1·5 billion people worldwide live with a physical, mental, sensory, or intellectual disability, about 80% of which are in low-income and middle-income countries. This Series paper provides a global overview of the prevalence, benefits, and promotion policies for physical activity for people living with disabilities (PLWD). PLWD are 16-62% less likely to meet physical activity guidelines and are at higher risk of serious health problems related to inactivity than people without disabilities. Meta-analyses have shown that physical activity has beneficial effects on cardiovascular fitness (average standardised mean difference [SMD] 0·69 [95% CI 0·31-1·01]), musculoskeletal fitness (0·59 [0·31-0·87]), cardiometabolic risk factors (0·39 [0·04-0·75]), and brain and mental health outcomes (0·47 [0·21-0·73]). These meta-analyses also show that health benefits can be achieved even with less than 150 min of physical activity per week, and suggest that some physical activity is better than none. Meta-analyses of interventions to increase physical activity for PLWD have reported effect sizes ranging from SMD 0·29 (95% CI 0·17-0·41, k=10) to 1·00 (0·46-1·53, k=10). There is increasing awareness among policy makers of the needs of PLWD for full participation in physical activity. Physical activity action plans worldwide must be adequately resourced, monitored, and enforced to truly advance the fundamental rights of PLWD to fully participate in physical activity.

Barriers and facilitators to changing bowel care practices after spinal cord injury: a Theoretical Domains Framework approach.

BACKGROUND: Improvement to autonomic processes such as bladder, bowel and sexual function are prioritised by individuals with spinal cord injury (SCI). Bowel care is associated with high levels of dissatisfaction and decreased quality of life. Despite dissatisfaction, 71% of individuals have not changed their bowel care routine for at least 5 years, highlighting a disconnect between dissatisfaction with bowel care and changing routines to optimise bowel care. OBJECTIVE: Using an integrated knowledge translation approach, we aimed to explore the barriers and facilitators to making changes to bowel care in individuals with SCI. METHODS: Our approach was guided by the Behaviour Change Wheel and used the Theoretical Domains Framework (TDF). Semi-structured interviews were conducted with individuals with SCI (n = 13, mean age 48.6 ± 13.1 years) and transcribed verbatim (duration 31.9 ± 7.1 min). Barriers and facilitators were extracted, deductively coded using TDF domains and inductively analysed for themes within domains. RESULTS: Changing bowel care after SCI was heavily influenced by four TDF domains: environmental context and resources (workplace flexibility, opportunity or circumstance, and access to resources); beliefs about consequences; social influences (perceived support and peer mentorship); and knowledge (knowledge of physiological processes and bowel care options). All intervention functions and policy categories were considered viable intervention options, with human (61%) and digital (33%) platforms preferred. CONCLUSIONS: Modifying bowel care is a multi-factorial behaviour. These findings will support the systematic development and implementation of future interventions to both enable individuals with SCI to change their bowel care and to facilitate the optimisation of bowel care approaches.

Implementation of the spinal cord injury exercise guidelines in the hospital and community settings: Protocol for a type II hybrid trial.

STUDY DESIGN: Type II hybrid effectiveness-implementation trial protocol. OBJECTIVES: To (1) evaluate the implementation of coordinated physical activity (PA) coaching delivered by physiotherapists and spinal cord injury (SCI) peers during the transition from in-hospital care to living in a community (implementation objective) and (2) assess the effect of coaching on PA behaviour and psychosocial predictors among people with SCI (effectiveness objective). SETTING: Rehabilitation hospital and home/community settings in British Columbia, Canada. METHODS: Implementation objective: PA coaches (physiotherapists and SCI peers) receive an implementation intervention including training, monitoring, feedback, and champion support. A Theoretical Domains Framework-based questionnaire is collected at baseline, post-training, 2, and 6 months follow-up and semi-structured interviews conducted at 6 months. Effectiveness objective: Using a quasi-experimental design, 55 adults with SCI are allocated to intervention (PA coaching, n = 30) or control (usual care, n = 25) groups. Participants in the intervention group are referred by physiotherapists to receive 11 SCI peer-delivered PA coaching sessions in the community. Control participants received usual care. Questionnaires assessing PA behaviour and psychosocial predictors are administered at baseline, 2-months, 6-months, and 1-year. Semi-structured interviews are conducted to assess intervention satisfaction at 6 months. Analyses include one-way (implementation objective) and two-way (effectiveness objective) repeated measures ANCOVAs for questionnaire-reported outcomes and thematic content analysis for interview data. Data are summarised using the reach effectiveness adoption implementation maintenance (RE-AIM) framework. ETHICS AND DISSEMINATION: The University of British Columbia Clinical Research Ethics Board approved the protocol (#H19-02694), clinicaltrials.gov registration NCT04493606. Documentation of the adoption process will inform implementation in future sites.

Integrated Knowledge Translation Guiding Principles for Conducting and Disseminating Spinal Cord Injury Research in Partnership.

OBJECTIVE: To address a gap between spinal cord injury (SCI) research and practice by rigorously and systematically co-developing integrated knowledge translation (IKT) guiding principles for conducting and disseminating SCI research in partnership with research users. DESIGN: The process was guided by the internationally accepted The Appraisal of Guidelines for REsearch & Evaluation (AGREE) II Instrument for evaluating the development of clinical practice guidelines. SETTING: North American SCI research system (ie, SCI researchers, research users, funders). PARTICIPANTS: The multidisciplinary expert panel (n=17) and end users (n=35) included individuals from a North American partnership of SCI researchers, research users, and funders who have expertise in research partnerships. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Clarity, usefulness, and appropriateness of the principles. RESULTS: Data regarding 125 principles of partnered research were systematically collected from 4 sources (review of reviews, scoping review, interviews, Delphi consensus exercise). A multidisciplinary expert panel held a 2-day meeting to establish consensus, select guiding principles, and draft the guidance. The panel reached 100% consensus on the principles and guidance document. The final document includes a preamble, 8 guiding principles, and a glossary. Survey data showed that the principles and guidance document were perceived by potential end users as clear, useful, and appropriate. CONCLUSIONS: The IKT Guiding Principles represent the first rigorously co-developed, consensus-based guidance to support meaningful SCI research partnerships. The principles are a foundational tool with the potential to improve the relevance and impact of SCI research, mitigate tokenism, and advance the science of IKT.

Enhancing participation while aging with spinal cord injury: applying behaviour change frameworks to develop intervention recommendations.

STUDY DESIGN: Knowledge translation study. OBJECTIVES: Use the Theoretical Domains Framework (TDF) and Behaviour Change Wheel (BCW) to (1) identify barriers and facilitators to participation in daily activities and social roles among people aging with spinal cord injury (SCI); and, (2) systematically co-develop participation-focused intervention recommendations with SCI community organizations that can support people aging with SCI. SETTING: Canadian SCI community. METHODS: Semi-structured interviews were conducted with 22 people (minimum 45 years of age; minimum 10 years post injury). Participants were asked about their experiences with participating in daily activities and social roles while aging and preferences for what participation-focused interventions should entail. Transcripts were analyzed to address three stages of behaviour change intervention design: (1) identify barriers and facilitators; (2) identify intervention functions and policy categories; (3) identify implementation options. Findings were synthesized into intervention recommendations and assessed for feasibility. RESULTS: Participation in daily activities and social roles was heavily influenced by three TDF domains: environmental context and resources, skills, and social influences. Six intervention functions and all policy categories within the BCW were considered viable intervention options. Multiple messengers and modes of delivery were identified as important. The synthesized recommendations included educating SCI organization membership, partnering with other disability organizations, and advocating to the provincial government. CONCLUSIONS: Findings suggest that multiple intervention formats delivered through a variety of implementation options are needed to enhance participation in daily activities and social roles while aging with SCI. Future efforts should focus on translating the recommendations into real-world behaviour change interventions.

Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3 character and an exquisite selectivity profile.

Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series.

Translating the international scientific spinal cord injury exercise guidelines into community and clinical practice guidelines: a Canadian evidence-informed resource.

STUDY DESIGN: Knowledge translation (KT) study. OBJECTIVES: To demonstrate how to use systematic, community-engaged methods to (1) translate the international scientific spinal cord injury (SCI) exercise guidelines into community and clinical practice guidelines, and (2) develop supporting resources. SETTING: Canada. METHODS: An expert panel of SCI researchers and stakeholders translated the guidelines and developed a supporting resource, using a KT process guided by an adapted version of the Appraisal of Guidelines, Research and Evaluation (AGREE) II Instrument. Pilot tests with end-users were conducted throughout. RESULTS: The panel recommended (1) the two scientific exercise guidelines be combined and presented in a single message titled "The Canadian SCI physical activity guidelines"; (2) development of an online supporting resource, with educational and motivational information presented in "layers" to address the needs and preferences of diverse end-users. The top layer presents and explains the Canadian SCI physical activity guidelines. The deeper layers include information on benefits, overcoming barriers, activity examples, safety tips, and links to existing resources. Interviews with adults with SCI (n = 8) and survey-data from end-users (n = 90) showed that the guidelines and supporting resource were perceived as clear, useful, and appropriate. CONCLUSION: Using community-engaged methods, the two scientific SCI exercise guidelines were combined into one single physical activity guideline message. This KT process provides a template for groups in other countries to translate the scientific SCI exercise guidelines to their local settings using a similar systematic, community-engaged approach. SPONSORSHIP: Rick Hansen Institute; Social Sciences and Humanities Research Council of Canada.

Using Target Engagement Biomarkers to Predict Clinical Efficacy of MetAP2 Inhibitors.

Target-engagement pharmacodynamic (PD) biomarkers are valuable tools in the prioritization of drug candidates, especially for novel, first-in-class mechanisms whose robustness to alter disease outcome is unknown. Methionine aminopeptidase 2 (MetAP2) is a cytosolic metalloenzyme that cleaves the N-terminal methionine from nascent proteins. Inhibition of MetAP2 leads to weight loss in obese rodents, dogs and humans. However, there is a need to develop efficacious compounds that specifically inhibit MetAP2 with an improved safety profile. The objective of this study was to identify a PD biomarker for selecting potent, efficacious compounds and for predicting clinical efficacy that would result from inhibition of MetAP2. Here we report the use of NMet14-3-3γ for this purpose. Treatment of primary human cells with MetAP2 inhibitors resulted in an approx. 10-fold increase in NMet14-3-3γ levels. Furthermore, treatment of diet-induced obese mice with these compounds reduced body weight (approx. 20%) and increased NMet14-3-3γ (approx. 15-fold) in adipose tissues. The effects on target engagement and body weight increased over time and were dependent on dose and administration frequency of compound. The relationship between compound concentration in plasma, NMet14-3-3γ in tissue, and reduction of body weight in obese mice was used to generate a pharmacokinetic-pharmacodynamic-efficacy model for predicting efficacy of MetAP2 inhibitors in mice. We also developed a model for predicting weight loss in humans using a target engagement PD assay that measures inhibitor-bound MetAP2 in blood. In summary, MetAP2 target engagement biomarkers can be used to select efficacious compounds and predict weight loss in humans. SIGNIFICANCE STATEMENT: The application of target engagement pharmacodynamic biomarkers during drug development provides a means to determine the dose required to fully engage the intended target and an approach to connect the drug target to physiological effects. This work exemplifies the process of using target engagement biomarkers during preclinical research to select new drug candidates and predict clinical efficacy. We determine concentration of MetAP2 antiobesity compounds needed to produce pharmacological activity in primary human cells and in target tissues from an appropriate animal model and establish key relationships between pharmacokinetics, pharmacodynamics, and efficacy, including the duration of effects after drug administration. The biomarkers described here can aid decision-making in early clinical trials of MetAP2 inhibitors for the treatment of obesity.

Investigating Characteristics of Quality Peer Mentors With Spinal Cord Injury.

OBJECTIVE: To identify characteristics (1) of high- and low-quality spinal cord injury (SCI) peer mentors; (2) that should be used to match SCI peer mentors and mentees. DESIGN: The study was conducted in partnership with three Canadian provincial SCI organizations using an integrated knowledge translation approach. The Delphi exercise was completed in three rounds. In Round 1, people with SCI completed a thought-listing exercise to identify characteristics of high- and low-quality peer mentors and for matching. In Rounds 2 and 3, people with SCI and community organization staff rated characteristics from the previous round on an 11-point scale. After the final round, the remaining characteristics were thematically analyzed. SETTING: Community-based peer mentorship programs in three Canadian provinces. PARTICIPANTS: People with SCI and SCI community organization staff (Round 1, n=45; Round 2, n=27; Round 3, n=25). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Consensus-based list of characteristics. RESULTS: Participants reached consensus on 215 characteristics of quality peer mentors and 11 characteristics for peer mentor-mentee matching (ICC=0.96). A consensus-based characterization of high- and low-quality peer mentorship was created and included six overarching themes: competencies, personality characteristics, emotional state, mentor outlook, reason for mentoring, and role model. CONCLUSION: A consensus-based characterization of quality peer mentorship was co-developed with input from over 50 members of the SCI community. Findings highlight that peers have both interpersonal and intrapersonal characteristics that contribute to quality mentorship. The findings highlighted the importance of matching mentors on lived experience and shared interests. Findings will inform future research and SCI peer mentorship programs.

Operationalizing the reach, effectiveness, adoption, implementation, maintenance (RE-AIM) framework to evaluate the collective impact of autonomous community programs that promote health and well-being.

BACKGROUND: The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework is a useful tool for evaluating the impact of programs in community settings. RE-AIM has been applied to evaluate individual programs but seldom used to evaluate the collective impact of community-based, public health programming developed and delivered by multiple autonomous organizations. The purposes of this paper were to (a) demonstrate how RE-AIM can be operationalized and applied to evaluate the collective impact of similar autonomous programs that promote health and well-being and (b) provide preliminary data on the collective impact of Canadian spinal cord injury (SCI) peer mentorship programs on the delivery of peer mentorship services. METHODS: Criteria from all five RE-AIM dimensions were operationalized to evaluate multiple similar community-based programs. For this study, nine provincial organizations that serve people with SCI were recruited from across Canada. Organizations completed a structured self-report questionnaire and participated in a qualitative telephone interview to examine different elements of their peer mentorship program. Data were analyzed using summary statistics. RESULTS: Having multiple indicators to assess RE-AIM dimensions provided a broad evaluation of the impact of Canadian SCI peer mentorship programs. Peer mentorship programs reached 1.63% of the estimated Canadian SCI population. The majority (67%) of organizations tracked the effectiveness of peer mentorship through testimonials and reports. Setting-level adoption rates were high with 100% of organizations offering peer mentorship in community and hospital settings. On average, organizations allocated 10.4% of their operating budget and 9.8% of their staff to implement peer mentorship and 89% had maintained their programming for over 10 years. Full interpretation of the collective impact of peer mentorship programs was limited as complete data were only collected for 52% of survey questions. CONCLUSIONS: The lack of available organizational data highlights a significant challenge when using RE-AIM to evaluate the collective impact of multiple programs that promote health and well-being. Although researchers are encouraged to use RE-AIM to evaluate the collective impact of programs delivered by different organizations, documenting limitations and providing recommendations should be done to further the understanding of how best to operationalize RE-AIM in these contexts.

Correction: Evidence-based scientific exercise guidelines for adults with spinal cord injury: an update and a new guideline.

Authors Victoria L. Goosey-Tolfrey and Karen M. Smith were listed under the incorrect affiliations at the time of publication.

Evidence-based scientific exercise guidelines for adults with spinal cord injury: an update and a new guideline.

OBJECTIVES: To describe the process and outcomes of using a new evidence base to develop scientific guidelines that specify the type and minimum dose of exercise necessary to improve fitness and cardiometabolic health in adults with spinal cord injury (SCI). SETTING: International. METHODS: Using Appraisal of Guidelines, Research and Evaluation (AGREE) II reporting criteria, steps included (a) determining the guidelines' scope; (b) conducting a systematic review of relevant literature; (c) holding three consensus panel meetings (European, Canadian and International) to formulate the guidelines; (d) obtaining stakeholder feedback; and (e) process evaluation by an AGREE II consultant. Stakeholders were actively involved in steps (c) and (d). RESULTS: For cardiorespiratory fitness and muscle strength benefits, adults with a SCI should engage in at least 20 min of moderate to vigorous intensity aerobic exercise 2 times per week AND 3 sets of strength exercises for each major functioning muscle group, at a moderate to vigorous intensity, 2 times per week (strong recommendation). For cardiometabolic health benefits, adults with a SCI are suggested to engage in at least 30 min of moderate to vigorous intensity aerobic exercise 3 times per week (conditional recommendation). CONCLUSIONS: Through a systematic, rigorous, and participatory process involving international scientists and stakeholders, a new exercise guideline was formulated for cardiometabolic health benefits. A previously published SCI guideline was endorsed for achieving fitness benefits. These guidelines represent an important step toward international harmonization of exercise guidelines for adults with SCI, and a foundation for developing exercise policies and programs for people with SCI around the world.

Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors.

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2.

Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1.

Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.

Transforming research systems for meaningful engagement: a reflexive thematic analysis of spinal cord injury researchers' barriers and facilitators to using the integrated knowledge translation guiding principles.

PURPOSE: To develop an in-depth understanding of spinal cord injury (SCI) researchers' barriers and facilitators to deciding to use 1) a partnered approach to research and, 2) systematically developed principles for guiding Integrated Knowledge Translation (IKT) in spinal cord injury research (IKT Guiding Principles). METHODS: Qualitative interview study with North American SCI researchers who were interested in using a partnered research approach. The research was conducted using an IKT approach, and interview data were analyzed using reflexive thematic analysis. RESULTS: Thirteen SCI researchers whose research focused on prevention, clinical, rehabilitation, and/or community SCI research were interviewed. Three themes were co-constructed with partners: 1) the principles are necessary but not sufficient for the implementation of a partnered approach to research; 2) relational capacity building is needed; and 3) institutional transformation is needed to value, resource, and support meaningful engagement. CONCLUSIONS: Supporting change that enables SCI researchers to adopt and implement the IKT Guiding Principles will require transformation at the individual (theme 1), relational (theme 2), and institutional levels (theme 3). Findings provide clear, practical, and tangible actions to promote change that can support meaningful engagement in the SCI Research System.

Providing researchers with clear, procedural information and strategies to use each of the Integrated Knowledge Translation Guiding Principles in practice can support the implementation of the principles and partnered research in rehabilitation-based research.Fostering and evaluating resources and initiatives that help researchers network, build connections, and receive mentorship could help spinal cord injury researchers partner more effectively.Academic, research, and funding systems must ensure their practices, structures, culture, and processes enable, value, resource, support, and/or incentivize partnered research to ensure the research being conducted is relevant and useful in addressing the needs and priorities of research users.

Discovery of TAK-960: an orally available small molecule inhibitor of polo-like kinase 1 (PLK1).

Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.