The art and science of a strategic grantmaker: the experience of the Public Health Agency of Canada's Innovation Strategy.

SETTING: The Public Health Agency of Canada's Innovation Strategy (PHAC-IS) was established amid calls for diverse structural funding mechanisms that could support research agendas to inform policy making across multiple levels and jurisdictions. Influenced by a shifting emphasis towards a population health approach and growing interest in social innovation and systems change, the PHAC-IS was created as a national grantmaking program that funded the testing and delivery of promising population health interventions between 2009 and 2020. INTERVENTION: During its decade-long tenure, the PHAC-IS supported the development of innovative, locally driven programs that emphasized health equity, encouraged iterative learning to respond reflexively to complex public health problems (the art), while at the same time promoting and integrating population health intervention research (the science) for improved health at the individual, community, and systems levels through four program components. OUTCOMES: PHAC-IS projects reached priority audiences in over 1700 communities. Over 1400 partnerships were established by community-led organizations across multiple sectors with more than $30 million of leveraged funds. By the final phase of funding, 90% of the projects and partnership networks had a sustained impact on policy and public health practice. By the end of the program, 82% of the projects were able to continue their intervention beyond PHAC-IS funding. Through a phased approach, projects were able to adapt, reflect, and build partnership networks to impact policy and practice while increasing reach and scale towards sustainability. IMPLICATIONS: Analysis and reflection throughout the course of this initiative showed that strong partnerships that contribute sufficient time to collaboration are critical to achieving meaningful outcomes. Building on evaluation cycles that strengthen project design can ensure both scale and sustainability of project achievements. Furthermore, a flexible, phased approach allows for iterative learning and adjustments across various phases to realize sustained population and systems change. The model and reflexive approach underlying the PHAC-IS has the potential to apply to a broad range of public programs.

RéSUMé: CONTEXTE: La Stratégie d'innovation de l'Agence de la santé publique du Canada (SI de l'ASPC) a été établie sur fonds d'appels demandant divers mécanismes de financement structurel qui pourraient soutenir les programmes de recherche et orienter l'élaboration des politiques à plusieurs niveaux et dans de nombreuses administrations. Influencée par une réorientation vers une approche axée sur la santé de la population et un intérêt croissant pour l'innovation sociale et le changement de systèmes, la SI de l'ASPC a été créée en tant que programme national d'octroi de subventions finançant la mise à l'essai et l'exécution d'interventions prometteuses en matière de santé de la population de 2009 à 2020. INTERVENTION: Au cours de ses dix ans de fonctionnement, la SI de l'ASPC a soutenu l'élaboration de programmes novateurs et locaux axés sur l'équité en santé et a encouragé l'apprentissage itératif afin de répondre instinctivement à des problèmes de santé publique complexes (l'art), tout en favorisant et en intégrant la recherche interventionnelle en santé de la population (la science) pour améliorer la santé au niveau des individus, des communautés et des systèmes au moyen de quatre éléments de programme. RéSULTATS: Les projets de la SI de l'ASPC ont rejoint des publics prioritaires dans plus de 1 700 communautés. Plus de 1 400 partenariats ont été établis par des organisations communautaires dans plusieurs secteurs, et plus de 30 millions de dollars de fonds ont été mobilisés. À la phase finale du financement, 90 % des projets et réseaux de partenariat avaient une incidence durable sur les politiques et pratiques en matière de santé publique. À la fin du programme, 82 % des projets ont pu poursuivre leur intervention au-delà du financement de la SI de l'ASPC. Grâce à une approche progressive, les projets ont pu s'adapter, réfléchir et créer des réseaux de partenariat pour avoir une incidence sur les politiques et pratiques tout en augmentant leur portée et leur mise à l'échelle vers la durabilité. IMPLICATIONS: L'analyse et la réflexion tout au long de cette initiative ont démontré que de solides partenariats qui accordent suffisamment de temps à la collaboration sont essentiels à l'obtention de résultats significatifs. S'appuyer sur des cycles d'évaluation qui permettent de renforcer la conception des projets peut favoriser la mise à l'échelle et la durabilité des réalisations des projets. De plus, l'adoption d'une approche flexible et progressive permet un apprentissage itératif et des ajustements à différentes phases pour réaliser des changements durables au sein de la population et des systèmes. Le modèle et l'approche réflexive qui sous-tendent la SI de l'ASPC pourraient être appliqués à un large éventail de programmes publics.

Readiness for scale-up: lessons learned from the Public Health Agency of Canada's Innovation Strategy.

SETTING: The Public Health Agency of Canada Innovation Strategy (PHAC-IS) funded the development and delivery of interventions that addressed priority population health issues over a 10-year period between 2009 and 2020. The design of the PHAC-IS funding program integrated the intentional effort of scale-up to increase the reach and impact of proven population health promotion interventions towards long-term, sustained impact benefit at individual, community, and systems levels. INTERVENTION: Recognizing that social innovation and adaptive cycles are necessary for effective scale-up, the PHAC-IS developed and applied a Scale-up Readiness Assessment Tool (SRAT) to assess the level of scale-up readiness of a funded project. OUTCOMES: Development of the SRAT included identifying predictors of success for the scale-up of effective population health interventions, organized into eight common characteristics among projects that indicated scale-up readiness: (1) intervention evidence and evaluation, (2) reach and scale, (3) organizational capacity, (4) partnership development, (5) system readiness, (6) community context, (7) cost factors, and (8) knowledge development and exchange. IMPLICATIONS: Although the SRAT was not a standalone decision-making rubric, it was a key part of a framework for review, consideration, and assessment for scale-up along a phased approach to funding. The development and application of the SRAT to measure readiness for scale-up provides insights into domains that can be used by funding organizations to inform scale-up decisions or for community organizations to assess their own readiness for scale-up.

RéSUMé: CONTEXTE: La Stratégie d'innovation de l'Agence de la santé publique du Canada (SI de l'ASPC) a financé l'élaboration et la mise en œuvre d'interventions liées à des questions prioritaires relatives à la santé de la population sur une période de 10 ans, de 2009 à 2020. La conception du programme de financement de la SI de l'ASPC comprend un effort déployé délibéré de mise à l'échelle pour accroître la portée et l'incidence des interventions éprouvées de promotion de la santé de la population et produire des avantages à long terme et durables pour les personnes, les collectivités et le système. INTERVENTION: Reconnaissant que l'innovation sociale et les cycles d'adaptation sont nécessaires pour une mise à l'échelle efficace, un outil d'évaluation de l'état de préparation à la mise à l'échelle (OEPME) a été élaboré et appliqué dans le cadre de la SI de l'ASPC pour évaluer le niveau de préparation à une mise à l'échelle d'un projet financé. RéSULTATS: L'élaboration de l'OEPME a inclus la détermination d'indicateurs de réussite pour la mise à l'échelle d'interventions efficaces en santé de la population, classés selon huit caractéristiques communes chez les projets ayant indiqués être prêt à une mise à l'échelle : 1) données probantes sur l'intervention et évaluation, 2) portée et échelle, 3) capacité organisationnelle, 4) établissement de partenariats, 5) état de préparation du système, 6) contexte communautaire, 7) facteurs de coût et 8) développement et échange de connaissances. IMPLICATIONS: Bien que l'OEPME ne soit pas une rubrique décisionnelle autonome, il constitue un élément clé d'un cadre d'examen, d'étude et d'évaluation en vue d'une mise à l'échelle qui s'inscrit dans une approche progressive de financement. L'élaboration et l'application de l'OEPME afin de mesurer l'état de préparation à la mise à l'échelle fournit de l'information sur des domaines qui peut être utilisée par les organismes de financement pour éclairer les décisions de mise à l'échelle ou par les organisations communautaires pour évaluer leur propre état de préparation à une mise à l'échelle.

"The magic is in the mix": lessons from research capacity building in the Canadian tobacco control community, 2000-2010.

Global public health issues, including tobacco use, will be addressed most effectively if informed by relevant evidence. Additional capacity is needed to undertake and sustain relevant and rigorous research that will inform and enable learning from interventions. Despite the undisputed importance of research capacity building (RCB), there is little evidence about how to create relevant capacities. RCB for tobacco control in Canada from 2000-2010 offers a rich experience from which to learn. Lessons were derived using structured data collection from seven capacity-building initiatives and an invitational workshop, at which reflections on major contributions and lessons learned were discussed by initiative leads. Ten years of RCB for tobacco control in Canada revealed the importance of a) taking an organic approach to RCB, b) targeting and sustaining investments in a mix of RCB activities, c) vision and collaborative leadership at organizational and initiative levels, d) a focus on building community, and e) studying capacity building. The experience also provided tangible examples of RCB initiatives and how independent investments can be linked to create a coherent approach. Looking ahead, promising directions may include positioning RCB within a broader context of "field building", focusing on practical approaches to sustainability, and enhancing research on RCB.

Efficacy of systemically administered mutant vesicular stomatitis virus (VSVDelta51) combined with radiation for nasopharyngeal carcinoma.

PURPOSE: Nasopharyngeal carcinoma (NPC) is a malignancy of the head and neck region that is associated with EBV latency. Curative treatments for NPC achieve modest survival rates, underscoring a need to develop novel therapies. We evaluated the therapeutic potential of a mutant vesicular stomatitis virus (VSVDelta51) as single treatment modality or in combination with ionizing radiation (RT) in NPC. EXPERIMENTAL DESIGN: MTS assay was used to assess cell viability in vitro; apoptosis was measured using propidium iodide staining and caspase activation. In vivo experiments were conducted using tumor-bearing nude mice with or without local RT (4 Gy). Apoptosis was assessed in excised tumor sections with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. RESULTS: Our data showed that NPC cells are exquisitely sensitive to VSVDelta51 oncolysis, which correlated with the presence of EBV. Efficacy of VSVDelta51 against NPC cells was further augmented when combined with RT. A single systemic injection of VSVDelta51 achieved 50% survival in treated mice, which increased to 83% when combined with local tumor RT. In addition to induction of apoptosis, an antiangiogenic effect of VSVDelta51 was observed in vivo, suggesting a novel tumoricidal mechanism for VSVDelta51. This virus also prevented growth of NPC sphere-forming cells in vitro, showing potential utility in targeting NPC-initiating cells. CONCLUSIONS: Our data represent the first report showing that EBV-positive NPC cells are exquisitely sensitive to VSVDelta51 oncolysis and documenting the successful utilization of this combinatorial regimen as a novel curative therapeutic strategy for NPC.

Nuclear factor-Y and Epstein Barr virus in nasopharyngeal cancer.

PURPOSE: The Epstein Barr virus (EBV) is intimately associated with nasopharyngeal cancer (NPC) in a latent state expressing a limited number of genes. The process of switching from latency to replication is not well understood, particularly in response to DNA stress; hence, the focus of this study is on an EBV-positive NPC model. EXPERIMENTAL DESIGN: C666-1 cells were exposed to radiation (2-15 Gy) or cisplatin (0.1-50 microg/mL) assayed subsequently for relative EBV copy number (BamHI) and lytic gene expression (BRLF1 and BZLF1) using quantitative real-time PCR. Chromatin immunoprecipitation was conducted to assess the interaction of the transcription factor nuclear factor-Y (NF-Y) with promoter sequences. RESULTS: Radiation-induced and cisplatin-induced BamHI expression, along with increased levels of BRLF1 and BZLF1 in a dose-dependent and time-dependent manner, associated with the immediate nuclear transactivation of the transcription factor NF-Y and its own increased transcription of NF-Y subunits 8 h posttreatment. In silico analysis revealed three putative NF-Y consensus-binding sequences in the promoter region of BRLF1, which all interacted with NF-Y in response to radiation and cisplatin, confirmed using chromatin immunoprecipitation. Introduction of dominant-negative NF-YA reduced BRLF1 expression after radiation and cisplatin by 2.8-fold; in turn, overexpression of NF-YA resulted in a 2-fold increase in both BRLF1 and BZLF1 expression. CONCLUSIONS: These results show that NF-Y is an important mediator of EBV stress response in switching from a latent to lytic state. This novel insight could provide a potential therapeutic strategy to enhance NPC response to radiation and cisplatin.

Potential utility of BimS as a novel apoptotic therapeutic molecule.

We have previously demonstrated a 1000-fold induction of gene expression exclusive to Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) cells using an adenoviral vector (ad5.oriP). This platform allows us to explore tumor-specific gene therapy with BimS (ad5.oriP.BimS), a potent proapoptotic Bcl-2 family member. Ad5.oriP.BimS (25 infectious units (ifu)/cell) reduced C666-1 viability in a time- and dose-dependent manner to 15% survival. The effect was enhanced with radiation (6 Gy). Three days after infection, the proportion of apoptotic cells increased from 3.5% (control) to 47.5% (25 ifu/cell). Confocal microscopy demonstrated Bim colocalization to the mitochondria within 18 h of ad5.oriP.BimS infection. Ad5.oriP.BimS induced a 2.8-, 2.1-, and 1.85-fold increase in caspase-3, -8, and -9 activities, respectively. When C666-1 cells were infected with ad5.oriP.BimS (20 ifu/cell), no tumors formed in 7/9 mice followed for 100 days. Six intratumoral injections of ad5.oriP.BimS (1.5 x 10(9) ifu/dose) in combination with radiation were sufficient to cause almost complete disappearance of established C666-1 or C15 xenograft tumors. Intravenous injections of ad5.oriP.BimS (10(9) ifu) induced mild perturbation in liver function tests, associated with hepatocyte apoptoses and mitoses. This vector appears to be safe and effectively cytotoxic to EBV-positive NPC cells both in vitro and in vivo, mediated primarily through the induction of apoptosis.

A conditionally replicating adenovirus for nasopharyngeal carcinoma gene therapy.

Successful attainment of tumor-specific gene expression was achieved in nasopharyngeal carcinoma (NPC) by exploiting the exclusive presence of the Epstein-Barr virus (EBV) genome in the cancer cells. In the current study, we have utilized an EBV-dependent transcriptional targeting strategy to construct a novel conditionally replicating adenovirus, adv.oriP.E1A. After treatment with adv.oriP.E1A, we observed extensive cell death in the EBV-positive NPC cell line C666-1. In contrast, no cytotoxicity was observed in a panel of other human EBV-negative cell lines, including fibroblasts from the nasopharynx. In vitro adenoviral replication was confirmed by the time-dependent increase in the expression of adenoviral capsid fiber protein and adenoviral DNA after C666-1 cells were infected with adv.oriP.E1A. Tumor formation was inhibited for more than 100 days after ex vivo infection of C666-1 cells with adv.oriP.E1A. Combination of local tumor radiation and adv.oriP.E1A caused complete disappearance of established tumors for at least 2 weeks in two distinct EBV-positive NPC xenograft models. Safety of this treatment was determined through the systemic delivery of adv.oriP.E1A in vivo, whereby minimal temporary perturbation of liver function was observed. We have successfully established a conditionally replicating adenovirus for EBV-positive NPC, which is both safe and efficacious, indicating a strategy that may be therapeutically applicable.

Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins.

Signal transduction pathways are typically controlled by protein-protein interactions, which are mediated by specific modular domains. One hypothetical use of such interaction domains is to generate new signaling pathways and networks during eukaryotic evolution, through the joining of distinct binding modules in novel combinations. In this manner, new polypeptides may be formed that make innovative connections among preexisting proteins. Adaptor proteins are specialized signaling molecules composed exclusively of interaction domains, that frequently link activated cell surface receptors to their intracellular targets. Receptor tyrosine kinases (RTKs) recruit adaptors, such as Grb2 and ShcA, that activate signaling pathways involved in growth and survival, whereas death receptors bind adaptors, such as Fadd, that promote apoptosis. To test the ability of interaction domains to create new signaling pathways, we have fused the phosphotyrosine recognition domains of Grb2 (Scr homology 2 domain) or ShcA (phosphotyrosine-binding domain) to the death effector domain of Fadd. We find that these chimeric adaptors can reroute mitogenic or transforming RTK signals to induce caspase activation and cell death. These hybrid adaptors can be used to selectively kill oncogenic cells in which RTK activity is deregulated.

Direct measure of insulin sensitivity with the hyperinsulinemic-euglycemic clamp and surrogate measures of insulin sensitivity with the oral glucose tolerance test: correlations with aberrant crypt foci promotion in rats.

The similarity in lifestyle risk factors for the development of colorectal cancer (CRC) and type 2 diabetes suggests that there are common underlying pathogenic mechanisms. High-risk lifestyle factors may lead to insulin resistance that, through increased circulating levels of energy substrates, insulin, and insulin-like growth factor-1, may promote the development of CRC. The objective was to determine the extent to which direct and surrogate measures of insulin resistance correlate with multiplicity of aberrant crypt foci, which are putative precursors of CRC. Rats were initiated with the carcinogen azoxymethane, then fed low, intermediate, or high saturated fat diets. Metabolic parameters were assessed at 50 days and ACF at 100 days after initiation. Results indicate that CRC promotion was most strongly correlated with direct measures of insulin sensitivity as assessed with the hyperinsulinemic-euglycemic clamp (r = -0.52, P < 0.009). Practical surrogate measures of insulin resistance such as insulin levels at 180 min after an oral glucose load were strongly correlated with direct measures of insulin sensitivity (r = -0.61, P < 0.001) and with CRC promotion (r = 0.42, P = 0.044) in this animal model. Fasting levels of glucose, insulin, total insulin-like growth factor-1, nonesterified fatty acids, and triglyceride, as well as body weight and insulin sensitivity indices (such as fasting insulin resistance index, quantitative insulin sensitivity check index, homeostasis model assessment formula, insulin sensitivity index of glycemia, oral glucose insulin sensitivity, and composite insulin sensitivity index for the hepatic and peripheral tissues) were all less strongly correlated with direct measures of insulin sensitivity and all poorly correlated with CRC promotion in this animal model. These correlations do not prove causality, however, they suggest possible mechanisms linking diet, insulin resistance with its related parameters, and promotion of CRC.