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Intronic GGGGCC (G4C2) hexanucleotide repeat expansion within the human C9orf72 gene represents the most common cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Repeat‐associated non‐AUG (RAN) translation of repeat‐containing C9orf72 RNA results in the production of neurotoxic dipeptide‐repeat proteins (DPRs). Here, we developed a high‐throughput drug screen for the identification of positive and negative modulators of DPR levels. We found that HSP90 inhibitor geldanamycin and aldosterone antagonist spironolactone reduced DPR levels by promoting protein degradation via the proteasome and autophagy pathways respectively. Surprisingly, cAMP‐elevating compounds boosting protein kinase A (PKA) activity increased DPR levels. Inhibition of PKA activity, by both pharmacological and genetic approaches, reduced DPR levels in cells and rescued pathological phenotypes in a Drosophila model of C9ALS/FTD. Moreover, knockdown of PKA‐catalytic subunits correlated with reduced translation efficiency of DPRs, while the PKA inhibitor H89 reduced endogenous DPR levels in C9ALS/FTD patient‐derived iPSC motor neurons. Together, our results suggest new and druggable pathways modulating DPR levels in C9ALS/FTD., Screening small‐molecule agonists for the ability to modulate accumulation of toxic polypeptides suggests PKA signaling, proteasomal and autophagy pathways as potential therapeutic targets for C9orf72‐associated ALS/FTD.

Background Numerous agencies are providing training, technical assistance, and other support to build community-based practitioners’ capacity to adopt and implement evidence-based prevention interventions. Yet, little is known about how best to design capacity-building interventions to optimize their effectiveness. Wandersman et al. (Am J Community Psychol.50:445–59, 2102) proposed the Evidence-Based System of Innovation Support (EBSIS) as a framework to guide research and thereby strengthen the evidence base for building practitioners’ capacity. The purpose of this review was to contribute to further development of the EBSIS by systematically reviewing empirical studies of capacity-building interventions to identify (1) the range of strategies used, (2) variations in the way they were structured, and (3) evidence for their effectiveness at increasing practitioners’ capacity to use evidence-based prevention interventions. Methods PubMed, EMBASE, and CINAHL were searched for English-language articles reporting findings of empirical studies of capacity-building interventions that were published between January 2000 and January 2014 and were intended to increase use of evidence-based prevention interventions in non-clinical settings. To maximize review data, studies were not excluded a priori based on design or methodological quality. Using the EBSIS as a guide, two researchers independently extracted data from included studies. Vote counting and meta-summary methods were used to summarize findings. Results The review included 42 publications reporting findings from 29 studies. In addition to confirming the strategies and structures described in the EBSIS, the review identified two new strategies and two variations in structure. Capacity-building interventions were found to be effective at increasing practitioners’ adoption (n = 10 of 12 studies) and implementation (n = 9 of 10 studies) of evidence-based interventions. Findings were mixed for interventions’ effects on practitioners’ capacity or intervention planning behaviors. Both the type and structure of capacity-building strategies may have influenced effectiveness. The review also identified contextual factors that may require variations in the ways capacity-building interventions are designed. Conclusions Based on review findings, refinements are suggested to the EBSIS. The refined framework moves the field towards a more comprehensive and standardized approach to conceptualizing the types and structures of capacity-building strategies. This standardization will assist with synthesizing findings across studies and guide capacity-building practice and research. Electronic supplementary material The online version of this article (doi:10.1186/s13012-015-0272-7) contains supplementary material, which is available to authorized users.

Many barriers to cervical cancer screening for Hispanic women have been documented, but few effective interventions exist. The Community Preventive Services Task Force recommends increasing cervical cancer screening through various methods. Building on this evidence, the Centers for Disease Control and Prevention funded the research and testing phases for an evidence-based and theoretically grounded intervention designed to increase cervical cancer screening among never and rarely screened Hispanic women of Mexican descent. In this article, we describe the development process of the AMIGAS (Ayudando a las Mujeres con Información, Guía, y Amor para su Salud) intervention, highlight the integration of scientific evidence and community-based participatory research principles, and identify opportunities for dissemination, adaptation, and implementation of this intervention.The AMIGAS team was a collaboration among researchers, promotoras (community health workers), and program administrators. The multiyear, multiphase project was conducted in Houston, Texas; El Paso, Texas; and Yakima, Washington. The team completed several rounds of formative research, designed intervention materials and methodology, conducted a randomized controlled trial, created a guide for program administrators, and developed an intervention dissemination plan.Trial results demonstrated that AMIGAS was successful in increasing cervical cancer screening among Hispanic women. Adaptation of AMIGAS showed minimal reduction of outcomes. Dissemination efforts are underway to make AMIGAS available in a downloadable format via the Internet.Developing a community-based intervention that is evidence-based and theoretically grounded is challenging, time-intensive, and requires collaboration among multiple disciplines. Inclusion of key stakeholders-in particular program deliverers and administrators-and planning for dissemination and translation to practice are integral components of successful intervention design. By providing explicit directions for adaptation for program deliverers, relevant information for program administrators, and access to the intervention via the Internet, AMIGAS is available to help increase cervical cancer screening among Hispanic women and other women disproportionately affected by cervical cancer.

Introduction CDC's Colorectal Cancer Control Program (CRCCP) funds 25 states and 4 tribal organizations to promote and increase colorectal cancer screening population-wide. The CRCCP grantees must use evidence-based strategies from the Guide to Community Preventive Services, including small media and client reminders. Methods To assess the existing resources and needs to promote colorectal cancer screening, we conducted 2 web-based surveys of CRCCP grantees and their community partners. Survey 1 sought to identify priority populations, the number and quality of existing colorectal cancer resources for different population subgroups, and the types of small media and client reminder they were most interested in using. Survey 2 assessed screening messages that were used in the past or might be used in the future, needs for non-English-language information, and preferences for screening-related terminology. Results In survey 1 (n = 125 from 26 CRCCPs), most respondents (83%) indicated they currently had some information resources for promoting screening but were widely dissatisfied with the quality and number of these resources. They reported the greatest need for resources targeting rural populations (62% of respondents), men (53%), and Hispanics (45%). In survey 2 (n = 57 from 25 CRCCPs), respondents indicated they were most likely to promote colorectal cancer screening using messages that emphasized family (95%), role models (85%), or busy lives (83%), and least likely to use messages based on faith (26%), embarrassment (25%), or fear (22%). Nearly all (85%) indicated a need for resources in languages other than English; 16 different languages were mentioned, most commonly Spanish. Conclusion These findings provide the first picture of CRCCP information resources and interests, and point to specific gaps that must be addressed to help increase screening.