BackgroundPolicy has a tremendous potential to improve population health when informed by research evidence. Such evidence, however, typically plays a suboptimal role in policymaking processes. The field of policy dissemination and implementation research (policy D&I) exists to address this challenge. The purpose of this study was to: (1) determine the extent to which policy D&I was funded by the National Institutes of Health (NIH), (2) identify trends in NIH-funded policy D&I, and (3) describe characteristics of NIH-funded policy D&I projects.MethodsThe NIH Research Portfolio Online Reporting Tool was used to identify all projects funded through D&I-focused funding announcements. We screened for policy D&I projects by searching project title, abstract, and term fields for mentions of “policy,” “policies,” “law,” “legal,” “legislation,” “ordinance,” “statute,” “regulation,” “regulatory,” “code,” or “rule.” A project was classified as policy D&I if it explicitly proposed to conduct research about the content of a policy, the process through which it was developed, or outcomes it produced. A coding guide was iteratively developed, and all projects were independently coded by two researchers. ClinicalTrials.gov and PubMed were used to obtain additional project information and validate coding decisions. Descriptive statistics—stratified by funding mechanism, Institute, and project characteristics—were produced.ResultsBetween 2007 and 2014, 146 projects were funded through the D&I funding announcements, 12 (8.2 %) of which were policy D&I. Policy D&I funding totaled $16,177,250, equivalent to 10.5 % of all funding through the D&I funding announcements. The proportion of funding for policy D&I projects ranged from 14.6 % in 2007 to 8.0 % in 2012. Policy D&I projects were primarily focused on policy outcomes (66.7 %), implementation (41.7 %), state-level policies (41.7 %), and policies within the USA (83.3 %). Tobacco (33.3 %) and cancer (25.0 %) control were the primary topics of focus. Many projects combined survey (58.3 %) and interview (33.3 %) methods with analysis of archival data sources.ConclusionsNIH has made an initial investment in policy D&I research, but the level of support has varied between Institutes. Policy D&I researchers have utilized a variety of designs, methods, and data sources to investigate the development processes, content, and outcomes of public and private policies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13012-015-0367-1) contains supplementary material, which is available to authorized users.

Runx1/AML1 is a transcription factor implicated in tissue stem cell regulation and belongs to the small Runx family of cancer genes. In the hair follicle (HF), Runx1 epithelial deletion in morphogenesis impairs normal adult hair homeostasis (cycle) and blocks adult hair follicle stem cells (HFSCs) in quiescence. Here, we show that these effects are overcome later in adulthood. By deleting Runx1 after the end of morphogenesis, we demonstrate its direct role in promoting anagen onset and HFSC proliferation. Runx1 deletion resulted in cyclin-dependent kinase inhibitor Cdkn1a (p21) upregulation. Interfering with Runx1 function in cultured HFSCs impaired their proliferation and normal G 0 /G1 and G 1 /S cell cycle progression. The proliferation defect could be rescued by Runx1 readdition or by p21 deletion. Chemically induced skin tumorigenesis in mice turned on broad Runx1 expression in regions of the skin epithelium, papillomas, and squamous cell carcinomas. In addition, it revealed reduced rates of tumor formation in the absence of Runx1 that were accompanied by decreased epithelial levels of phospho-Stat3. Runx1 protein expression was similar in normal human and mouse hair cycles. We propose that Runx1 may act as a skin oncogene by directly promoting proliferation of the epithelial cells.

Cysteine homeostasis is dependent on the regulation of cysteine dioxygenase (CDO) in response to changes in sulfur amino acid intake. CDO oxidizes cysteine to cysteinesulfinate, which is further metabolized to either taurine or to pyruvate plus sulfate. To gain insight into the physiological function of CDO and the consequence of a loss of CDO activity, mice carrying a null CDO allele (CDO(+/-) mice) were crossed to generate CDO(-/-), CDO(+/-), and CDO(+/+) mice. CDO(-/-) mice exhibited postnatal mortality, growth deficit, and connective tissue pathology. CDO(-/-) mice had extremely low taurine levels and somewhat elevated cysteine levels, consistent with the lack of flux through CDO-dependent catabolic pathways. However, plasma sulfate levels were slightly higher in CDO(-/-) mice than in CDO(+/-) or CDO(+/+) mice, and tissue levels of acid-labile sulfide were elevated, indicating an increase in cysteine catabolism by cysteine desulfhydration pathways. Null mice had lower hepatic cytochrome c oxidase levels, suggesting impaired electron transport capacity. Supplementation of mice with taurine improved survival of male pups but otherwise had little effect on the phenotype of the CDO(-/-) mice. H(2)S has been identified as an important gaseous signaling molecule as well as a toxicant, and pathology may be due to dysregulation of H(2)S production. Control of cysteine levels by regulation of CDO may be necessary to maintain low H(2)S/sulfane sulfur levels and facilitate the use of H(2)S as a signaling molecule.

Previous studies showed that a considerable proportion of Listeria monocytogenes isolates obtained from foods carry a premature stop codon (PMSC) mutation in inlA that leads to production of a truncated and secreted InlA. To further elucidate the role these mutations play in virulence of L. monocytogenes, we created isogenic mutants, including (i) natural isolates where an inlA PMSC was reverted to a wild-type inlA allele (without a PMSC) and (ii) natural isolates where a PMSC mutation was introduced into a wild-type inlA allele; isogenic mutant sets were constructed to represent two distinct inlA PMSC mutations. Phenotypical and transcriptional analysis data showed that inlA PMSC mutations do not have a polar effect on the downstream inlB. Isogenic and natural strains carrying an inlA PMSC showed significantly reduced invasion efficiencies in Caco-2 and HepG2 cell lines as well as reduced virulence in oral guinea pig infections. Guinea pigs were also orally infected with a natural strain carrying the most common inlA PMSC mutation (vaccinated group), followed by challenge with a fully virulent L. monocytogenes strain 15 days postvaccination to probe potentially immunizing effects of exposure to L. monocytogenes with inlA PMSC mutations. Vaccinated guinea pigs showed reduced bacterial loads in internal organs and improved weight gain postchallenge, indicating reduced severity of infections in guinea pigs exposed to natural strains with inlA PMSC mutations. Our data support that (i) inlA PMSC mutations are causally associated with attenuated virulence in mammalian hosts and (ii) naturally occurring virulence-attenuated L. monocytogenes strains commonly found in food confer protective immunity.

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This study compares clinical, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and pathology findings in 16 prospectively, and seven retrospectively recruited dogs presented for suspected thyroid carcinoma. Of these, 17 were confirmed thyroid carcinoma, while six were initially misdiagnosed. These included four carotid body tumors, one para-esophageal abscess, and one undifferentiated squamous cell carcinoma. Thyroid carcinomas occurred in older dogs without evidence of sex predilection, and were more often unilateral. All were large, heterogeneous, moderately to strongly vascularized, and most commonly contained areas of dystrophic mineralization and/or fluid accumulations. On MRI, thyroid carcinomas appeared hyperintense compared to surrounding musculature in all imaging sequences used, while on CT they had a lower attenuation value than normal thyroid gland tissue. Histologically confirmed tumor capsule disruption with invasion of the surrounding structures was most commonly detected with MRI. Palpation was not an accurate predictor of locally invasive vs. well-encapsulated masses. Computed tomography had the highest specificity (100%) and MRI had the highest sensitivity (93%) in diagnosing thyroid carcinoma, while ultrasound had considerably lower results. We conclude that ultrasound is adequate for use as a screening tool for dogs with suspected thyroid carcinoma, but recommend either CT or MRI for preoperative diagnosis and staging. C 2012 Veterinary Radiology & Ultrasound.

BackgroundMicroRNAs (miRNA) are varied in length, under 25 nucleotides, single-stranded noncoding RNA that regulate post-transcriptional gene expression via translational repression or mRNA degradation. Elevated levels of miRNAs can be detected in systemic circulation after tissue injury, suggesting that miRNAs are released following cellular damage. Because of their remarkable stability, ease of detection in biofluids, and tissue specific expression patterns, miRNAs have the potential to be specific biomarkers of organ injury. The identification of miRNA biomarkers requires a systematic approach: 1) determine the miRNA tissue expression profiles within a mammalian species via next generation sequencing; 2) identify enriched and/or specific miRNA expression within organs of toxicologic interest, and 3) in vivo validation with tissue-specific toxicants. While miRNA tissue expression has been reported in rodents and humans, little data exists on miRNA tissue expression in the dog, a relevant toxicology species. The generation and evaluation of the first dog miRNA tissue atlas is described here.ResultsAnalysis of 16 tissues from five male beagle dogs identified 106 tissue enriched miRNAs, 60 of which were highly enriched in a single organ, and thus may serve as biomarkers of organ injury. A proof of concept study in dogs dosed with hepatotoxicants evaluated a qPCR panel of 15 tissue enriched miRNAs specific to liver, heart, skeletal muscle, pancreas, testes, and brain. Dogs with elevated serum levels of miR-122 and miR-885 had a correlative increase of alanine aminotransferase, and microscopic analysis confirmed liver damage. Other non-liver enriched miRNAs included in the screening panel were unaffected. Eli Lilly authors created a complimentary Sprague Dawely rat miRNA tissue atlas and demonstrated increased pancreas enriched miRNA levels in circulation, following caerulein administration in rat and dog.ConclusionThe dog miRNA tissue atlas provides a resource for biomarker discovery and can be further mined with refinement of dog genome annotation. The 60 highly enriched tissue miRNAs identified within the dog miRNA tissue atlas could serve as diagnostic biomarkers and will require further validation by in vivo correlation to histopathology. Once validated, these tissue enriched miRNAs could be combined into a powerful qPCR screening panel to identify organ toxicity during early drug development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2958-x) contains supplementary material, which is available to authorized users.

Canine ALF is associated with multiple etiologies and a high mortality rate. Strategies to increase survival are urgently required.