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Context: Worksites can serve as community sites for local health jurisdictions (LHJs) to assist with implementation of evidence-based interventions (EBIs) to prevent and control chronic diseases., Objective: To assess the feasibility and effectiveness of using LHJ staff to disseminate Connect to Wellness (CtW), an effective dissemination package for increasing implementation of EBIs for chronic disease control by small worksites., Design: Single-arm, multisite intervention trial, with measurement at baseline, after 6 months of intervention, and after a maintenance period of 6 months., Setting: Six geographically dispersed counties in Washington State. Target worksites had 20 to 250 employees., Participants: Nine staff members from 6 LHJs delivered CtW to 35 worksites., Intervention: Connect to Wellness seeks to increase worksites' implementation of 14 EBIs classified as communication, policy, or program approaches to increasing 4 behaviors: cancer screening, healthy eating, physical activity, and tobacco cessation., Main Outcome Measure: Evidence-based intervention implementation measured on a scale from 0% to 100%., Results: Participating worksites showed a significant increase (P < .001, t test) in total mean implementation scores from baseline (33%) to 6-month follow-up (47%). Increases in implementation for communications, policy, healthy eating, and tobacco EBIs were statistically significant at 6 months and maintained at 12 months. Increased implementation at 6 months of a group physical activity program was not sustained after the program became unavailable, and total implementation scores at 12 months (38%) showed little change from baseline., Conclusions: Local health jurisdiction-delivered CtW increased worksites' implementation of EBIs at 6 months, and increased implementation in communication, policy, healthy eating, and tobacco was maintained at 12 months. This package, delivered by LHJ staff working part-time on CtW, was nearly as successful as prior delivery by staff working full-time on CtW., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc.)

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity., Competing Interests: The authors declare no conflict of interest.

Introduction: Although the regionalization of public health systems has been well documented in the case of emergency preparedness, there is little literature on the application of regional approaches to other aspects of public health. From 2011 through 2014 the Washington State Department of Health implemented a Community Transformation Grant to support community-level policy and systems changes to decrease chronic disease risk factors and increase access to clinical preventive services. The Department of Health implemented the grant through a regional model, grouping 32 of the state's 35 local health jurisdictions into 5 regions. Our process evaluation identifies the challenges and facilitators to Community Transformation Grant planning and implementation., Methods: We conducted 34 key informant interviews with people directly involved in the implementation of the Community Transformation Grant. We interviewed state and local partners, including representatives from each region, the Department of Health, external consultants, and regional partners. We collected data from October 2013 through July 2014., Results: Challenges for planning, building, and implementing a regional model for chronic disease prevention included stakeholder buy-in, regional geography, and communication; facilitators included shared regional history and infrastructure, strong leadership, collaborative relationships, shared vision and goals, sufficient funding, and direct technical assistance and training., Conclusion: Lessons learned in Washington State provide a foundation for other states interested in using a regional approach to reduce chronic disease risk. Policy and systems changes require adequate time, funding, and staffing. States and funders should work closely with local leaders to address these challenges and facilitators.

Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf(V600E) mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.

Purpose: To image a genetically engineered mouse model of non-small-cell lung cancer with micro-computed tomography (micro-CT) to measure tumor response to radiation therapy., Methods and Materials: The Cre-loxP system was used to generate primary lung cancers in mice with mutation in K-ras alone or in combination with p53 mutation. Mice were serially imaged by micro-CT, and tumor volumes were determined. A comparison of tumor volume by micro-CT and tumor histology was performed. Tumor response to radiation therapy (15.5 Gy) was assessed with micro-CT., Results: The tumor volume measured with free-breathing micro-CT scans was greater than the volume calculated by histology. Nevertheless, this imaging approach demonstrated that lung cancers with mutant p53 grew more rapidly than lung tumors with wild-type p53 and also showed that radiation therapy increased the doubling time of p53 mutant lung cancers fivefold., Conclusions: Micro-CT is an effective tool to noninvasively measure the growth of primary lung cancers in genetically engineered mice and assess tumor response to radiation therapy. This imaging approach will be useful to study the radiation biology of lung cancer., (Copyright 2010 Elsevier Inc. All rights reserved.)

Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells affected by radiation to cause the GI syndrome are derived from the epithelium or endothelium and whether the target cells die by apoptosis or other mechanisms are controversial issues. Studying mouse models, we found that selective deletion of the proapoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after sub-total-body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not from endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by the death of GI epithelial cells and that these epithelial cells die by a mechanism that is regulated by p53 but independent of apoptosis.

Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.

The basal eudicot Aquilegia (columbine) has an unusual floral structure that includes two morphologically distinct whorls of petaloid organs and a clearly differentiated fifth organ type, the staminodium. In this study, we have sought to determine how Aquilegia homologs of the B class genes APETALA3 (AP3) and PISTILLATA (PI) contribute to these novel forms of organ identity. Detailed expression analyses of the three AP3 paralogs and one PI homolog in wild-type and floral homeotic mutant lines reveal complex patterns that suggest that canonical B class function has been elaborated in Aquilegia. Yeast two-hybrid studies demonstrate that the protein products of Aquilegia's AP3 and PI homologs can form heterodimers, much like what has been observed for their core eudicot homologs. Downregulation of AqvPI using virus-induced gene silencing indicates that in addition to petal and stamen identity, this locus is essential to staminodial identity but may not control the identity of the petaloid sepals. Our findings show that preexisting floral organ identity programs can be partitioned and modified to produce additional organ types. In addition, they indicate that some types of petaloid organs are not entirely dependent on AP3/PI homologs for their identity.

Using gene expression profiling, we identified cathepsin cysteine proteases as highly up-regulated genes in a mouse model of human lung adenocarcinoma. Overexpression of cathepsin proteases in these lung tumors was confirmed by immunohistochemistry and Western blotting. Therefore, an optical probe activated by cathepsin proteases was selected to detect murine lung tumors in vivo as small as 1 mm in diameter and spatially separated. We generated 3D maps of the fluorescence signal and fused them with anatomical computed tomography images to show a close correlation between fluorescence signal and tumor burden. By serially imaging the same mouse, optical imaging was used to follow tumor progression. This study demonstrates the capability for molecular imaging of a primary lung tumor by using endogenous proteases expressed by a tumor. It also highlights the feasibility of using gene expression profiling to identify molecular targets for imaging lung cancer.

Spinicauda dugesii sp. n. (Heterakoidea, Heterakidae), parasite of the gut of the lizard Podarcis dugesii Milne-Edwards, 1829 (Reptilia, Lacertidae) from Madeira Island is described. Males of the new species are characterized by their narrow lateral alae, and curved and very chitinized spicules of the same length: females by their thick-shelled, almost round and embryonated eggs. At the external wall of the host's gut, parasitic cysts of this nematode with immature stages inside were also observed.