Publications

Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7(Δpan) mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7(Δpan) mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7(Δpan) mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses by liver metastasis 1 . Cancer-associated fibroblasts (CAF), extracellular matrix (ECM), and type I collagen (Col I) support 2–5 or restrain PDAC progression and may impede blood supply and nutrient availability 6–8 . The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers escape nutrient limitation remain poorly understood. Here we show that matrix metalloprotease (MMP)-cleaved or intact Col I (cCol I and iCol I, respectively) exert opposing effects on PDAC bioenergetics, macropinocytosis (MP), tumor growth and liver metastasis. While cCol I activates DDR1 (discoidin domain receptor-1)-NF-κB-p62-NRF2 signaling to promote PDAC growth, iCol I triggers DDR1 degradation and restrains PDAC growth. Patients whose tumors are enriched in iCol I and low in DDR1 and NRF2 have improved median survival compared to those enriched in cCol I, DDR1 and NRF2. Inhibition of DDR1-stimulated NF-κB or mitochondrial biogenesis blocked tumorigenesis in wildtype mice but not in mice expressing MMP-resistant Col I. In summary, the diverse effects of tumor stroma on PDAC growth, metastasis, and patient survival are mediated through the Col I-DDR1-NF-κB-NRF2-mitochondrial biogenesis pathway, presenting multiple new opportunities for PDAC therapy.

The study's purpose was to examine age, gender, and education as potential moderators of the associations of perceived neighborhood environment variables with accelerometer-based moderate-to-vigorous physical activity (MVPA). Data were from 7273 adults from 16 sites (11 countries) that were part of a coordinated multi-country cross-sectional study. Age moderated the associations of perceived crime safety, and perceiving no major physical barriers to walking, with MVPA: positive associations were only found in older adults. Perceived land use mix-access was linearly (positive) associated with MVPA in men, and curvilinearly in women. Perceived crime safety was related to MVPA only in women. No moderating relationships were found for education. Overall the associations of adults' perceptions of environmental attributes with MVPA were largely independent of the socio-demographic factors examined. These findings are encouraging, suggesting that efforts to optimize the perceived built and social environment may act in a socially-equitable manner to facilitate MVPA.

Factors that make people vulnerable to or resilient against posttraumatic stress disorder (PTSD) following overwhelming stress are not well understood. The objective of this study was to prospectively examine the relation between prior assault and new-onset PTSD symptoms in a large US military cohort deployed in the wars in Iraq and Afghanistan.Data on exposures and health outcomes were collected in the Millennium Cohort study at enrollment (July 2001 to June 2003) and follow-up (June 2004 to February 2006) from over 55,000 participants. Of these, 5324 were deployed in Iraq and Afghanistan, reported combat exposures, and were free of PTSD at baseline (881 women and 4443 men). We used multivariable logistic regression analysis to model the odds of new-onset PTSD in relation to prior assault.New-onset PTSD symptoms or diagnosis among deployers reporting combat exposures occurred in 22% of women who reported prior assault and 10% not reporting prior assault. Among men reporting prior assault, rates were 12% and 6%, respectively. Adjusting for baseline factors, the odds of new-onset PTSD symptoms was more than 2-fold higher in both women and men who reported assault prior to deployment.Prior assault appears to confer increased vulnerability for, rather than resilience against, PTSD symptoms among military professionals deployed to recent combat operations.

Background Healthy aging requires support from local built and social environments. Using latent profile analysis, this study captured the multidimensionality of the built environment and examined relations between objective and perceived built environment profiles, neighborhood social cohesion and quality of life among seniors. Methods In total, 693 participants aged 66–97 were sampled from two US locales in 2005–2008 as part of the Senior Neighborhood Quality of Life Study (SNQLS). Perceived social cohesion and quality of life were assessed using validated surveys. Six objective (geographic information system (GIS)-based) and seven perceived built environment latent profiles generated in previous SNQLS publications were used for analyses. Mixed-effects models estimated social cohesion and quality of life separately as a function of the built environment profiles. Results More walkable and destination-rich perceived built environment profiles were associated with higher social cohesion and quality of life. Objective built environment profiles were not associated with social cohesion and only positively associated with quality of life in only one locale (Baltimore/DC). Conclusions Latent profile analysis offered a comprehensive approach to assessing the built environment. Seniors who perceived their neighborhoods to be highly walkable and recreationally dense experienced higher neighborhood social cohesion and quality of life, which may set the stage for healthier aging.

2274 Preliminary evidence suggests that the physical environment and access to transportation affects physical activity levels of youth. One of the first steps in studying this topic is to establish reliable instruments with the population under study. PURPOSE: The objective of this study was to examine the test-retest reliability of a survey designed for youth to assess perceptions of environmental factors and access to transportation for physical activity. METHODS: Test and retest surveys were conducted on average 11 days apart with 480 sixth and eighth grade girls in or near Tuscon, AZ, San Diego, CA, New Orleans, LA, Baltimore, MD, Minneapolis, MN, and Columbia, SC. The instrument consisted of 24 questions on safety and aesthetics of the perceived environment and access to transportation and related facilities. Additionally, girls were asked if they were aware of 14 different recreational facilities (structured and unstructured activities), and if so, would they go there and was it easy to get there. Test-retest reliability was determined using unweighted (2 level items) and weighted (>=3 level items) kappa coefficients, overall and separately by grade. RESULTS: Item-specific reliability for 8 items assessing safety of the perceived environment ranged from 0.37-0.52, with no differences by grade. Four items assessing aesthetics ranged from 0.31-0.39, and 9 items assessing access to transportation ranged from 0.34-0.55. For some of these items, reliability was lower among 6th graders compared to 8th graders. Three items assessing access to facilities ranged from 0.42-0.58, with no differences by grade. Awareness of and interest in going to the 14 recreational facilities ranged from 0.47-0.64, and reports on being able to get to those locations ranged from 0.39-0.63. CONCLUSION: Test-retest reliability of this survey to assess perceptions of environmental factors and access to transportation for physical activity indicated fair to moderate agreement for most items among 6th and 8th grade girls. Further work is needed to improve reliability of these self-report items and to examine the association of these factors with physical activity. Supported by NIH/NHLBI.