Publications

Characterization of HCC Mouse Models: Towards an Etiology-Oriented Subtyping Approach

Murine liver tumors often fail to recapitulate the complexity of human hepatocellular carcinoma (HCC), which might explain the difficulty to translate preclinical mouse studies into clinical science. The aim of this study was to evaluate a subtyping approach for murine liver cancer models with regard to etiology-defined categories of human HCC, comparing genomic changes, histomorphology, and IHC profiles. Sequencing and analysis of gene copy-number changes [by comparative genomic hybridization (CGH)] in comparison with etiology-dependent subsets of HCC patients of The Cancer Genome Atlas (TCGA) database were conducted using specimens (75 tumors) of five different HCC mouse models: diethylnitrosamine (DEN) treated wild-type C57BL/6 mice, c-Myc and AlbLTαβ transgenic mice as well as TAK1^LPC-KO and Mcl-1^Δhep mice. Digital microscopy was used for the assessment of morphology and IHC of liver cell markers (A6-CK7/19, glutamine synthetase) in mouse and <i>n</i> = 61 human liver tumors. Tumor CGH profiles of DEN-treated mice and c-Myc transgenic mice matched alcohol-induced HCC, including morphologic findings (abundant inclusion bodies, fatty change) in the DEN model. Tumors from AlbLTαβ transgenic mice and TAK1^LPC-KO models revealed the highest overlap with NASH-HCC CGH profiles. Concordant morphology (steatosis, lymphocyte infiltration, intratumor heterogeneity) was found in AlbLTαβ murine livers. CGH profiles from the Mcl-1^Δhep model displayed similarities with hepatitis-induced HCC and characteristic human-like phenotypes (fatty change, intertumor and intratumor heterogeneity). IMPLICATIONS: Our findings demonstrate that stratifying preclinical mouse models along etiology-oriented genotypes and human-like phenotypes is feasible. This closer resemblance of preclinical models is expected to better recapitulate HCC subgroups and thus increase their informative value.

SEX AND AGE DIFFERENCES IN POSSIBLE ENVIRONMENTAL CORRELATES OF PHYSICAL ACTIVITY IN 3 POPULATION BASED SAMPLES

Physical environments are the least studied potential determinants of physical activity. The aims of this study are to investigate sex and age differences in perceived environmental variables, and to study the relationship of environmental variables with physical activity. For 3 age groups, a random sample in Ghent, Belgium, was drawn. 2390 respondents participated: 980 16–25 years olds, 750 35–45 year olds and 660 50–65 year olds. Environmental variables included safety of the neighborhood, difficulty to walk or jog in the neighborhood, knowledge of exercise facilities in the region, and convenience of the facilities. A structured interview assessed leisure time physical activity over one year. Energy expenditure in low, moderate and vigorous activities for the past year were calculated. Knowledge about where facilities can be found declined with age. This decline was not found for perceived convenience of the listed facilities. Males in youngest group were able to locate more facilities (t = 4.83, P < 0.001), and females in the youngest group reported higher convenience (t = 2.82, P < 0.005). Perceived safety to walk alone during the day in the respondents' neighborhoods was high, with a mean of about 3 at a 4-point scale. However, women of all ages perceived their neighborhoods as less safe than men. Respondents of all age groups found it easy to walk or jog in their neighborhood, nothing few problems with dogs, traffic, lack of sidewalks, etc. (mean score above 3 on a 4-point scale). Significant correlations were found between the knowledge about the perceived convenience of facilities, and physical activity of almost all intensities in all three age groups (r between .08 and .32). Correlations with safety of the neighborhood were low but significant for physical activity of low and high intensity in the youngest age group (r = 0.11 and .08), and for physical activity of high intensity and walking in the oldest age group (r = .09). The perceived difficulty to walk or jog in the neighborhood was significantly related to walking and cycling in older adults (r = .10 and .11). Further research is needed to identify other environmental characteristics that may influence physical activity.

The Human Metallothionein Gene Family: Structure and Expression

Metallothioneins (MTs) are encoded by a multigene family in man. We have isolated those genes and analyzed the structure of some of them. The MT-II variant is encoded by a single functional gene: MT-IIA. The MT-IIB gene is a processed pseudogene derived from a reverse transcript of MT-II mRNA. On the other hand, the MT-I class of variants are encoded by a large number of genes, arranged in tandem. The MT-IIA and the MT-IA genes show a differential response to glucocorticoid hormones and heavy metals, yet they are both expressed in primary human fibroblasts and in HeLa cells. Expression of both of those genes, in high level after transfer on bovine papilloma virus vectors, leads to increased resistance of the host cells to cadmium-induced toxicity.

Direct Home Observations of the Prompting of Physical Activity in Sedentary and Active Mexican-and Anglo-American Children

Social interactions are important correlates of physical activity in children. Previous studies used global measures; the present study examined the influence of specific social interactions on immediate physical activity in children with data obtained from the Behaviors of Eating and Activity for Child Health: Evaluation System (BEACHES). The study examined parental and peer prompting of physical activity at home among 178 Mexican-American and 113 Anglo-American children at age 4 years and again at age 6.5 years. Most activity prompts came from adults interacting with children when they were sedentary. A reduction in the frequency of prompts from baseline to follow-up occurred in the prompter group (adult or child peer), gender, ethnicity, and preprompted activity level categories. Children's responses to these prompts showed that as they aged, they seemed to rely less on the interpersonal (especially adult) aspects of their environment for cues to be more active.

Efficacy of self-help behavior modification materials in smoking cessation.

Physical Activity Levels and Prompts in Young Children at Recess: A Two-Year Study of a Bi-Ethnic Sample

We investigated physical activity and encouragement for activity in a bi-ethnic cohort during recess. Activity and associated interactions of 287 children were recorded at preschool and again 2.2 years later. Children expended nearly twice as much energy at preschool recess than at elementary recess. Activity levels declined as recess time elapsed. At preschool, European-American children engaged in more moderate to vigorous activity than Mexican-Americans. As participants moved to elementary school, teachers' prompts to be active decreased and prompts from peers increased. Boys and girls received similar amounts of activity prompts at preschool, but prompts to boys increased over time. The findings suggest that school environments could be altered to promote healthful physical activity among young children.

Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production

Interplay of IKK/NF-κB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder associated with dystrophin deficiency that results in chronic inflammation and severe skeletal muscle degeneration. In DMD mouse models and patients, we find that IκB kinase/NF-κB (IKK/NF-κB) signaling is persistently elevated in immune cells and regenerative muscle fibers. Ablation of 1 allele of the p65 subunit of NF-κB was sufficient to improve pathology in mdx mice, a model of DMD. In addition, conditional deletion of IKKβ in mdx mice elucidated that NF-κB functions in activated macrophages to promote inflammation and muscle necrosis and in skeletal muscle fibers to limit regeneration through the inhibition of muscle progenitor cells. Furthermore, specific pharmacological inhibition of IKK resulted in improved pathology and muscle function in mdx mice. Collectively, these results underscore the critical role of NF-κB in the progression of muscular dystrophy and suggest the IKK/NF-κB signaling pathway as a potential therapeutic target for DMD.

A Lymphotoxin-Driven Pathway to Hepatocellular Carcinoma

Environmental and Safety Barriers to Youth Physical Activity in Neighborhood Parks and Streets: Reliability and Validity

Few studies have explored barriers to physical activity in parks and streets among children, adolescents, and their parents. The purpose of this article is to evaluate the psychometric properties of a new survey of barriers to physical activity in neighborhood parks and streets. Adolescents and parents of children and adolescents completed surveys twice. Two barrier subscales (environment and safety) emerged that applied to both locations and all participant groups. Results generally supported acceptable, internal consistency as well as construct validity, but test-retest reliabilities were lower than desired. These scales may be used to improve understanding of perceptions of barriers to physical activity in neighborhood parks and streets, but further development is needed.

Urban form correlates of pedestrian travel in youth: Differences by gender, race-ethnicity and household attributes

This paper looks at pedestrian travel in Atlanta by US youths aged 5–18 years. Relationships between five urban form variables and walking in specific demographic subgroups are assessed using stratified logistic models and controlling for participant demographics. All five urban form and recreation measures were related to walking among whites, but only land use mix and access to recreation spaces were significantly related to walking in non-whites. There were more significant urban form physical activity associations in high-income than in low-income households. More urban form variables were related to walking in households with 3 or more cars than in households with no cars. Living in mixed use-areas and having access to recreational space were related to youth walking for transport in 11 of 13 population subgroups studied.

A Commentary On Children and Fitness: A Public Health Perspective

(1987). A Commentary On Children and Fitness: A Public Health Perspective. Research Quarterly for Exercise and Sport: Vol. 58, No. 4, pp. 326-330.

TRANSPORTATION, HUMAN HEALTH, AND PHYSICAL ACTIVITY: RESOURCE PAPER

The design of communities and transportation systems is strongly related to nonmotorized transportation (NMT) behavior; however, the effect of environmental policy variables on total physical activity is not clear. Because large proportions of people in the United States live in the sprawling and exclusively residential environments associated with low levels of walking for transport, land use and transportation policies may already be having a substantial, although generally undocumented, impact on public health. Professionals from numerous fields are concerned that we have built our communities so that it is difficult, and in many cases dangerous, to walk or bike, and have thus engineered physical activity out of our daily lives. There is a public health imperative to evaluate environmental and policy variables and their associations with NMT, recreational physical activity, and total physical activity. The results of such studies can inform efforts to alter the environments in which people live their daily lives so as to promote population shifts in physical activity and improve transportation systems. Conducting and applying research on environmental correlates of NMT and physical activity will require collaboration among researchers from a wide range of professions.

Survey Report of Strategy Use

<i>Nod2</i> Mutation in Crohn's Disease Potentiates NF-κB Activity and IL-1ß Processing

Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor kappaB (NF-kappaB) and antibacterial defenses, but CD clinical specimens display elevated NF-kappaB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-kappaB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1beta (IL-1beta). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-kappaB activation and IL-1beta secretion.

Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB

Agreement between Student-Reported and Proxy-Reported Physical Activity Questionnaires

Parents and 531 students (46% males, 78% white) completed equivalent questionnaires. Agreement between student and parent responses to questions about hypothesized physical activity (PA) correlates was assessed. Relationships between hypothesized correlates and an objective measure of student's moderate-to-vigorous physical activity (MVPA) in a subset of 177 students were also investigated. Agreement between student and parent ranged from r = .34 to .64 for PA correlates. Spearman correlations between MVPA and PA correlates ranged from--.04 to .21 for student report and--.14 to .32 for parent report, and there were no statistical differences for 8 out of 9 correlations between parent and student. Parents can provide useful data on PA correlates for students in Grades 7-12.

New Approaches for Studying Alcoholic Liver Disease

Alcoholic liver disease (ALD) is major cause of chronic liver injury which results in liver fibrosis and cirrhosis. According to the surveillance report published by the National Institute on Alcohol Abuse and Alcoholism, liver cirrhosis is the 12th leading cause of death in the United States with 48 % of these deaths being attributed to excessive alcohol consumption. ALD includes a spectrum of disorders from simple steatosis to steatohepatitis, fibrosis, and hepatocellular carcinoma. Several mechanisms play a critical role in the pathogenesis of ALD. These include ethanol-induced oxidative stress and depletion of glutathione, pathological methionine metabolism, increased gut permeability and release of endotoxins into the portal blood, recruitment and activation of inflammatory cells including bone marrow-derived and liver resident macrophages (Kupffer cells). Chronic alcohol consumption results in liver damage and activation of hepatic stellate cells (HSCs) and myofibroblasts, leading to liver fibrosis. Here we discuss the current view on factors that are specific for different stages of ALD and those that regulate its progression, including cytokines and chemokines, alcohol-responsive intracellular signaling pathways, and transcriptional factors. We also review recent studies demonstrating that alcohol-mediated changes can be regulated on an epigenetic level, including microRNAs. Finally, we discuss the reversibility of liver fibrosis and inactivation of HSCs as a potential strategy for treating alcohol-induced liver damage.

Proteotyping of Mammary Tissue from Transgenic and Gene Knockout Mice with Immunohistochemical Markers: a Tool To Define Developmental Lesions

Through the use of transgenic and gene knockout mice, several studies have identified specific genes required for the functional development of mammary epithelium. Although histological and milk protein gene analyses can provide useful information regarding functional differentiation, they are limited in their ability to precisely define the molecular lesions. For example, mice that carry a mutation in one of the subunits of the IkappaB kinase, IKKalpha, cannot lactate despite the presence of histologically normal alveolar compartment and the expression of milk protein genes. To further define and understand such lesions on a molecular level, we sought evidence for proteins that are differentially expressed during mammary gland development with a view to generating a tissue proteotype. Using database screens and immunohistochemical analyses, we have identified three proteins that exhibit distinct profiles. Here, using mouse models as test biological systems, we demonstrate the development and application of mammary tissue proteotyping and its use in the elucidation of specific developmental lesions. We propose that the technique of proteotyping will have wide applications in the analyses of defects in other mouse models.