Publications

Androgen-deprived prostate cancer (PCa) is infiltrated by B lymphocytes that produce cytokines that activate IκB kinase α (IKKα) to accelerate the emergence of castration-resistant tumors. We now demonstrate that infiltrating B lymphocytes and IKKα are also required for androgen-dependent expansion of epithelial progenitors responsible for prostate regeneration. In these cells and in PCa cells, IKKα phosphorylates transcription factor E2F1 on a site that promotes its nuclear translocation, association with the coactivator CBP, and recruitment to critical genomic targets that include Bmi1, a key regulator of normal and cancerous prostate stem cell renewal. The IKKα-BMI1 pathway is also activated in human PCa.

TROST, S. G., N. OWEN, A. E. BAUMAN, J. F. SALLIS, and W. BROWN. Correlates of adults' participation in physical activity: review and update. Med. Sci. Sports Exerc., Vol. 34, No. 12, pp. 1996–2001, 2002. Purpose To review and update the evidence relating to the personal, social, and environmental factors associated with physical activity (PA) in adults. Methods Systematic review of the peer-reviewed literature to identify papers published between 1998 and 2000 with PA (and including exercise and exercise adherence). Qualitative reports or case studies were not included. Results Thirty-eight new studies were located. Most confirmed the existence of factors already known to be correlates of PA. Changes in status were noted in relation to the influence of marital status, obesity, smoking, lack of time, past exercise behavior, and eight environmental variables. New studies were located which focused on previously understudied population groups such as minorities, middle and older aged adults, and the disabled. Conclusion The newly reported studies tend to take a broader "ecological" approach to understanding the correlates of PA and are more focused on environmental factors. There remains a need to better understand environmental influences and the factors that influence different types of PA. As most of the work in this field still relies on cross-sectional studies, longitudinal and intervention studies will be required if causal relationships are to be inferred.

To develop an epidemiological profile of children that work in the streets of Tijuana, Mexico, and to determine the prevalence of cigarette smoking in this group, as well as the prevalence of those factors associated with tobacco experimentation.cross-sectional.Children aged 8 through 15, who work in the streets of Tijuana were included. Demographic, socioeconomic, and smoking related variables were analyzed.The study included 110 children, with a mean age of 11.43 years. Of these 91.7% live with one or both of their parents; 60% attend school and an additional 30% did so in the past. Only 6.4% of these children are the principal economic support of the household, and 51.8% reported an average daily income of $US 10 or less. Only 9.1% reported experimentation with tobacco, and 31% of them tobacco prompting (in the form of lighting up a cigarette) by an adult of the family; this is significantly more frequent on behalf of the father than of the mother (21.8% vs 4.5% p < 0.001).Most of the children under 15 years of age who work in the streets of Tijuana live with their parents and maintain close relationships with their family. Most of them attend school and work in the streets only to complement the family income. Their tobacco experimentation is not greater than that of other children of the same age group.

&lt;div&gt;Abstract&lt;p&gt;Myeloid cells are capable of promoting or eradicating tumor cells and the nodal functions that contribute to their different roles are still obscure. Here, we show that mice with myeloid-specific genetic loss of the NF-κB pathway regulatory kinase IKKβ exhibit more rapid growth of cutaneous and lung melanoma tumors. In a &lt;i&gt;BRAF&lt;sup&gt;V600E/PTEN&lt;sup&gt;−/−&lt;/sup&gt;&lt;/sup&gt;&lt;/i&gt; allograft model, IKKβ loss in macrophages reduced recruitment of myeloid cells into the tumor, lowered expression of MHC class II molecules, and enhanced production of the chemokine CCL11, thereby negatively regulating dendritic-cell maturation. Elevated serum and tissue levels of CCL11 mediated suppression of dendritic-cell differentiation/maturation within the tumor microenvironment, skewing it toward a Th2 immune response and impairing CD8&lt;sup&gt;+&lt;/sup&gt; T cell–mediated tumor cell lysis. Depleting macrophages or CD8&lt;sup&gt;+&lt;/sup&gt; T cells in mice with wild-type &lt;i&gt;IKKβ&lt;/i&gt; myeloid cells enhanced tumor growth, where the myeloid cell response was used to mediate antitumor immunity against melanoma tumors (with less dependency on a CD8&lt;sup&gt;+&lt;/sup&gt; T-cell response). In contrast, myeloid cells deficient in IKKβ were compromised in tumor cell lysis, based on their reduced ability to phagocytize and digest tumor cells. Thus, mice with continuous IKKβ signaling in myeloid-lineage cells (IKKβ&lt;sup&gt;CA&lt;/sup&gt;) exhibited enhanced antitumor immunity and reduced melanoma outgrowth. Collectively, our results illuminate new mechanisms through which NF-κB signaling in myeloid cells promotes innate tumor surveillance. &lt;i&gt;Cancer Res; 74(24); 7274–84. ©2014 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Liver cell death has an essential role in nonalcoholic steatohepatitis (NASH). The activity of the energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK) is repressed in NASH. Liver-specific AMPK knockout aggravated liver damage in mouse NASH models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 or -7. Active caspase-6 cleaved Bid to induce cytochrome c release, generating a feedforward loop that leads to hepatocyte death. Thus, the AMPK-caspase-6 axis regulates liver damage in NASH, implicating AMPK and caspase-6 as therapeutic targets.

The activation of IkappaB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-kappaB. IKK is a complex composed of three subunits: IKKalpha, IKKbeta, and IKKgamma (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKalpha and IKKbeta catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKalpha, IKKbeta, and the RING finger domain of TRAF2, and either IKKalpha or IKKbeta alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKgamma is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKgamma-deficient cells. Using TRAF2(-/-) cells, we demonstrated that the TNF-induced interaction between IKKgamma and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

This study investigated the longitudinal association between changes in older adults' physical activity and neighborhood walkability measured by geographic information systems (GISs, (ArcGIS, ESRI Inc., Redlands, CA, USA)).A mail survey was conducted for Japanese older adults who were randomly selected from three different settlement types. Data on walking, total moderate to vigorous physical activity (MVPA), and sociodemographic characteristics were collected at baseline (in 2010) and follow-up (in 2015). Multiple linear regression analyses were employed to assess the association between MVPA change and neighborhood walkability, adjusted for potential confounders. Effect sizes for independent variables on MVPA change were estimated.Data from 731 community-dwelling older adults (43.7% women) were analyzed. During the follow-up, older adults' MVPA was reduced by 94.4 min/week (-14.2%) on average (675.5 and 579.9 min/week in 2010 and 2015, respectively). Overall, older adults living in highly walkable areas showed a smaller reduction than those in low walkable areas (beta: 99.7 min/week, 95% confidence interval: 28.5⁻171.0). Similar associations were observed among those in the urban and suburban area, but not in the rural area. Walkability had larger effect sizes for explaining MVPA change than demographic characteristics. In addition, the findings for walking were similar to MVPA.Neighborhood walkability mitigated the 5-year reduction of walking and total MVPA among older adults, especially in urban areas.

Residents of neighbourhoods with high destination accessibility (higher population density, more-interconnected streets, and better access to services, public transport and parks) are more physically active. Evidence on the factors that underlie these associations is sparse and inconsistent. We examined (1) five socio-demographic and four non-destination perceived neighbourhood attributes as moderators of the relationship between objectively-assessed destination accessibility and moderate-to-vigorous physical activity (MVPA); (2) perceived indicators of destination accessibility as mediators of those relationships; and, (3) the generalizability of findings across 14 cities. Data were from the International Physical Activity and Environment Network (IPEN) Adult study (N = 6822), which provided comparable objective and perceived environmental variables and accelerometer-based MVPA from 14 cities across 10 countries. Mediation and mediation moderation analyses were performed. Objective net residential density, public transport density, and number of parks in the neighbourhood were consistently associated with MVPA across all examined socio-demographic groups and non-destination perceived neighbourhood characteristics. However, only the association between number of parks and MVPA was mediated by its conceptually-comparable perceived indicator. While the associations of objective intersection density and land use mix with MVPA were moderated by both gender and perceived pedestrian infrastructure/safety, only the latter moderating effects were mediated by the conceptually-comparable perceived indicators. Perceived neighbourhood safety and/or aesthetics moderated the associations of objective ratio of retail/civic land to total area and distance to nearest transport stop with MVPA. These associations were not mediated by the conceptually-comparable perceived indicators. Densely populated neighbourhoods with access to public transport and parks have the potential to significantly and equitably contribute to adults' MVPA on a global scale. Perceived neighbourhood aesthetics, pedestrian-friendliness and safety can magnify the positive effects of mixed-use neighbourhoods on residents' MVPA by interacting with the perceived ease of access to a variety of destinations.