Publications

These results suggest that there is a partial but significant contribution of JNP to the induction of apoptosis in RGCs by ON transection.

Thermal injury induces nuclear factor-kappaB activation of intestinal mucosa and IKK protects intestinal mucosa from thermal injury-induced gut damage. IKK blocks caspase 3 expression by up-regulating BCL-xL and cellular FLICE inhibitory protein expression. IKK inhibits JNK and p38 but not p44/42 phosphorylation of intestinal mucosa. JNK inhibition increases p38 and tumor necrosis factor receptor-associated factor 2 expression and decreases thermal injury-induced gut damage. Taken together with the enhanced thermal injury-induced gut damage by p38 inhibition, we conclude that IKK maintains gut function by inhibiting JNK phosphorylation, which suppresses p38 phosphorylation and induces gut damage.

Physical inactivity and unhealthy diet are modifiable behaviors that lead to several cancers. Biologically, these behaviors are linked to cancer through obesity-related insulin resistance, inflammation, and oxidative stress. Individual strategies to change physical activity and diet are often short lived with limited effects. Interventions are expected to be more successful when guided by multi-level frameworks that include environmental components for supporting lifestyle changes. Understanding the role of environment in the pathways between behavior and cancer can help identify what environmental conditions are needed for individual behavioral change approaches to be successful, and better recognize how environments may be fueling underlying racial and ethnic cancer disparities.This cross-sectional study was designed to select participants (n = 602 adults, 40% Hispanic, in San Diego County) from a range of neighborhoods ensuring environmental variability in walkability and food access. Biomarkers measuring cancer risk were measured with fasting blood draw including insulin resistance (fasting plasma insulin and glucose levels), systemic inflammation (levels of CRP), and oxidative stress measured from urine samples. Objective physical activity, sedentary behavior, and sleep were measured by participants wearing a GT3X+ ActiGraph on the hip and wrist. Objective measures of locations were obtained through participants wearing a Qstarz Global Positioning System (GPS) device on the waist. Dietary measures were based on a 24-h food recall collected on two days (weekday and weekend). Environmental exposure will be calculated using static measures around the home and work, and dynamic measures of mobility derived from GPS traces. Associations of environment with physical activity, obesity, diet, and biomarkers will be measured using generalized estimating equation models.Our study is the largest study of objectively measured physical activity, dietary behaviors, environmental context/exposure, and cancer-related biomarkers in a Hispanic population. It is the first to perform high quality measures of physical activity, sedentary behavior, sleep, diet and locations in which these behaviors occur in relation to cancer-associated biomarkers including insulin resistance, inflammation, impaired lipid metabolism, and oxidative stress. Results will add to the evidence-base of how behaviors and the built environment interact to influence biomarkers that increase cancer risk.ClinicalTrials.gov NCT02094170 , 03/21/2014.

Noninvasive prenatal testing (NIPT) using sequencing of fetal cell-free DNA from maternal plasma has enabled accurate prenatal diagnosis of aneuploidy and become increasingly accepted in clinical practice. We investigated whether NIPT using semiconductor sequencing platform (SSP) could reliably detect subchromosomal deletions/duplications in women carrying high-risk fetuses. We first showed that increasing concentration of abnormal DNA and sequencing depth improved detection. Subsequently, we analyzed plasma from 1,456 pregnant women to develop a method for estimating fetal DNA concentration based on the size distribution of DNA fragments. Finally, we collected plasma from 1,476 pregnant women with fetal structural abnormalities detected on ultrasound who also underwent an invasive diagnostic procedure. We used SSP of maternal plasma DNA to detect subchromosomal abnormalities and validated our results with array comparative genomic hybridization (aCGH). With 3.5 million reads, SSP detected 56 of 78 (71.8%) subchromosomal abnormalities detected by aCGH. With increased sequencing depth up to 10 million reads and restriction of the size of abnormalities to more than 1 Mb, sensitivity improved to 69 of 73 (94.5%). Of 55 false-positive samples, 35 were caused by deletions/duplications present in maternal DNA, indicating the necessity of a validation test to exclude maternal karyotype abnormalities. This study shows that detection of fetal subchromosomal abnormalities is a viable extension of NIPT based on SSP. Although we focused on the application of cell-free DNA sequencing for NIPT, we believe that this method has broader applications for genetic diagnosis, such as analysis of circulating tumor DNA for detection of cancer.

Contrary to common expectations, chronic NF-κB activation induced intestinal crypt apoptosis after TNF stimulation, resulting in severe mucosal erosion. RIPK1 kinase inhibitors selectively inhibited TNF destructive properties while preserving its survival and proliferative properties, which do not require RIPK1 kinase activity. RIPK1 kinase inhibition could be a potential treatment for IBD.

IKK-complex subunits transmit a previously unrecognized signal through RIPK1, which is fundamental for the long-term consequences of chronic hepatic inflammation and might have potential implications for future pharmacological strategies against cholestatic liver disease and cancer. (Hepatology 2016;64:1217-1231).

induced by these agents, it was con-ceivable that the AP-1 activity induced by TPA containsmorec-Jun-c-Fos heterodimers than the activity induced byUVor H202. However, the use of Fos antibodies (Fig. 6)indicates that after several hours, the AP-1 complexes in-duced by TPA, UV, and H202 contain similar amounts ofc-Fos protein. Therefore, it is unlikely that the AP-1 com-plexes induced by the different agents control differentsubsets of genes. In fact, at least two AP-1 target genes,collagenase and metallothionein

The E3 ubiquitin (Ub) ligase Itch is a critical regulator of T helper 2 (Th2) cytokine production through its ability to induce Ub-dependent JunB degradation. After T cell receptor engagement, Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222, which are located within a Pro-rich region. Phosphorylation of these sites is necessary and sufficient for disrupting an inhibitory interaction between the WW domain of Itch and its catalytic HECT (Homologous to E6-AP C Terminus) domain and induces a conformational change that greatly enhances the catalytic activity of Itch, a HECT E3 ligase found to be directly activated upon its phosphorylation.

Socioeconomic factors appear to impact mental health conditions such as depression, but little is known about the relative and combined role of neighborhood and personal socioeconomic deprivation among Hispanics/Latinos. This study examined cross‐sectional associations of neighborhood and personal socioeconomic deprivation with depression symptoms in a US Hispanic/Latino population from the San Diego Field Center of the Hispanic Community Health Study/Study of Latinos ( n = 3,851). Depression symptoms were assessed with the ten‐item Centers for Epidemiological Studies in Depression Scale. Neighborhood socioeconomic deprivation was a composite of eleven variables (e.g., neighborhood income, education, employment, household crowding). Greater personal socioeconomic deprivation based on education, income, and employment was generally associated with higher depression symptoms, including after adjusting for neighborhood socioeconomic deprivation. Greater neighborhood socioeconomic deprivation was associated with higher depression symptoms in females but not males, but the association in females became non‐significant when adjusting for personal socioeconomic deprivation. Neighborhood socioeconomic deprivation did not significantly interact with personal socioeconomic deprivation in relation to depression symptoms. The present findings support the association of personal socioeconomic status with mental health (indicated by depression symptoms) among Hispanic/Latino populations, whereas neighborhood socioeconomic deprivation did not relate to depression beyond the impact of personal indicators.

Abstract Building on our previous six study series, the current studies 7 and 8 evaluated behavioral methods of improving adherence to exercise in adults. The studies tested the effectiveness of a single exercise modality versus choice of a variety of exercises and were conducted as part of a 12-week extended studies college course in San Diego, CA. Recruitment efforts were targeted to individuals who reported that they were sedentary and/or had experienced difficulty adhering to regular exercise. Participants were 42 adults (32F, 10M; mean age = 42.0) in Study 7 and 48 adults (35F, 8M; mean age = 47.9) in Study 8. In each study, subjects were randomly assigned to a single focus or variety exercise condition. There were no significant group differences in class attendance or out-of-class exercise adherence rates in Studies 7 or 8. In Study 7, significantly lower drop-out rates were detected in the single focus group (19%) than the variety condition (47.6%) (p = 0.04). No significant group differences were detected for drop-out rates in Study 8. Suggestions for further research are offered. Key Words: ExerciseExercise adherenceBehavioral modificationChoice.

Clinical observations and mouse models have suggested that inflammation can be pro-tumorigenic. Since chemokines are critical in leukocyte trafficking, we hypothesized that chemokines play essential roles in inflammation-associated cancers. Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine. Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells. Expression levels of CXCL16 and CXCR6 on cancer cells correlated with poor prognostic features including high-stage and high-grade, and expression also correlated with post-inflammatory changes in the cancer stroma as revealed by loss of alpha-smooth muscle actin. Moreover, CXCL16 enhanced the growth of CXCR6-expressing cancer and primary CD4 T cells. We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation. Our study is the first to describe the expression of CXCL16/CXCR6 on both cancer cells and adjacent T cells in humans, and to demonstrate correlations between CXCL16 and CXCR6 vs. poor both prognostic features and reactive changes in cancer stoma. Taken together, our data suggest that CXCL16 and CXCR6 may mark cancers arising in an inflammatory milieu and mediate pro-tumorigenic effects of inflammation through direct effects on cancer cell growth and by inducing the migration and proliferation of tumor-associated leukocytes.

Apply It! From this article, readers should: • Identify how health and fitness professionals can promote health and wellness among their fitness center, health club, or gym members, clients, patients, and communities by working collaboratively with colleagues across multiple levels of an ecological model. • Understand how using evidence-based intervention approaches recommended by the Community Preventive Services Task Force may enhance the effect of health and fitness professionals on increasing physical activity. • Learn why it's important to help create physical activity-friendly communities and how they can help support fitness centers, health clubs, or gyms and the efforts of members, clients, or patients to be more physically active in and out of health and fitness facilities. • Identify ways to take action in their community in support of Active People, Healthy Nation sm , CDC's national initiative to increase physical activity, by creating and contributing to equitable policy, systems, and environmental changes to support active lifestyles and decrease physical inactivity.