Publications

Exposure to hepatitis C virus (HCV) typically results in chronic infection that leads to progressive liver disease ranging from mild inflammation to severe fibrosis and cirrhosis as well as primary liver cancer. HCV triggers innate immune signaling within the infected hepatocyte, a first step in mounting of the adaptive response against HCV infection. Persistent inflammation is strongly associated with liver tumorigenesis. The goal of our work was to investigate the initiation of the inflammatory processes triggered by HCV viral proteins in their host cell and their possible link with HCV-related liver cancer. We report a dramatic upregulation of the lymphotoxin signaling pathway and more specifically of lymphotoxin-β in tumors of the FL-N/35 HCV-transgenic mice. Lymphotoxin expression is accompanied by activation of NF-κB, neosynthesis of chemokines and intra-tumoral recruitment of mononuclear cells. Spectacularly, IKKβ inactivation in FL-N/35 mice drastically reduces tumor incidence. Activation of lymphotoxin-β pathway can be reproduced in several cellular models, including the full length replicon and HCV-infected primary human hepatocytes. We have identified NS5B, the HCV RNA dependent RNA polymerase, as the viral protein responsible for this phenotype and shown that pharmacological inhibition of its activity alleviates activation of the pro-inflammatory pathway. These results open new perspectives in understanding the inflammatory mechanisms linked to HCV infection and tumorigenesis.

Background Latina women are less likely to report engaging in leisure-time physical activity (PA) than non-Latina white women. This study evaluated the 24-month impact of a faith-based PA intervention targeting Latinas. Methods The study is a cluster randomized controlled trial of a PA intervention or cancer screening comparison condition, with churches as the randomization unit. A total of 436 Latinas (aged 18-65 years) from 16 churches who engaged in low levels of self-report and accelerometer-based PA were enrolled. The experimental condition was a 24-month PA intervention, with in-person classes, social support, and environmental changes, led by community health workers (i.e., promotoras ). At baseline, 12-, and 24 months, we assessed changes in accelerometer-based and self-reported moderate to vigorous physical activity (MVPA; primary outcomes). Secondary outcomes were light intensity activity, sedentary time, body mass index (BMI), and waist circumference. Results After adjusting for sociodemographic factors, a mixed effects analysis found significant increases in self-reported leisure time MVPA ( p < 0.005) and marginal increases in accelerometer-assessed MVPA ( p < 0.08) 24 months post-baseline in the intervention compared to the attention-control condition. Data showed significant associations between PA class attendance and engaging in MVPA as assessed by self-report and accelerometry. No significant changes were found for light activity, sedentary time, BMI, or waist circumference. Conclusions Participants who attended the PA classes at least once a month engaged in significantly higher MVPA compared to those who did not. Maximizing engagement and maintenance strategies to enhance PA maintenance could contribute to important long-term health benefits. Trial registration NCT01776632 , Registered March 18, 2011.

The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the <i>MUP-uPA</i> mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated <i>MUP-uPA</i> mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.

Purpose Develop strategic priorities to guide future physical activity surveillance in the United States. Methods The Centers for Disease Control and Prevention and the American College of Sports Medicine convened a scientific roundtable of physical activity and measurement experts. Participants summarized the current state of aerobic physical activity surveillance for adults, focusing on practice and research needs in three areas: 1) behavior, 2) human movement, and 3) community supports. Needs and challenges for each area were identified. At the conclusion of the meeting, experts identified one overarching strategy and five strategic priorities to guide future surveillance. Results The identified overarching strategy was to develop a national plan for physical activity surveillance similar to the U.S. National Physical Activity Plan for promotion. The purpose of the plan would be to enhance coordination and collaboration within and between sectors, such as transportation and public health, and to address specific strategic priorities identified at the roundtable. These strategic priorities were used 1) to identify and prioritize physical activity constructs; 2) to assess the psychometric properties of instruments for physical activity surveillance; 3) to provide training and technical assistance for those collecting, analyzing, or interpreting surveillance data; 4) to explore accessing data from alternative sources; and 5) to improve communication, translation, and dissemination about estimates of physical activity from surveillance systems. Conclusion This roundtable provided strategic priorities for physical activity surveillance in the United States. A first step is to develop a national plan for physical activity surveillance that would provide an operating framework from which to execute these priorities.

Physical inactivity is a global concern, but diverse physical activity measures in use prevent international comparisons. The International Physical Activity Questionnaire (IPAQ) was developed as an instrument for cross-national monitoring of physical activity and inactivity.Between 1997 and 1998, an International Consensus Group developed four long and four short forms of the IPAQ instruments (administered by telephone interview or self-administration, with two alternate reference periods, either the "last 7 d" or a "usual week" of recalled physical activity). During 2000, 14 centers from 12 countries collected reliability and/or validity data on at least two of the eight IPAQ instruments. Test-retest repeatability was assessed within the same week. Concurrent (inter-method) validity was assessed at the same administration, and criterion IPAQ validity was assessed against the CSA (now MTI) accelerometer. Spearman's correlation coefficients are reported, based on the total reported physical activity.Overall, the IPAQ questionnaires produced repeatable data (Spearman's rho clustered around 0.8), with comparable data from short and long forms. Criterion validity had a median rho of about 0.30, which was comparable to most other self-report validation studies. The "usual week" and "last 7 d" reference periods performed similarly, and the reliability of telephone administration was similar to the self-administered mode.The IPAQ instruments have acceptable measurement properties, at least as good as other established self-reports. Considering the diverse samples in this study, IPAQ has reasonable measurement properties for monitoring population levels of physical activity among 18- to 65-yr-old adults in diverse settings. The short IPAQ form "last 7 d recall" is recommended for national monitoring and the long form for research requiring more detailed assessment.

To examine relations between parents' perceived neighborhood recreation environments and multiple measures of adolescent physical activity (PA).Participants (N = 928; age 14.1 [1.4] y, 50.4% girls, and 33.4% nonwhite/Hispanic) and their parents were recruited. Teen moderate to vigorous PA (MVPA) was assessed with 7-day accelerometry. Self-reported total PA, PA near home, and PA at recreation locations were also assessed. Proximity of home to 8 types of recreation facilities was reported by parents. Mixed-model linear regressions relating environments to various measures of PA were adjusted for demographics and neighborhood clustering.Perceiving more availability of recreation facilities around home was related to higher reports of days per week with 60+ minutes of PA (b = 0.153; P < .05), reported PA time near home (b = 0.152; P < .001), PA time at recreation facilities (b = 0.161; P < .001), accelerometer-measured total MVPA (b = 1.741; P < .05), and nonschool MVPA (b = 1.508; P < .01). Adolescents living in lowest quintile of recreation facility availability averaged 27.6 (3.2) minutes per day of total MVPA versus 49.8 (3.5) minutes per day for those living in highest quintile.Adolescents living in neighborhoods that parents reported having more availability of recreation facilities around homes had higher activity across 5 indicators of PA.

Growth factors activate mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs) and Jun kinases (JNKs). Although the signaling cascade from growth factor receptors to ERKs is relatively well understood, the pathway leading to JNK activation is more obscure. Activation of JNK by epidermal growth factor (EGF) or nerve growth factor (NGF) was dependent on H-Ras activation, whereas JNK activation by tumor necrosis factor alpha (TNF-alpha) was Ras-independent. Ras activates two protein kinases, Raf-1 and MEK (MAPK, or ERK, kinase) kinase (MEKK). Raf-1 contributes directly to ERK activation but not to JNK activation, whereas MEKK participated in JNK activation but caused ERK activation only after overexpression. These results demonstrate the existence of two distinct Ras-dependent MAPK cascades--one initiated by Raf-1 leading to ERK activation, and the other initiated by MEKK leading to JNK activation.

Performing regular muscle-strengthening activity has numerous health benefits, including improvements in blood pressure, hemoglobin A1c, and lean body mass. Despite the disproportionate prevalence of lifestyle-related chronic disease in Latinas (diabetes, hypertension, obesity), most do not report meeting the national guidelines for muscle-strengthening activity. Existing physical activity (PA) research in Latinas has focused almost exclusively on aerobic PA. Our study examined Latinas' sociodemographic and psychosocial correlates of meeting muscle-strengthening PA guidelines that can inform future PA interventions. A cross-sectional study of participants (N = 436) enrolled in a randomized controlled trial promoting PA and cancer screening in Latinas was conducted, and t tests examined the associations between sociodemographic and psychosocial factors with self-reported muscle-strengthening activities. Hierarchical regression was conducted in separate blocks guided by the socioecological model (sociodemographic, individual, and interpersonal factors) to examine the independent contribution of each block to the outcome of meeting national guidelines for muscle-strengthening PA. Participants who met the national PA guidelines of ≥2 days/week of muscle-strengthening activities reported significantly higher social support for PA (p < .001), greater use of behavioral strategies for PA (p < .001), and lower barriers to PA (p < .03) than those who did not meet the guidelines. Hierarchical binary logistic regression indicated behavioral strategies for PA was the only significant correlate of meeting the national guidelines for muscle-strengthening PA (odds ratio = 1.39, 95% confidence interval [1.18, 1.65], p < .001). Results support a hypothesis that instructing Latinas to use behavior change strategies could help them increase muscle-strengthening PA.