Caffeine consumption and onset of alcohol use among early adolescents.

Preventing or delaying the onset of alcohol use among children and youth is an important public health goal. One possible factor in alcohol use onset among early adolescents is caffeine. The aim of this study was to assess the possible contribution of caffeine to the onset of alcohol use during early adolescence. We used data from the Young Mountaineer Health Study Cohort. Survey data were collected from 1349 (response rate: 80.7%) 6th grade students (mean age at baseline 11.5 years) in 20 middle schools in West Virginia during the fall of 2020, and again approximately 6 months later in spring of 2021. We limited our analyses to students reporting never having used any form of alcohol at baseline. Logistic regression was employed in multivariable analyses and both Odds Ratios and Relative Risks reported. At follow-up, almost 14% of participants reported having consumed alcohol at least once and 57% used caffeine of 100 mg + daily. In multivariable analyses we controlled for social and behavioral variables known to impact tobacco use. Caffeine use was operationalized as a three-level factor: no use, <100 mg per day, and 100 + mg per day, with the latter being the approximate equivalent of the minimum of a typical cup of coffee or can of energy drink. Caffeine use of 100 mg + per day was significantly related to alcohol use at 6-months follow-up (OR: 1.79, RR: 1.56, p = .037). We conclude that caffeine consumption among 11-12-year-old adolescents may be a factor in early onset of alcohol use.

Resectability, Recurrence, and Risk Stratification of Giant Solitary Fibrous Tumors in the Thoracic Cavity.

BACKGROUND: Solitary fibrous tumors (SFTs) are rare mesenchymal tumors most commonly arising from the pleura in the thoracic cavity. The impact of tumor size on risk of recurrence in thoracic SFTs is not well understood. METHODS: A single institution review was performed on all resected thoracic SFTs (1992-2019) with giant SFT defined as ≥ 15 cm. Clinical information, pathologic characteristics, and long-term survival data were collected, and predictors of recurrence and survival were evaluated with regression and Kaplan-Meier analysis. RESULTS: There were 38 thoracic SFTs resected from patients, with the majority of tumors (n = 23, 60.5%) originating from visceral pleura. There were nine (23.7%) giant SFTs with a mean size 20.4 cm (range 17-30 cm). Mean follow-up time was 81.0 months (range 1-261 months), during which 4 of 38 (10.5%) patients experienced a recurrence within the thorax (range 51-178 months). The presence of tumor necrosis (p = 0.021) and ≥ 4 mitoses per high-powered field (p = 0.010) were associated with SFT recurrence on univariate regression. Overall 5-year, 10-year, and 20-year survival was 78.2%, 72.6%, and 42.4%, respectively, and SFT-related mortality occurred in three patients at 83, 180, and 208 months postoperatively. There were no recurrences or SFT-related mortality among patients with giant SFT. CONCLUSION: This study represents one of the largest contemporary single institution reviews of long-term outcomes of giant thoracic SFT. Our data suggest that size is not a risk factor for recurrence in thoracic SFTs and long-term survival is excellent for giant SFTs.

Improved outcomes and staging in non-small-cell lung cancer guided by a molecular assay.

There remains a critical need for improved staging of non-small-cell lung cancer, as recurrence and mortality due to undetectable metastases at the time of surgery remain high even after complete resection of tumors currently categorized as 'early stage.' A 14-gene quantitative PCR-based expression profile has been extensively validated to better identify patients at high-risk of 5-year mortality after surgical resection than conventional staging - mortality that almost always results from previously undetectable metastases. Furthermore, prospective studies now suggest a predictive benefit in disease-free survival when the assay is used to guide adjuvant chemotherapy decisions in early-stage non-small-cell lung cancer patients.

Lay abstract There is a need for improvement in the way early-stage non-small-cell lung cancers are staged and treated because many patients with 'early-stage' disease suffer high rates of cancer recurrence after surgery. In recent years, a specialized test has been developed to allow better characterization of a tumor's risk of recurrence based on the genes being expressed by tumor cells. Use of this test, in conjunction with standard staging methods, is better able to identify patients at high risk of cancer recurrence after surgery. Evidence suggests that giving chemotherapy to patients at high risk of recurrence after surgery reduces recurrence rates and improves long-term patient survival.

Parental support and monitoring as associated with adolescent alcohol and tobacco use by gender and age.

BACKGROUND: Parental support (PS) and parental monitoring (PM) are known protective factors against adolescent substance use (SU). However, little is known about whether PS and PM may affect SU outcomes differently by gender and age. This study examined the relationship between PS and PM and adolescent SU, specifically alcohol and tobacco use, stratified by gender and age group. METHODS: Middle and high school students (n = 2351, 48.5% Female) completed surveys of self-reported SU, perceived PS and PM, and socioeconomic background. Age group was defined dichotomously as grade 7-8 Middle school and grade 9-10 High school students. PS and PM were each measured using previously validated tools. SU was measured by lifetime and past 30 days cigarette/alcohol use. One-way ANOVA and binary logistic regression models were completed. Odds ratios and means were reported. RESULTS: PS and PM were significantly and negatively related to all outcome variables regardless of gender and age group. Mean differences in PS and PM were insignificant between age groups. Between genders, PM scores were significantly higher for girls (14.05) compared to boys (13.48) (p < 0.01). Odds Ratios of all four SU types (for alcohol and tobacco use) increased with higher age group, with ORs ranging from 1.45-2.61 (p < .05). CONCLUSIONS: PS and PM were protective against SU for all participants, consistent with previous literature. Girls reported greater parental monitoring than boys, irrespective of age-group. While girls experienced higher levels of monitoring, they did not report lower SU than boys. This suggests that monitoring girls more closely than boys appears unnecessary in preventing adolescent SU. Finally, PS was a more significant factor in preventing SU for older adolescents (high school aged group) than for younger adolescents, irrespective of gender suggesting that PS may be more impactful and important as adolescents age. As children mature, particularly from middle school to high school, PS may play a larger role in preventing SU for older adolescents compared to younger ones.

Testing risk and protective factor assumptions in the Icelandic model of adolescent substance use prevention.

Iceland has witnessed a dramatic decline in adolescent substance use that may be partly the result of efforts related to the Icelandic prevention model (IPM). We sought to test risk and protective factor assumptions of the IPM using a prospective cohort study with 12 months separating baseline from follow-up. Participants were students in grades 8 and 9 in the national Icelandic school system enrolled in the spring of 2018 and 2019 (N=2165). Participants self-reported their experiences of cigarette smoking, alcohol consumption, and cannabis use and seven risk and protective factors. Analyses were conducted with generalized linear modeling with extension to general estimating equations with correlated outcomes data. Both individual main-effects models and collective models including all main-effects were tested. Out of 28 individual main-effects models, 23 produced findings consistent with study premises (P<0.05). Multiple main-effects models largely sustained the findings of the individual main-effects models. Findings support the assumption that the risk and protective factors commonly emphasized in the IPM are associated with the four different substance use outcomes in the hypothesized direction. Communities that plan to implement the IPM among adolescents might consider these factors in their work.

Prevention Is Possible: A Brief History of the Origin and Dissemination of the Icelandic Prevention Model.

In two decades, the Icelandic prevention model (IPM) has been employed to dramatically reduce rates of adolescent substance use in Iceland. Briefly, the IPM is a multisectoral, community-based, collaborative system where researchers, policy makers, administrative leaders, and practitioners join forces to reduce the odds of adolescent substance use over time. Comparatively, Iceland now ranks among the lowest in adolescent substance use in all of Europe. Since 2005, the IPM has garnered considerable international attention, and several countries or municipalities within them have adapted, or are presently adapting, the model to their needs. In this commentary, we first briefly review the history and formation of the IPM in Iceland from a school-based survey to a fully integrated prevention system. In the second part, we present a short overview of the national consensus building and institutional collaboration that led to the implementation of the model in Chile in Latin America, as a demonstrative example. In this volume of Health Promotion Practice, we also present a series of two practice-based articles that introduce the IPM. The first article, titled "Development and Guiding Principles of the Icelandic Model for Preventing Adolescent Substance Use," introduces the theoretical origins of the model, five guiding principles, and evidence of effectiveness to date. In the second article, titled "Implementing the Icelandic Model for Preventing Adolescent Substance Use," we outline 10 practice-based steps to guide model implementation in other countries. Both articles are available via open access, and both are also available online in Spanish.

Development and Guiding Principles of the Icelandic Model for Preventing Adolescent Substance Use.

Adolescent substance use-the consumption of alcohol, tobacco, and other harmful drugs-remains a persistent global problem and has presented ongoing challenges for public health authorities and society. In response to the high rates of adolescent substance use during the 1990s, Iceland has pioneered in the development of the Icelandic Model for Primary Prevention of Substance Use-a theory-based approach that has demonstrated effectiveness in reducing substance use in Iceland over the past 20 years. In an effort to document our approach and inform potentially replicable practice-based processes for implementation in other country settings, we outline in a two-part series of articles the background and theory, guiding principles of the approach, and the core steps used in the successful implementation of the model. In this article, we describe the background context, theoretical orientation, and development of the approach and briefly review published evaluation findings. In addition, we present the five guiding principles that underlie the Icelandic Prevention Model's approach to adolescent substance use prevention and discuss the accumulated evidence that supports effectiveness of the model. In a subsequent Part 2 article, we will identify and describe key processes and the 10 core steps of effective practice-based implementation of the model.

Implementing the Icelandic Model for Preventing Adolescent Substance Use.

This is the second in a two-part series of articles about the Icelandic Model for Primary Prevention of Substance Use (IPM) in this volume of Health Promotion Practice. IPM is a community collaborative approach that has demonstrated remarkable effectiveness in reducing substance use initiation among youth in Iceland over the past 20 years. While the first article focused attention on the background context, theoretical orientation, evaluation and evidence of effectiveness, and the five guiding principles of the model, this second article describes the 10 core steps to practical implementation. Steps 1 to 3 focus on building and maintaining community capacity for model implementation. Steps 4 to 6 focus on implementing a rigorous system of data collection, processing, dissemination, and translation of findings. Steps 7 to 9 are designed to focus community attention and to maximize community engagement in creating and sustaining a social environment in which young people become progressively less likely to engage in substance use, including demonstrative examples from Iceland. And Step 10 focuses on the iterative, repetitive, and long-term nature of the IPM and describes a predictable arc of implementation-related opportunities and challenges. The article is concluded with a brief discussion about potential variation in community factors for implementation.

Addressing Challenges to the Reliable, Large-Scale Implementation of Effective School Health Education.

The long-held priority of teaching young people the knowledge and skills needed for healthy living has recently been diminished in many preK-12 schools. Driven by federal and state priorities, laws, and policies associated with high-stakes testing, instruction in untested subjects has been reduced or eliminated in most schools in order to devote more attention to tested subjects, like reading, math, writing, and science. This article proposes a pathway to ensure that all children are able to learn what society knows about health. To that end, four challenges to the reliable, large-scale implementation of effective school health education are identified: (1) establishing school health education as an undeniable social and cultural priority through improved advocacy; (2) strengthening educational institutions' capacities to reliably deliver large-scale, high-quality, school-based health education; (3) collaboratively coordinating efforts of health-promoting governmental and nongovernmental organizations that generate thought leadership for school health education; and (4) creating multidisciplinary research capacities for solving problems associated with the implementation of reliable, large-scale, effective school health education. By implementing specific strategies associated with each challenge, health educators can promote the social and system-level conditions required to support, elevate, and ensure delivery of effective health education to every student in every school every year.

Social Profile of Middle School-Aged Adolescents Who Use Electronic Cigarettes: Implications for Primary Prevention.

Electronic cigarette (EC) use continues to increase among adolescents. From a primary prevention point of view, an important gap in our knowledge includes determining whether young smokers that use EC maintain a distinct social profile from kids who use combustible cigarettes (CC). Survey data from middle school students in West Virginia, USA were collected between September and November of 2015 (N = 6547, response rate 84.7%) as part of a state wide school-based mental health intervention program. Data was analyzed using multinomial logistic regression for categorical data. The results show that compared to never smokers, EC-only users possessed a weaker social support and parental monitoring profile and performed worse in school. Additionally, EC-only users were more likely to feel alienated from school, to associate with delinquent peers, to spend time outside late at night, and to engage in unsupervised gatherings with their friends. In 11 of 13 statistical models no difference was observed between EC-only users compared with CC-only users. However, dual users (that had used both EC and CC in their lifetime) demonstrated a significantly greater risk profile compared with EC-only users. We conclude that middle school-aged kids that use EC share a similar risk profile as kids of the same age that use CC. Similar to traditional cigarette smoking, EC use in young adolescents is likely to be a social marker of a pathway to further delinquency and should therefore be subject to primary prevention approaches.

Evaluation of an Intimate Partner Violence Training for Home Visitors Using the Theory of Planned Behavior.

INTRODUCTION: Intimate partner violence (IPV) is a public health issue with recent intervention focus by home visiting programs with at-risk families in the United States. Home visitors are typically required to assess IPV but feel unprepared to do so and desire training. Our aim was to evaluate the impact of a daylong IPV training on the intention to enact three key IPV behaviors (screening, making referrals, and safety planning) using the theory of planned behavior. METHOD: Survey of 125 home visitors in West Virginia was conducted before and after a daylong IPV training. RESULTS: The IPV training had a positive impact on intention to perform the three behaviors of interest, with the greatest impact on the intention to conduct IPV screenings. DISCUSSION: Results provide important preliminary evidence supporting the effectiveness of professional development as a means of increasing intentions to conduct activities related to IPV. The impact on IPV screening intention is promising because screening is the first step in addressing IPV. CONCLUSION: The IPV training proved beneficial in increasing intentions and such trainings should be expanded, but further study is needed to link intentions to subsequent behaviors to address IPV with at-risk families.

Spacial and Temporal Patterns of Gene Expression After Cardiac MEK1 Gene Transfer Improve Post-Infarction Remodeling Without Inducing Global Hypertrophy.

Alteration of mitogen activated protein (MAP) kinase signaling in transgenic mice can ameliorate post-myocardial infarction (MI) remodeling. However, pre-existing changes in transgenic hearts and clinically unrealistic transgene expression likely affect the response to injury; it is unknown whether clinically relevant induction of transgene expression in an otherwise normal heart can yield similar benefits. Constitutively active MEK1 (aMEK1) or LacZ adeno-associated virus 9 (AAV9) vectors were injected into the left ventricular (LV) chambers of mice either just before or after coronary ligation. Hearts were evaluated via Western blot, quantitative polymerase chain reaction, histology, and echocardiography. AAV9-mediated aMEK1 delivery altered ERK1/2 expression/activation as in transgenic mice. Transgene expression was not immediately detectable but plateaued at 17 days, and therefore did not likely impact acute ischemia as it would in transgenics. With AAV9-aMEK1 injection just prior to MI, robust expression in the infarct border zone during post-MI remodeling increased border zone wall thickness and reduced infarct size versus controls at 4 weeks, but did not induce global hypertrophy. Significant improvements in local and global LV function were observed, as were trends toward a preservation of LV volume. Delivery after ligation significantly lowered transgene expression in the infarct border zone and did not yield structural or functional benefits. The primary benefits observed in transgenic mice, ameliorated remodeling, and reduced chronic infarct size, were achievable via clinically relevant gene transfer of aMEK1, supporting ongoing translational efforts. Important differences, however, were observed, and consideration must be given to the timing and distribution of transgene delivery and expression. J. Cell. Biochem. 118: 775-784, 2017. © 2016 Wiley Periodicals, Inc.

Atrial ERK1/2 activation in the embryo leads to incomplete Septal closure: a novel mouse model of atrial Septal defect.

BACKGROUND: MEK1 mutation and activated MAPK signaling has been found in patients with RASopathies and abnormal cardiac development. Previous studies have suggested that regulation of fetal MAPK signaling is essential for normal cardiac development. We investigated the effect of active MEK1 overexpression on fetal atrial septal development. METHODS AND RESULTS: An inducible double transgenic (DTg) mouse model was developed in which cardiac-specific fetal expression of a constitutively active form of human MEK1 (aMEK1) was induced primarily in the atrium via the withdrawal of doxycycline from the drinking water of pregnant mice. Atrial septal defect (ASD) was found in 51% (23/45) of DTg mice. Fifty-two percent (12/23) of ASD mice died before weaning, and surviving ASD mice exhibited hypertrophic hearts with enlarged right atria and decreased fractional shorting (40 ± 2% vs. 48 ± 0%, p < 0.05). The model mimicked human ASD in several key clinical features: severe ASD was associated with growth impairment; ASD-specific mortality was highest within the early postnatal period; despite an even distribution of ASD among the sexes, early mortality was significantly higher in males. The expression of aMEK1 and increased phosphorylation of ERK1/2 was documented via Western blot in DTg fetal hearts, with the largest increases seen in atrial tissue. In an alternative transgenic aMEK1 model with elevated atrial MKP3 expression and corresponding suppression of increases in ERK1/2 phosphorylation, animals did not develop ASD. CONCLUSION: This new model of ASD suggests that enhanced atrial MEK1-ERK1/2 signaling during fetal development disrupts normal atrial septation, possibly regulated by the balance of ERK1/2 phosphorylation.

Prevalence of substance use among middle school-aged e-cigarette users compared with cigarette smokers, nonusers, and dual users: Implications for primary prevention.

BACKGROUND: The objective of this study was to compare the prevalence of substance use in e-cigarette (EC)-only users with combustible cigarette (CC)-only users, dual users, and nonusers in a large sample of middle school-aged adolescents. METHODS: Population-based cross-sectional school survey conducted in 15 middle schools in 3 counties in West Virginia in the United States between October and December of 2015 (N = 6547, girls = 49.6%; response rate 84.7%). RESULTS: Approximately 4.3% of participants had used EC only, 4.5% had used CC only, and around 5.5% were dual users. Nonusers had the lowest prevalence of all 9 forms of substance use assessed in the study (i.e., chewing tobacco, any alcohol, drunkenness, marijuana, sniffing, prescription drugs, hallucinogens, synthetic marijuana, and bath salts), followed by EC and CC users. Dual users had the highest prevalence of 8 of 9 forms of substance use. Multinomial logistic regression models showed that EC-only users had significantly greater odds over nonusers of using 8 of 9 types of substances included in the study. Conversely, EC-only users had significantly lower odds of using 7 of 9 types of substances when compared with dual users. However, EC-only users did not differ from CC-only users in odds of use in any of the 9 substances included in this analysis. CONCLUSIONS: Among middle school-aged adolescents, EC-only users do not differ from CC-only users in odds for other forms of substance use. Primary prevention programs should consider EC use initiation as a pathway to greater risk of other licit and illicit substances among young adolescents.

Caffeinated sugar-sweetened beverages and common physical complaints in Icelandic children aged 10-12 years.

OBJECTIVE: Consumption of caffeinated sugar-sweetened beverages (CSSBs) among children and adolescents has increased markedly in recent years but the consequence of their consumption is not well understood. The objective of this study was to assess the prevalence of CSSBs in children aged 10­12 years and examine the relationship between CSSBs and common physical complaints. METHODS: Data from the 2013 cross-sectional population school survey Youth in Iceland (N=11,267, response rate: 90.1%, girls 49.7%)was used to assess the prevalence of cola and energy drink consumption and associations to headaches, stomachaches, sleeping problems and low appetite. RESULTS: Around 19% of boys and 8% of girls reported consuming cola drinks on a daily basis and 7% of boys and 3% of girls reported consuming energy drinks. A general trend of a dose­response relationship was observed between CSSBs and physical complaints for both types of beverages. These relationships were generally stronger for energy drinks than cola drinks. CONCLUSION: Our findings call into question the acceptability, availability, and marketing of CSSBs to 10­12 year-old children and adolescents. For validation purposes replications of these analyses are needed in other parts of the world, including studies using prospective longitudinal designs.

Beyond School Climate: Conceptualizing the School as a Protective Factor Approach.

BACKGROUND: The school climate concept has been promising, but has long-standing critiques that have not been adequately addressed to date. The School as a Protective Factor approach represents one attempt to offer a new approach that builds on and extends beyond the concept of school climate while addressing previously identified limitations. CONTRIBUTIONS TO THEORY: The School as a Protective Factor approach offers a new framework for conceptualizing, measuring, and establishing protective school social and learning environments that co-promote academic achievement and student health in schools, especially student mental health and substance use/abuse prevention. This new framework includes clear definitions, explicit goals, firmly established constructs, validated measures, and an intentionally parsimonious approach that prioritizes the implementation of well-established, high-impact constructs. CONCLUSIONS AND IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: The School as a Protective Factor approach presents a simple, easy-to-use means of ensuring a school social environment that meets the developmental, academic, and health needs of all children and adolescents while maximizing protection across a range of desired outcomes. Perhaps most importantly, it does so in a manner that is manageable and easily integrated into every aspect of schooling, resonates with the practical experience of school personnel, and includes brief, effective, and free measurement tools.

The Icelandic Prevention Model Evaluation Framework and Implementation Integrity and Consistency Assessment.

The Icelandic Prevention Model (IPM) follows a systematic but flexible process of community capacity building, data collection, analysis, dissemination, and community-engaged decision-making to guide the data-informed selection, prioritization, and implementation of intervention strategies in preventing adolescent substance use. This paper describes two new evaluation tools intended to assess the: 1) integrity of IPM implementation, and 2) unique aspects of IPM implementation in different community contexts. These evaluation tools include a: 1) five-phase IPM Evaluation Framework for Assessing Value Across Communities, Cultures, and Outcomes (IPM-EF); and 2) 10-Step IPM Implementation Integrity and Consistency Assessment (IPM-IICA) that utilizes both quantitative (scored) and qualitative (narrative) data elements to characterize implementation integrity and consistency at both community coalition and school community levels. The IPM-EF includes five phases. Phase 1: Describe the Intervention Context; Phase 2a: Document the Extent to Which the 10 Steps of the IPM were Implemented (using the IPM-IICA scored); Phase 2b: Document the Unique Community-Specific Methods Used within the 10 Steps of the IPM to Tailor Local Intervention Delivery (using the IPM-IICA narrative); Phase 3: Measure Changes in Community Risk and Protective Factors; Phase 4: Measure the Outcomes Associated with the IPM; and Phase 5: Investigate Multiple Full Cycles Over Time.

Beyond School Climate: Validating the School as a Protective Factor-Brief Survey.

BACKGROUND: The conceptual framework for School as a Protective Factor approach was presented in a companion article in this issue of the journal. The current article describes the validation of the School as a Protective Factor-Brief (SPF-Brief), a 13-item survey measuring the 3 core constructs and 13 defining characteristics of this framework. METHODS: The SPF-Brief was validated through 2 studies. The developmental study used a longitudinal design including 1349 participants who completed surveys over 5 semesters, while the validation study used a cross-sectional design with 2775 participants. Both studies included middle and high school students. Factor analysis, growth model analysis, criterion-related validation, and outcome analysis were employed. RESULTS: Analyses provided strong evidence supporting the reliability and validity of the instrument and conceptual framework. Higher SPF-Brief scores were associated with higher math grades, English grades, and quality of life, as well as lower rates of anxiety, depression, conduct disorder, alcohol, e-cigarette, tobacco, and cannabis use. Effect size estimates ranged from moderate to strong. CONCLUSIONS: These findings suggest the utility of the SPF-Brief instrument and the School as a Protective Factor framework. Together, they may offer advantages to the traditional school climate approach.

MEK1-induced physiological hypertrophy inhibits chronic post-myocardial infarction remodeling in mice.

Although activation of MEK-ERK signaling is known to be cardioprotective during acute reperfusion injury, the effect of MEK activation on chronic changes in ventricular structure and function during the more complex process of remodeling after myocardial infarction (MI) with or without reperfusion remains uncertain. Four weeks after permanent coronary ligation, LV fractional shorting, preload recruitable stroke work, and end-systolic elastance were all preserved in transgenic mice with CM-specific upregulation of the MEK1-ERK1/2 signaling pathway (MEK1 Tg) compared to wildtype (WT) controls (5.8% decline vs. 17.3%, P < 0.01; 603 ± 98 mmHg vs. 335 ± 98, P < 0.05; 6.14 ± 0.57 mmHg/µl vs. 3.92 ± 0.60, P < 0.05, respectively). Despite similar initial infarct sizes, post-MI remodeling was significantly reduced in MEK1 Tg, demonstrated by reductions in chronic infarct size (28.5 ± 3.1% vs. 47.8 ± 3.2%), myocardial fibrosis (3.98 ± 0.74% vs. 9.27 ± 1.97%) and apoptosis (0.66 ± 0.11% vs. 1.60 ± 0.34%). Higher phosphorylation (i.e., activation) of pro-survival transcription factor STAT3, higher expression of anti-apoptotic protein Bcl2, and higher phosphorylation (i.e., inactivation) of pro-apoptotic BAD were observed in the post-MI remote myocardium of MEK1 Tg. MMP2 activity was higher in MEK1 Tg, while expression of TIMP3 and MMP9 activity were lower in transgenic mice. Beyond any immediate cardioprotective effect, therapeutic activation of MEK1-ERK1/2 signaling during the chronic post-MI period may preserve LV function by increasing the expression of pro-survival factors and by suppressing factors, such as the balance between matrix modulating proteins, that promote pathological remodeling in the remote myocardium.

A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies.

BACKGROUND: The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging. METHODS: A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I-III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC). FINDINGS: Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5-80·0) in low-risk, 58·3% (48·9-66·6) in intermediate-risk, and 49·2% (42·2-55·8) in high-risk patients (p(trend)=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0-80·6) in low-risk, 57·4% (48·3-65·5) in intermediate-risk, and 44·6% (40·2-48·9) in high-risk patients (p(trend)<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages. INTERPRETATION: Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection. FUNDING: UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.