BMI Growth Profiles Among Black Children from Immigrant and US-Born Families.

A large body of research has documented racial/ethnic disparities in childhood obesity in the United States (US) but less work has sought to understand differences within racial groups. Longitudinal studies are needed to describe BMI trajectories across development, particularly for Black children from immigrant families who have been underrepresented in childhood obesity research. The current study utilizes BMI data collected longitudinally from ages 5 to 8 years and growth mixture modeling to (1) identify and visualize growth patterns among Black children from primarily Caribbean immigrant families, and (2) to compare these patterns to growth trajectories among Black children from US-born families. First, we identified four classes or trajectories of growth for Black children from immigrant families. The largest trajectory (70% of the sample) maintained non-overweight throughout the study period. A second trajectory developed overweight by age 8 (25%). Two small trajectory groups demonstrated high rates of moderate and severe obesity-i.e., specifically, a trajectory of accelerated weight gain ending in moderate/severe obesity (3%), and a trajectory of early severe obesity with BMI decreasing slightly with age (2%). We identified a very similar four class/trajectory model among Black children from US-born families, and compared the model to the one for children from immigrant families using multi-group growth mixture modeling. We found that the patterns of growth did not differ significantly between the populations, with two notable exceptions. Among Black children from immigrant families, ∼ 5% were classified into the two heavier BMI trajectories, compared to ∼ 11% of children from US-born families. Additionally, among children with an accelerated weight gain trajectory, children from immigrant families had lower BMIs on average at each time point than children from US-born families. These findings describe the multiple trajectories of weight gain among Black children from immigrant families and demonstrate that although these trajectories are largely similar to those of Black children from US-born families, the differences provide some evidence for lower obesity risk among Black children from immigrant families compared to Black children from US-born families. As this study is the first to describe BMI trajectories for Black children from immigrant families across early and middle childhood, future work is needed to replicate these results and to explore differences in heavier weight trajectories between children from immigrant and US-born families.

Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. METHODS: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. DISCUSSION: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.

The Children, Caregivers, and Community (C3) study of together growing strong: A protocol for an observational, place-based initiative in Sunset Park, Brooklyn.

Reaching population-level impact for families in poverty requires moving beyond a sole focus on individuals, to a wider focus on interactions between individuals and their broader environmental contexts. Place-based initiatives have emerged as a policy response to promote community-level change around these broader interactions between individuals and their local communities through addressing long-standing disparities in housing, employment, education, and health. Together Growing Strong (TGS) is one such place-based initiative focused on transforming the health, wellbeing, and development of young children and their families in Sunset Park, Brooklyn. The Children, Caregivers, and Community (C3) Study is an outcomes-based study designed to assess the trajectories of children and families in Sunset Park along indicators such as family health and wellbeing and child development in relation to TGS program participation. The aims, scope, and protocol of the C3 Study are the subjects of this paper.

Strategies to Engage Blacks in Sleep Medicine: Lessons Learned from Three Studies Applying Community-Based Participatory Research Principles.

Introduction: Awareness, assessment and treatment of sleep apnea are disproportionately lower among Blacks, compared to other racial/ethnic groups. To address this health disparity gap, communication strategies that connect Blacks to OSA education, detection and treatment adherence interventions are needed. Strategies that engage individuals through communication technologies, community-level social network support, and medical providers in clinical settings are also needed. We present lessons learned from three studies that offer these solutions using a community-engaged research model: The Metabolic Syndrome Outcome Study (MetSO), Peer-enhanced Education to Reduce Sleep Ethnic Disparities (PEERS-ED), and Tailored Approach to Sleep Health Education (TASHE), to capture program effectiveness and lessons learned from project successes and failures. Methods: The methods of OSA community-based programs included the application of an OSA community-engaged research model. This model served as a strategic guideline for effective interventions to engage communities in research and ensure cultural appropriateness in OSA interventions. Focus groups, in-depth interviews and community steering committee meetings were conducted with various stakeholders. Delphi surveys were used to identify high priority diseases and conditions. Community barriers and needs were identified through iterative combinations of surveys and focus group meetings. Stakeholder groups participated in all aspects of our studies, including the development, dissemination and implementation phases, reflecting a bi-directional decision-making process that ensures the interests of both parties were considered. The MetSO, PEERS-ED and TASHE studies were reviewed to understand the effectiveness of the programs and to evaluate lessons learned. Results: MetSO, PEERS-ED and TASHE interventions revealed that community-engaged strategies are successful in enrolling Black populations into clinical trials. The study teams reached nearly 3,000 Blacks at risk of OSA and screened about 2,000 people in sleep apnea studies in New York City. Sleep brochures were distributed to over 10,000 people. Lessons learned from MetSO, PEERS-ED and TASHE interventions revealed that building relationships, establishing trust, identifying a study champion, learning to adjust and providing participant incentives are key strategic elements for successful recruitment and retention of Blacks participations in clinical trials. Conclusion: Strategic application of community-oriented frameworks ensures active community engagement throughout the research process, allowing for greater enrollment of Blacks in clinical studies as well as increased OSA awareness, diagnosis, and treatment.

Out Like a Light: Feasibility and Acceptability Study of an Audio-Based Sleep Aide for Improving Parent-Child Sleep Health.

Our study examines the acceptability and feasibility of Moshi, an audio-based mobile application, among children 3-8 years old using a parent-child dyadic approach. Our 10-day within-subject pre-post study design consisted of five nights of a normal bedtime routine and a subsequent five nights exposed to one story on the Moshi application during the intervention. Each five-night period spanned three weeknights and two weekend nights. The Short-Form Children's Sleep Habits Questionnaire (SF-CSHQ) was used to measure children's sleep at baseline and post-intervention. The PROMIS, Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index were used to assess parents' sleep. Among the 25 child-parent dyads, the mean child age was 4 (SD = 1.23) and 63% were male (n = 15). Mean parent age was 35 (SD = 5.83), 84% were female (n = 21), and 48.0% were Black (n = 12). For child-only comparisons, mean post-SF-CSHQ measures were lower compared to baseline. A trend in parent sleep is reported. This study shows the potential of an audio-based mobile sleep aid to improve sleep health in a racially diverse parent and child dyad sample.

Development and Evaluation of the Clinical Trial HEalth Knowledge and Beliefs Scale (CHEKS).

Patient health literacy is vital to clinical trial engagement. Knowledge and beliefs about clinical trials may contribute to patient literacy of clinical trials, influencing engagement, enrollment and retention. We developed and assessed a survey that measures clinical trial health knowledge and beliefs, known as the Clinical trial HEalth Knowledge and belief Scale (CHEKS). The 31 survey items in CHEKS represent knowledge and beliefs about clinical trial research (n = 409) in 2017. We examined item-scale correlations for the 31 items, eliminated items with item-scale correlations less than 0.30, and then estimated internal consistency reliability for the remaining 25 items. We used the comparative fit index (CFI) and the root mean squared error of approximation (RMSEA) to evaluate model fit. The average age of the sample was 34 (SD = 15.7) and 48% female. We identified 6 of the 31 items that had item-scale correlations (corrected for overlap) lower than 0.30. Coefficient alpha for the remaining 25 items was 0.93 A one-factor categorical confirmatory factor analytic model with 16 correlated errors was not statistically significant (chi-square = 10011.994, df = 300, p < 0.001) but fit the data well (CFI = 0.95 and RMSEA = 0.07). CHEKS can assess clinical trial knowledge and beliefs.

"It made all the difference": a qualitative study of parental experiences with pediatric obstructive sleep apnea detection.

STUDY OBJECTIVES: To assess parental experience of their child's obstructive sleep apnea (OSA) detection process and inform the development of interventions and health communication strategies to improve OSA detection. METHODS: Semistructured interviews were conducted with 30 parents of children (ages 3-14) who snored and were referred for an overnight polysomnogram (PSG). Parents (60.0% Black race, 93.3% mothers) described how their child was referred for PSG and their perceptions and feelings throughout the detection process. Parents also completed an OSA knowledge measure. Interview data were analyzed using a descriptive approach and thematic analysis was conducted using the NVivo 12 software system. RESULTS: Twenty-one themes were identified across 5 categories (first steps; PSG facilitators and barriers; health information; health care experiences; parent experiences). Respondents experienced multiple pathways to OSA detection, with more than half of referrals initiated by parental concerns (vs. screening efforts). Parents reported a willingness to take any necessary steps to help their child. Both barriers and facilitators to completing a PSG were described. Parents observed both nighttime and daytime symptoms related to OSA in their child but often did not connect the symptoms to each other until later in the process. Participants had varying degrees of OSA knowledge, with a mean knowledge score of 56% correct (range 10%-90% correct). CONCLUSIONS: Parental experiences highlight aspects of the health care system that are both effective and ineffective in detecting children with OSA. Implications include a need for strategies to promote timely detection and to provide parents with accurate information about pediatric OSA. CITATION: Honaker SM, Gopalkrishnan A, Brann M, Wiehe S, Clark AA, Chung A. "It made all the difference": a qualitative study of parental experiences ith pediatric obstructive sleep apnea detection. J Clin Sleep Med. 2022;18(8):1921-1931.

The development and psychometric evaluation of the Survey of Obstructive Sleep Apnea Functional Health Literacy.

OBJECTIVE AND OBJECTIVE: Obstructive Sleep Apnea (OSA) is a highly prevalent disorder that disparately affects racial/ethnic minorities. OSA functional health literacy can contribute to health disparities. Documenting poor OSA functional health literacy is needed to inform research agendas, policy, and advocacy efforts. The objective of this study is to develop a scale for measuring OSA functional health literacy among diverse audiences and a variety of reading levels and to ascertain its reliability and validity. METHODS: Development of the 18-item Survey of OSA Functional Health Literacy (SOFHL) was guided by literature review and input from experts. A convenience sample of persons enrolled in a clinical trial completed the survey (n=194). The psychometric evaluation was conducted using factor analysis to identify the number of dimensions in the SOFHL and their relationship to other domains that are relevant to OSA functional health literacy. RESULTS: Internal consistency reliability (alpha) was estimated for the resulting scale and correlations with educational attainment and income completed. All respondents were Black and 29% reported average household income less than $10,000 USD. Confirmatory factor analysis provided support for two dimensions: OSA general knowledge (alpha=0.81) and self-efficacy for OSA self-management (alpha=0.71). CONCLUSIONS: Higher educational attainment and socioeconomic status were associated with better OSA functional health literacy. These results provide preliminary support for the SOFHL, a measure that can be used to assess OSA functional health literacy.

Adolescent Peer Influence on Eating Behaviors via Social Media: Scoping Review.

BACKGROUND: The influence of social media among adolescent peer groups can be a powerful change agent. OBJECTIVE: Our scoping review aimed to elucidate the ways in which social media use among adolescent peers influences eating behaviors. METHODS: A scoping review of the literature of articles published from journal inception to 2019 was performed by searching PubMed (ie, MEDLINE), Embase, CINAHL, PsycINFO, Web of Science, and other databases. The review was conducted in three steps: (1) identification of the research question and clarification of criteria using the population, intervention, comparison, and outcome (PICO) framework; (2) selection of articles from the literature using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines; and (3) charting and summarizing information from selected articles. PubMed's Medical Subject Headings (MeSH) and Embase's Emtree subject headings were reviewed along with specific keywords to construct a comprehensive search strategy. Subject headings and keywords were based on adolescent age groups, social media platforms, and eating behaviors. After screening 1387 peer-reviewed articles, 37 articles were assessed for eligibility. Participant age, gender, study location, social media channels utilized, user volume, and content themes related to findings were extracted from the articles. RESULTS: Six articles met the final inclusion criteria. A final sample size of 1225 adolescents (aged 10 to 19 years) from the United States, the United Kingdom, Sweden, Norway, Denmark, Portugal, Brazil, and Australia were included in controlled and qualitative studies. Instagram and Facebook were among the most popular social media platforms that influenced healthful eating behaviors (ie, fruit and vegetable intake) as well as unhealthful eating behaviors related to fast food advertising. Online forums served as accessible channels for eating disorder relapse prevention among youth. Social media influence converged around four central themes: (1) visual appeal, (2) content dissemination, (3) socialized digital connections, and (4) adolescent marketer influencers. CONCLUSIONS: Adolescent peer influence in social media environments spans the spectrum of healthy eating (ie, pathological) to eating disorders (ie, nonpathological). Strategic network-driven approaches should be considered for engaging adolescents in the promotion of positive dietary behaviors.

Sleep, Classroom Behavior, and Achievement Among Children of Color in Historically Disinvested Neighborhoods.

Children of color are more likely to have poor sleep health than White children, placing them at risk for behavioral problems in the classroom and lower academic performance. Few studies, however, have utilized standardized measures of both classroom behavior and achievement. This study examined whether children's sleep (parent and teacher report) in first grade concurrently related to independent observations of classroom behavior and longitudinally predicted achievement test scores in second grade in a sample of primarily Black (86%) children (n = 572; age = 6.8) living in historically disinvested neighborhoods. Higher teacher-reported child sleepiness was associated with lower adaptive behaviors and higher problem behaviors in the classroom, and predicted lower achievement. Parent-reported bedtime resistance and disordered breathing also predicted lower achievement.

Benefits of Community-Based Approaches in Assessing and Addressing Sleep Health and Sleep-Related Cardiovascular Disease Risk: a Precision and Personalized Population Health Approach.

PURPOSE OF REVIEW: In this current review, we describe the benefits of community-based and "precision and personalized population health" (P3H) approaches to assessing and addressing sleep health problems and sleep-related cardiovascular diseases (CVD) among vulnerable populations such as racial/ethnic minorities, the elderly, and the socioeconomically disadvantaged. RECENT FINDINGS: Very few sleep health programs utilize a community-based or P3H approach, which may account for low estimates of sleep health problems, related CVD outcomes, and inadequate healthcare infrastructure to address sleep-related health outcomes at the community and population level. We describe community-based and P3H approaches and programs as solutions to accurately capture estimates of sleep health and reduce burden of sleep health problems and corollary CVD outcomes at the level of the community and population. Specifically, we describe seven critical steps needed to successfully implement a community-based and P3H approach to address sleep health problems. Community-based and P3H approaches are effective strategies to assessing and addressing sleep health problems and related health conditions.

Development of "Advancing People of Color in Clinical Trials Now!": Web-Based Randomized Controlled Trial Protocol.

BACKGROUND: Participation in clinical trials among people of color remains low, compared with white subjects. This protocol describes the development of "Advancing People of Color in Clinical Trials Now!" (ACT Now!), a culturally tailored website designed to influence clinical trial decision making among people of color. OBJECTIVE: This cluster randomized study aims to test the efficacy of a culturally tailored website to increase literacy, self-efficacy, and willingness to enroll in clinical trials among people of color. METHODS: ACT Now! is a randomized trial including 2 groups: (1) intervention group (n=50) with access to the culturally tailored website and (2) control group (n=50) exposed to a standard clinical recruitment website. Clinical trial literacy and willingness to enroll in a clinical trial will be measured before and after exposure to the website corresponding to their assigned group (intervention or control). Surveys will be conducted at baseline and during the 1-month postintervention and 3-month follow-up. Website architecture and wireframing will be informed by the literature and experts in the field. Statistical analysis will be conducted using a two-tailed t test, with 80% power, at .05 alpha level, to increase clinical trial literacy, self-efficacy, and willingness to enroll in clinical trials 3 months post intervention. RESULTS: We will design a culturally tailored website that will provide leverage for community stakeholders to influence clinical trial literacy, self-efficacy, and willingness to enroll in clinical trials among racial and ethnic groups. ACT Now! applies a community-based participatory research approach through the use of a community steering committee (CSC). The CSC provides input during the research study conception, development, implementation, and enrollment. CSC relationships help foster trust among communities of color. ACT Now! has the potential to fill a gap in clinical trial enrollment among people of color through an accessible web-based website. This study was funded in July 2017 and obtained institutional review board approval in spring 2017. As of December 2019, we had enrolled 100 participants. Data analyses are expected to be completed by June 2020, and expected results are to be published in fall 2020. CONCLUSIONS: ACT Now! has the potential to fill an important gap in clinical trial enrollment among people of color through an accessible web-based website. TRIAL REGISTRATION: ClinicalTrials.gov NCT03243071; https://clinicaltrials.gov/ct2/show/NCT00102401. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17589.

Obstructive Sleep Apnea Risk and Stroke among Blacks with Metabolic Syndrome: Results from Metabolic Syndrome Outcome (MetSO) Registry.

INTRODUCTION: The American Stroke Association estimates that stroke is the fifth leading cause of death in the United States. According to the Center for Disease Control and Prevention someone in the United States has a stoke every 40 seconds, affecting more than 795,000 people of which 140,000 result in death [1]. Emerging evidence suggests that obstructive sleep apnea (OSA) is a strong risk factor for stroke. This study using The Metabolic Syndrome Outcome (MetSO) registry explored whether blacks at risk for obstructive sleep apnea (OSA) are at greater risk for a stroke. METHOD: The present study utilized data from the MetSO study, an NIH-funded cohort study of blacks with metabolic syndrome (MetS). Patients were diagnosed with MetS using standard criteria articulated in the joint interim statement for harmonizing the MetS. The study assessed OSA risk using the Apnea Risk Evaluation System (ARES); defining high risk as a total ARES score ≥6. Data was coded and analyzed by an experienced statistician using SPSS 20.0. RESULTS: A total of 1035 participants were screened for MetS in the MetSO registry. During the data collection period 875 participants were enrolled during the time of analysis. The average age of the sample was 62±14 years (range: 20-97); 71% were female, and all were of black race/ethnicity. Seventy-one percent reported finishing high school, and 43% reported annual income <10K. Descriptive analyses showed 93% of the participants were diagnosed with hypertension; 61%, diabetes; 72%, dyslipidemia; 90% were overweight/obese; 33% had a history of heart disease and 10% had a stroke history. Using the ARES screener, we estimated that 48% were at high risk for OSA. Logistic regression analysis, adjusting for age and gender, showed that patients at high risk for OSA had a nearly three-fold increase in the odds of having a stroke (OR = 2.79, 95% CI: 1.64-4.73). CONCLUSION: In the MetSO registry, a cohort of blacks with MetS, the prevalence of stroke is greater than in the general US population. Blacks at risk for OSA are particularly vulnerable to experiencing a stroke.

A Pantheoretical Framework to Optimize Adherence to Healthy Lifestyle Behaviors and Medication Adherence: The Use of Personalized Approaches to Overcome Barriers and Optimize Facilitators to Achieve Adherence.

Patient nonadherence to healthy lifestyle behaviors and medical treatments (like medication adherence) accounts for a significant portion of chronic disease burden. Despite the plethora of behavioral interventions to overcome key modifiable/nonmodifiable barriers and enable facilitators to adherence, short- and long-term adherence to healthy lifestyle behaviors and medical treatments is still poor. To optimize adherence, we aimed to provide a novel mobile health solution steeped in precision and personalized population health and a pantheoretical approach that increases the likelihood of adherence. We have described the stages of a pantheoretical approach utilizing tailoring, clustering/profiling, personalizing, and optimizing interventions/strategies to obtain adherence and highlight the minimal engineering needed to build such a solution.

Feasibility and Acceptability of a Culturally Tailored Website to Increase Fruit and Vegetable Intake and Physical Activity Levels in African American Mother-Child Dyads: Observational Study.

BACKGROUND: African American youth (aged 8-14 years) do not adhere to national dietary and physical activity guidelines. Nonadherence to these recommendations contributes to disproportionate rates of obesity compared with their white counterparts. Culturally tailored electronic health (eHealth) solutions are needed to communicate nutrition and physical activity messages that resonate with this target population. OBJECTIVE: This study aimed to identify the impact of exposure to a website hosting culturally tailored cartoons to inspire fruit and vegetable uptake and physical activity levels in African American mother-child dyads. METHODS: Statistical analysis included paired sample t tests to evaluate knowledge gains, self-efficacy, and readiness to change. Adapted items from Prochaska's Stages of Change toward the following 4 behaviors were assessed with pre- and posttest surveys: (1) fruit and vegetable selection on my plate, (2) meal preparation, (3) fruit and vegetable selection outside of home, and (4) physical activity. Open-ended comments on videos from mother-child dyads were used to determine user acceptance. Observations of repeated responses during content analysis informed coding and development of key themes. RESULTS: A final sample size of 93 mother-child dyads completed the study. Mothers reported significant improvement from precontemplation or contemplation stages to preparation or action stages for (1) fruit and vegetable selection on her plate (P=.03), (2) meal preparation for her family (P=.01), (3) fruit and vegetable selection outside the home (P<.001), and (4) physical activity (P<.001). Significant improvements were found in knowledge, stage of change, and self-efficacy for the 4 target behaviors of interest (P<.001). Children's open-ended commentary reported vicarious learning and positive character identification with brown-skinned cartoons exhibiting healthful food and exercise behaviors. Mothers commented on the lack of accessible produce in their neighborhoods not depicted in the cartoon videos. CONCLUSIONS: Culturally adapted cartoons that incorporate tailored preferences by African American families, such as race or demography, may help increase adherence to target health behaviors when developing eHealth behavior solutions.

Obstructive sleep apnea and stroke.

Obstructive Sleep Apnea (OSA) is a common co-morbid condition in stroke patients. It represents a very important risk factor for stroke in addition to the other established ones such as hypertension, cardiovascular disease (CVD), hyperlipidemia, atrial fibrillation (AF), type 2 diabetes mellitus (T2DM), stress, smoking, and heavy drinking. Although in the United States the prevalence of OSA has somewhat decreased from the previous years, globally its prevalence remains constant, or in some cases, is on the rise. In this review we present the epidemiology for OSA in stroke populations and discuss the risk factors for stroke as well as the underlying pathogenetic mechanisms linking OSA, stroke and CVD. We also emphasize the more thorough evaluation and control of OSA in order to prevent the disabling side effects of a stroke, which not only compromises the physical and mental health of a person and increases the burden on families, but also adds a severe burden to national health economics. OSA should always be considered when assessing a patient with transient ischemic attacks (TIA). Work up and treatment for OSA will not only help prevent stroke with its devastating consequences, but will also help prevent CVD, and ameliorate co-morbid conditions such as diabetes and hypertension in these vulnerable populations.

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation.

NKX3.1 is a homeobox transcription factor whose function as a prostate tumor suppressor remains insufficiently understood because neither the transcriptional program governed by NKX3.1, nor its interacting proteins have been fully revealed. Using affinity purification and mass spectrometry, we have established an extensive NKX3.1 interactome which contains the DNA repair proteins Ku70, Ku80, and PARP, thus providing a molecular underpinning to previous reports implicating NKX3.1 in DNA repair. Transcriptomic profiling of NKX3.1-negative prostate epithelial cells acutely expressing NKX3.1 revealed a rapid and complex response that is a near mirror image of the gene expression signature of human prostatic intraepithelial neoplasia (PIN). Pathway and network analyses suggested that NKX3.1 actuates a cellular reprogramming toward luminal cell differentiation characterized by suppression of pro-oncogenic c-MYC and interferon-STAT signaling and activation of tumor suppressor pathways. Consistently, ectopic expression of NKX3.1 conferred a growth arrest depending on TNFα and JNK signaling. We propose that the tumor suppressor function of NKX3.1 entails a transcriptional program that maintains the differentiation state of secretory luminal cells and that disruption of NKX3.1 contributes to prostate tumorigenesis by permitting luminal cell de-differentiation potentially augmented by defects in DNA repair.

An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy.

Although angiogenesis inhibitors have provided substantial clinical benefit as cancer therapeutics, their use is limited by resistance to their therapeutic effects. While ample evidence indicates that such resistance can be influenced by the tumor microenvironment, the underlying mechanisms remain incompletely understood. Here, we have uncovered a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance in multiple tumor models: lymphoma, lung and colon. Tumor-infiltrating T helper type 17 (T(H)17) cells and interleukin-17 (IL-17) induced the expression of granulocyte colony-stimulating factor (G-CSF) through nuclear factor κB (NF-κB) and extracellular-related kinase (ERK) signaling, leading to immature myeloid-cell mobilization and recruitment into the tumor microenvironment. The occurrence of T(H)17 cells and Bv8-positive granulocytes was also observed in clinical tumor specimens. Tumors resistant to treatment with antibodies to VEGF were rendered sensitive in IL-17 receptor (IL-17R)-knockout hosts deficient in T(H)17 effector function. Furthermore, pharmacological blockade of T(H)17 cell function sensitized resistant tumors to therapy with antibodies to VEGF. These findings indicate that IL-17 promotes tumor resistance to VEGF inhibition, suggesting that immunomodulatory strategies could improve the efficacy of anti-angiogenic therapy.

Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies.

PURPOSE: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients. EXPERIMENTAL DESIGN: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy. RESULTS: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies. CONCLUSIONS: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials.