Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

The Association Between Regular Cannabis Smoking and Oral Human Papillomavirus Infection in Young Adults: A Cross-Sectional Study Using NHANES Data, 2011-2016

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the U.S., and the incidence rates of HPV-related oropharyngeal cancers in the U.S. have doubled in the last 20 years. While cigarette smoking is a known risk factor for oral HPV infection, it is unknown if smoking cannabis is associated with greater occurrence of oral HPV infections. The objective of this study was to estimate the association between cannabis smoking status and oral HPV infection in U.S. young adults ages 18-30 years and examine whether this association differs by HPV vaccination status. This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) 2011-2016 cycles. Multivariable logistic regression models, stratified by HPV vaccination status, were used to test the association between cannabis smoking status and oral HPV infection. The final analytic sample (N=2,696) had a mean age of 24.4 (standard error: 0.1) years and most participants were female (50.9%), Non-Hispanic White (59.2%) and unvaccinated against HPV (74.7%). The overall unadjusted prevalence of oral HPV infection was 5.2% (95% CI: 4.1%, 6.5%). Among unvaccinated young adults, and compared to those who do not smoke cannabis, those who regularly smoke cannabis had 3.2 times the odds of oral HPV infection (AOR: 3.2; 95% CI: 1.6, 6.3) and those who irregularly smoke cannabis had 1.5 times the odds of oral HPV infection (AOR: 1.5; 95% CI: 0.8, 3.2). These findings suggest that smoking cannabis should be further examined in prospective studies as a risk factor for oral HPV infection

Stakeholder Perspectives on Advancing Understanding of Prenatal Opioid Exposure and Brain Development From the iOPEN Consortium of the Healthy Brain and Child Development Study.

Introduction: There is a dire need for research regarding the implications of opioid use during pregnancy on fetal and childhood development to better inform both medical practice and policy. The Healthy Brain and Child Development Study will examine brain and behavioral development from birth through the first decade of life. Due to large scope and anticipated complexity of this initiative, an 18-month planning phase was implemented across 28 sites across the nation. A core element of the Phase I initiative involved the development of Stakeholder Advisory Committees to inform the next phase of the initiative. Methods: Phase I stakeholder meetings were conducted at Oregon Health and Science University, New York University Langone Medical Center, the University of Pittsburgh, and the University of Vermont to better understand perspectives and inform upcoming research. Despite differences in the structure of the stakeholder meetings by site, the overarching goals for the meetings included establishing relationships, gathering input, and learning about research engagement. Documents from each meeting were reviewed for location, duration, attendees, common research themes, and pertinent suggestions for improving research approaches. Results: All stakeholders had high levels of interest in research for pregnant people with substance use disorders and agreed on research priorities including collaboration, connection, communication, and support. Different stakeholders offered unique perspectives on various aspects of study design and themes that emerged through meetings. Discussion: Overall, there was excitement about the research, especially the opportunity to include the voices of people with lived experience; collaboration between providers, peer support specialists, patients, and others; and excitement around contributing to research that could elucidate new and pertinent findings in the realm of addiction medicine and child development. Sites also found that there is mistrust between people with substance use disorder and the medical system, and this could be addressed by including people with lived experience on the research team, forming connections, communicating clearly, training the research team in implicit bias, and practicing trauma-informed care. In conclusion, these stakeholder meetings provided valuable information for structuring upcoming studies; however, researchers would have benefitted from more time and more opportunities for in-person connection

Prenatal Adversities and Latino Children’s Autonomic Nervous System Reactivity Trajectories from 6 Months to 5 Years of Age

The purpose of the study was to determine whether mothers’ adversities experienced during early pregnancy are associated with offspring’s autonomic nervous system (ANS) reactivity trajectories from 6 months to 5 years of age. This cohort study of primarily Latino families included maternal interviews at 13–14 weeks gestation about their experience of a range of adversities: father’s absence, general social support, poverty level, and household density. ANS measures of heart rate, respiratory sinus arrhythmia (parasympathetic nervous system) and preejection period (sympathetic nervous system) were collected during resting and challenging conditions on children at 6 months and 1, 3.5 and 5 years of age. Reactivity measures were calculated as the mean of the responses to challenging conditions minus a resting condition. Fixed effects models were conducted for the 212 children with two or more timepoints of ANS measures. Interactions between maternal prenatal adversity levels and child age at time of ANS protocol were included in the models, allowing the calculation of separate trajectories or slopes for each level of adversity. Results showed no significant relations between mothers’ prenatal socioeconomic or social support adversity and offspring’s parasympathetic nervous system trajectories, but there was a statistically significant relationship between social support adversity and offspring’s heart rate trajectories (p<.05) and a borderline significant relationship between socioeconomic adversity and offspring’s sympathetic nervous system trajectories (p = .05). Children whose mothers experienced one, not two, social support adversity had the smallest increases in heart rate reactivity compared to children whose mothers experienced no adversity. The children whose mothers experienced no social support and no socioeconomic adversity had the largest increases in heart rate and preejection period respectively from 6 months to 5 years showing the most plasticity. Mothers’ prenatal adverse experiences may program their children’s physiologic trajectory to dampen their heart rate or sympathetic responsivity to challenging conditions

Reducing cardiovascular disease risk in mid-life and older African Americans: A church-based longitudinal intervention project at baseline

INTRODUCTION: African Americans (AAs) experience higher age-adjusted morbidity and mortality than Whites for cardiovascular disease (CVD). Church-based health programs can reduce risk factors for CVD, including elevated blood pressure [BP], excess body weight, sedentary lifestyle and diet. Yet few studies have incorporated older adults and longitudinal designs. PURPOSES: The aims of this study are to: a) describe a theory-driven longitudinal intervention study to reduce CVD risk in mid-life and older AAs; b) compare selected dietary (fruit and vegetable servings/day, fat consumption), physical activity (PA) and clinical variables (BMI, girth circumferences, systolic and diastolic BP, LDL, HDL, total cholesterol [CHOL] and HDL/CHOL) between treatment and comparison churches at baseline; c) identify selected background characteristics (life satisfaction, social support, age, gender, educational level, marital status, living arrangement and medication use) at baseline that may confound results; and d) share the lessons learned. METHODS: This study incorporated a longitudinal pre/post with comparison group quasi-experimental design. Community-based participatory research (CBPR) was used to discover ideas for the study, identify community advisors, recruit churches (three treatment, three comparison) in two-counties in North Florida, and randomly select 221 mid-life and older AAs (45+) (n = 104 in clinical subsample), stratifying for age and gender. Data were collected through self-report questionnaires and clinical assessments. RESULTS AND CONCLUSIONS: Dietary, PA and clinical results were similar to the literature. Treatment and comparison groups were similar in background characteristics and health behaviors but differed in selected clinical factors. For the total sample, relationships were noted for most of the background characteristics. Lessons learned focused on community relationships and participant recruitment