Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer.

BACKGROUND/OBJECTIVE: To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null and WT prostate tumours. METHODS: Mechanisms associated with docetaxel capivasertib treatment activity in prostate cancer were examined using a panel of in vivo tumour models and cell lines. RESULTS: Combining docetaxel and capivasertib had increased activity in PTEN null and WT prostate tumour models in vivo. In vitro short-term docetaxel treatment caused cell cycle arrest in the majority of cells. However, a sub-population of docetaxel-persister cells did not undergo G2/M arrest but upregulated phosphorylation of PI3K/AKT pathway effectors GSK3ß, p70S6K, 4E-BP1, but to a lesser extent AKT. In vivo acute docetaxel treatment induced p70S6K and 4E-BP1 phosphorylation. Treating PTEN null and WT docetaxel-persister cells with capivasertib reduced PI3K/AKT pathway activation and cell cycle progression. In vitro and in vivo it reduced proliferation and increased apoptosis or DNA damage though effects were more marked in PTEN null cells. Docetaxel-persister cells were partly reliant on GSK3ß as a GSK3ß inhibitor AZD2858 reversed capivasertib-induced apoptosis and DNA damage. CONCLUSION: Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3ß.

The role of social cohesion in explaining rural/urban differences in healthcare access and health status among older adults in the mid-Atlantic United States.

Social cohesion can influence health. It is higher among rural versus urban residents, but the burden of chronic disease is higher in rural communities. We examined the role of social cohesion in explaining rural/urban differences in healthcare access and health status. Rural (n = 1080) and urban (n = 1846) adults (ages 50+) from seven mid-Atlantic U.S. states completed an online, cross-sectional survey on social cohesion and health. We conducted bivariate and multivariable analyses to evaluate the relationships of rurality and social cohesion with healthcare access and health status. Rural participants had higher social cohesion scores than did urban participants (rural: mean = 61.7, standard error[SE] = 0.40; urban: mean = 60.6, SE = 0.35; adjusted beta = 1.45, SE = 0.54, p < .01). Higher social cohesion was associated with greater healthcare access: last-year check-up: adjusted odds ratio[aOR] = 1.25, 95% confidence interval[CI] = 1.17-1.33; having a personal provider: aOR = 1.11, 95% CI = 1.03-1.18; and being up-to-date with CRC screening: aOR = 1.17, 95% CI = 1.10-1.25. In addition, higher social cohesion was associated with improved health status: higher mental health scores (adjusted beta = 1.03, SE = 0.15, p < .001) and lower body mass index (BMI; beta = -0.26, SE = 0.10, p = .01). Compared to urban participants, rural participants were less likely to have a personal provider, had lower physical and mental health scores, and had higher BMI. Paradoxically, rural residents had higher social cohesion but generally poorer health outcomes than did urban residents, even though higher social cohesion is associated with better health. These findings have implications for research and policy to promote social cohesion and health, particularly for health promotion interventions to reduce disparities experienced by rural residents.

Assessing the use of constructs from the consolidated framework for implementation research in U.S. rural cancer screening promotion programs: a systematic search and scoping review.

BACKGROUND: Cancer screening is suboptimal in rural areas, and interventions are needed to improve uptake. The Consolidated Framework for Implementation Research (CFIR) is a widely-used implementation science framework to optimize planning and delivery of evidence-based interventions, which may be particularly useful for screening promotion in rural areas. We examined the discussion of CFIR-defined domains and constructs in programs to improve cancer screening in rural areas. METHODS: We conducted a systematic search of research databases (e.g., Medline, CINAHL) to identify studies (published through November 2022) of cancer screening promotion programs delivered in rural areas in the United States. We identified 166 records, and 15 studies were included. Next, two reviewers used a standardized abstraction tool to conduct a critical scoping review of CFIR constructs in rural cancer screening promotion programs. RESULTS: Each study reported at least some CFIR domains and constructs, but studies varied in how they were reported. Broadly, constructs from the domains of Process, Intervention, and Outer setting were commonly reported, but constructs from the domains of Inner setting and Individuals were less commonly reported. The most common constructs were planning (100% of studies reporting), followed by adaptability, cosmopolitanism, and reflecting and evaluating (86.7% for each). No studies reported tension for change, self-efficacy, or opinion leader. CONCLUSIONS: Leveraging CFIR in the planning and delivery of cancer screening promotion programs in rural areas can improve program implementation. Additional studies are needed to evaluate the impact of underutilized CFIR domains, i.e., Inner setting and Individuals, on cancer screening programs.

Behaviors and Advocacy Related to COVID-19 among Cancer Patients: The Health Belief Model and Opportunities for Messaging and Education.

Cancer patients have an increased risk of severe COVID-19 outcomes and were recommended to be vaccinated, wear a mask, practice social distancing, and increase hand hygiene. We used the Health Belief Model (HBM) to identify constructs that were associated with the likelihood of adhering to and advocating for CDC COVID-19 prevention recommendations. We surveyed adult cancer patients who had an onsite appointment at the Penn State Cancer Institute or at the Hematology and Oncology Associates of Northeastern Pennsylvania. Survey measures included adherence to and informing others of COVID-19 recommendations as well as HBM constructs. Relationships between HBM constructs and outcomes were assessed with Spearman's correlation and multivariable ordinal logistic regression. Of the 106 participants who completed the survey for our objectives of interest, 76% always wore a mask, 29% always practiced social distancing, and 24% washed their hands at least 10 times a day. Limited advocacy behaviors were captured for the COVID-19 vaccine (30%), social distancing (36%), and wearing masks (27%). Perceived benefits, perceived barriers, and cues-to-action were positively associated with the likelihood of adherence or advocacy of COVID-19 recommendations among cancer patients, whereas perceived susceptibility and self-efficacy were negatively associated with the likelihood of adherence or advocacy of COVID-19 recommendations among cancer patients. Perceived benefits may be the strongest predictor for adherence and advocacy for specific COVID-19 guidelines. Future messaging and educational campaigns focused on improving adherence to or advocacy of specific health behaviors should be informed by the HBM and originate from multiple outlets.

Improving cervical cancer screening rates: a scoping review of resources and interventions.

INTRODUCTION: Cervical cancer mortality can be prevented through early detection with screening methods such as Pap and high-risk human papillomavirus (hrHPV) tests; however, only 81% of women aged 21-65 are up-to-date on screening. Many interventions to increase cervical cancer screening have been implemented, but there is limited understanding about which intervention components are most successful. METHODS: We conducted a scoping review of existing literature and available resources for cervical cancer screening interventions to identify gaps in the research. We used t tests and correlations to identify associations among intervention components and effect sizes. RESULTS: Out of nine studies, the mean overall effect size for interventions was 11.3% increase in Pap testing for cervical cancer screening (range = - 4-24%). Interventions that included community health workers or one-on-one interaction had the biggest effect size (p < 0.05). No associations with effect size were noted for literacy level, number of intervention components, or targeting by race/ethnicity. CONCLUSIONS: Future interventions may include educational sessions with community health workers or one-on-one patient interaction to improve cervical cancer screening. Further research is needed to establish effect sizes for large-scale interventions and hrHPV screening interventions.

Perspectives on Self-Sampling for Cancer Screening From Staff at Federally Qualified Health Centers in Rural and Segregated Counties: A Preliminary Qualitative Study.

BACKGROUND: Self-sampling for colorectal and cervical cancer screening can address the observed geographic disparities in cancer burden by alleviating barriers to screening participation, such as access to primary care. This preliminary study examines qualitative themes regarding cervical and colorectal cancer self-sampling screening tools among federally qualified health center clinical and administrative staff in underserved communities. METHODS: In-depth interviews were conducted with clinical or administrative employees (≥18 years of age) from FQHCs in rural and racially segregated counties in Pennsylvania. Data were managed and analyzed using QSR NVivo 12. Content analysis was used to identify themes about attitudes towards self-sampling for cancer screening. RESULTS: Eight interviews were conducted. Average participant age was 42 years old and 88% of participants were female. Participants indicated that a shared advantage for both colorectal and cervical cancer self-sampling tests was their potential to increase screening rates by simplifying the screening process and offering an alternative to those who decline traditional screening. A shared disadvantage to self-sampling was the potential for inaccurate sample collection, either through the test itself or the sample collection by the patient. CONCLUSIONS: Self-sampling offers a promising solution to increase cervical and colorectal cancer screening in rural and racially segregated communities. This study's findings can guide future research and interventions which integrate self-sampling screening into routine primary care practice.

Disparities in Cancer Screening: The Role of County-Level Metropolitan Status and Racial Residential Segregation.

Mortality from cervical and colorectal cancers can be reduced through routine screening, which can often be accessed through primary care. However, uptake of screening in the US remains suboptimal, with disparities observed across geographic characteristics, such as metropolitan status or level of racial residential segregation. Little is known about the interaction of metropolitan status and segregation in their relationship with cancer screening. We conducted a quantitative survey of 474 women aged 45-65 in central Pennsylvania. The survey collected county-level characteristics and participant-level demographics, beliefs, cancer screening barriers, and cervical and colorectal cancer screening. We used bivariate and multivariable logistic regression to analyze relationships between metropolitan status and segregation with screening. For cervical cancer screening, 82.8% of participants were up-to-date, which did not differ by county type in the final analysis. Higher healthcare trust, higher cancer fatalism, and reporting cost as a barrier were associated with cervical cancer screening. For colorectal cancer screening, 55.4% of participants were up-to-date, which differed by county type. In metropolitan counties, segregation was not associated with colorectal cancer screening, but in non-metropolitan counties, segregation was associated with greater colorectal cancer screening. The relationship between metropolitan status and being up-to-date with colorectal, but not cervical, cancer screening varied by segregation. Other important beliefs and barriers to screening varied by county type. This research can guide future cancer screening interventions in primary care settings in underserved communities.

Multilevel Associations with Cancer Screening Among Women in Rural, Segregated Communities Within the Northeastern USA: a Mixed-Methods Study.

We recruited women (primarily non-Hispanic White) from 14 rural, segregated counties in a Northeastern US state for an explanatory sequential study: 100 women (ages 50-65 years) completed a survey, and 16 women participated in focus groups. We sought to identify personal (e.g., healthcare mistrust) and environmental (e.g., travel time to healthcare providers) factors related to colorectal and cervical cancer screening. Quantitatively, 89% of participants were up-to-date for cervical screening, and 65% for colorectal screening. Factors interacted such that compounding barriers were associated with lower odds of screening (e.g., insurance status and healthcare mistrust: interaction p = .02 for cervical; interaction p = .05 for colorectal). Qualitatively, three themes emerged regarding barriers to screening: privacy concerns, logistical barriers, and lack of trust in adequacy of healthcare services. While cancer screening was common in rural, segregated counties, women who reported both environmental and personal barriers to screening had lower uptake. Future interventions to promote screening can target these barriers.

Method to Investigate the Distribution of Water-Soluble Drug-Delivery Systems in Fresh Frozen Tissues Using Imaging Mass Cytometry.

Imaging mass cytometry (IMC) offers the opportunity to image metal- and heavy halogen-containing xenobiotics in a highly multiplexed experiment with other immunochemistry-based reagents to distinguish uptake into different tissue structures or cell types. However, in practice, many xenobiotics are not amenable to this analysis, as any compound which is not bound to the tissue matrix will delocalize during aqueous sample-processing steps required for IMC analysis. Here, we present a strategy to perform IMC experiments on a water-soluble polysarcosine-modified dendrimer drug-delivery system (S-Dends). This strategy involves two consecutive imaging acquisitions on the same tissue section using the same instrumental platform, an initial laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MSI) experiment followed by tissue staining and a standard IMC experiment. We demonstrated that settings can be found for the initial ablation step that leave sufficient residual tissue for subsequent antibody staining and visualization. This workflow results in lateral resolution for the S-Dends of 2 µm followed by imaging of metal-tagged antibodies at 1 µm.

Promoting colorectal cancer screening: A scoping review of screening interventions and resources.

BACKGROUND: Early detection through screening can reduce colorectal cancer (CRC) mortality, but approximately 33% of adults aged 50-75 are not getting screened as recommended. Many interventions to increase CRC screening have been tested, but clinical and community organizations may be challenged in identifying the optimum programs and program materials to increase screening and ultimately reduce CRC mortality. METHODS: We conducted a scoping review to characterize existing, US-based interventions to improve CRC screening and to identify gaps in the literature. We used t-tests and correlations to analyze the relationship between project features and intervention effect sizes. RESULTS: The overall effect sizes were + 16% for changes in screening by any modality. The average effect sizes were greater for projects with more components, used patient navigation, and provided free/low-cost testing. CONCLUSION: Interventions varied greatly in terms of follow-up time, test modality, and data sources. Organizations seeking to implement a program aimed at increasing CRC screening should consider both intervention components and relevant program materials.

Comparisons of individual- and area-level socioeconomic status as proxies for individual-level measures: evidence from the Mortality Disparities in American Communities study.

BACKGROUND: Area-level measures are often used to approximate socioeconomic status (SES) when individual-level data are not available. However, no national studies have examined the validity of these measures in approximating individual-level SES. METHODS: Data came from ~ 3,471,000 participants in the Mortality Disparities in American Communities study, which links data from 2008 American Community Survey to National Death Index (through 2015). We calculated correlations, specificity, sensitivity, and odds ratios to summarize the concordance between individual-, census tract-, and county-level SES indicators (e.g., household income, college degree, unemployment). We estimated the association between each SES measure and mortality to illustrate the implications of misclassification for estimates of the SES-mortality association. RESULTS: Participants with high individual-level SES were more likely than other participants to live in high-SES areas. For example, individuals with high household incomes were more likely to live in census tracts (r = 0.232; odds ratio [OR] = 2.284) or counties (r = 0.157; OR = 1.325) whose median household income was above the US median. Across indicators, mortality was higher among low-SES groups (all p < .0001). Compared to county-level, census tract-level measures more closely approximated individual-level associations with mortality. CONCLUSIONS: Moderate agreement emerged among binary indicators of SES across individual, census tract, and county levels, with increased precision for census tract compared to county measures when approximating individual-level values. When area level measures were used as proxies for individual SES, the SES-mortality associations were systematically underestimated. Studies using area-level SES proxies should use caution when selecting, analyzing, and interpreting associations with health outcomes.

Rural-urban differences in health-related quality of life: patterns for cancer survivors compared to other older adults.

PURPOSE: Health-related quality of life (HRQOL) among older cancer survivors can be impaired by factors such as treatment, comorbidities, and social challenges. These HRQOL impairments may be especially pronounced in rural areas, where older adults have higher cancer burden and more comorbidities and risk factors for poor health. This study aimed to assess rural-urban differences in HRQOL for older cancer survivors and controls. METHODS: Data came from Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey (SEER-MHOS), which links cancer incidence from 18 U.S. population-based cancer registries to survey data for Medicare Advantage Organization enrollees (1998-2014). HRQOL measures were 8 standardized subscales and 2 global summary measures. We matched (2:1) controls to breast, colorectal, lung, and prostate cancer survivors, creating an analytic dataset of 271,640 participants (ages 65+). HRQOL measures were analyzed with linear regression models including multiplicative interaction terms (rurality by cancer status), controlling for sociodemographics, cohort, and multimorbidities. RESULTS: HRQOL scores were higher in urban than rural areas (e.g., global physical component summary score for breast cancer survivors: urban mean = 38.7, standard error [SE] = 0.08; rural mean = 37.9, SE = 0.32; p < 0.05), and were generally lower among cancer survivors compared to controls. Rural cancer survivors had particularly poor vitality (colorectal: p = 0.05), social functioning (lung: p = 0.05), role limitation-physical (prostate: p < 0.01), role limitation-emotional (prostate: p < 0.01), and global mental component summary (prostate: p = 0.02). CONCLUSION: Supportive interventions are needed to increase physical, social, and emotional HRQOL among older cancer survivors in rural areas. These interventions could target cancer-related stigma (particularly for lung and prostate cancers) and/or access to screening, treatment, and ancillary healthcare resources.

Synthesis and Characterization of Dendrimer-Based Polysarcosine Star Polymers: Well-Defined, Versatile Platforms Designed for Drug-Delivery Applications.

This paper describes the synthesis of star polymers designed for future drug-delivery applications. A generation-5 lysine dendrimer was used as a macroinitiator for the ring-opening polymerization of the sarcosine N-carboxyanhydride monomer to produce 32-arm star polymers with narrow molar mass distributions and desirable hydrodynamic size control. Fluorescent dye-labeled polymers were dosed in mice to measure plasma pharmacokinetics. Long circulation times were observed, representing ideal properties for biophysical targeting of tumors. In vivo efficacy of one of these star polymers conjugated to the therapeutic molecule SN-38 was evaluated in mice bearing SW620 xenografted tumors to demonstrate high antitumor activity and low body weight loss compared to the SN-38 prodrug irinotecan and this shows the potential of these delivery systems. As a further build, we demonstrated that these star polymers can be easily chain-end-functionalized with useful chemical moieties, giving opportunities for future receptor-targeting strategies. Finally, we describe the synthetic advantages of these star polymers that make them attractive from a pharmaceutical manufacturing perspective and report characterization of the polymers with a variety of techniques.

Disparities in health-related quality of life in women undergoing treatment for advanced ovarian cancer: the role of individual-level and contextual social determinants.

PURPOSE: Social determinants may influence health-related quality of life (HRQOL) among women with ovarian cancer, potentially creating disparities in clinical outcomes. We investigated the relationship between HRQOL and social determinants of health, including travel distance to access cancer care and health insurance type, among women participating in a randomized trial of primary adjuvant treatment for advanced ovarian cancer. METHODS: The Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire captured HRQOL (physical well-being, functional well-being, ovarian-specific, and trial outcome index [TOI]) prior to chemotherapy (baseline), during the trial, and 84 weeks after initiation of chemotherapy for women with advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. We constructed bivariate and multivariable linear mixed effects models examining the associations of social determinants of health (individual-level and contextual factors) with HRQOL scores at 84 weeks, clustering participants (n = 993) within treatment centers, and Census regions and controlling for baseline HRQOL. RESULTS: Most individual-level (race, age, cancer stage, adverse events) and contextual (travel distance to treatment center, community socioeconomic status) factors were not statistically significantly associated with HRQOL. Compared to participants with private health insurance, other participants had lower mean HRQOL (physical well-being: public insurance, - 1.00 (standard error[SE] = 0.49) points, uninsured, - 1.93 (SE = 0.63) points; functional well-being: public, - 1.29 (SE = 0.59), uninsured, - 1.98 (SE = 0.76); ovarian cancer-specific: public, - 1.60 (SE = 0.59), uninsured, - 1.66 (SE = 0.75); TOI: public, - 3.81 (SE = 1.46), uninsured, - 5.51 (SE = 1.86); all p < .05). CONCLUSIONS: Private health insurance was associated with improved HRQOL at the completion of treatment for advanced stage ovarian cancer. Implications of health insurance on HRQOL should be further investigated, particularly among women with ovarian cancer who receive standard of care treatment.

A Qualitative Comparative Analysis of Combined State Health Policies Related to Human Papillomavirus Vaccine Uptake in the United States.

OBJECTIVES: To examine how combinations of state policies, rather than single policies, are related to uptake of human papillomavirus (HPV) vaccine. METHODS: Using publicly available records and the literature, we characterized policies for each US state and Washington, DC, in 2015 (n = 51), including (1) Medicaid expansion, (2) policies permitting HPV vaccination in pharmacies, (3) school-entry requirements, (4) classroom sex education mandates, and (5) parental education mandates. Using qualitative comparative analysis, we identified which existing combinations of these policies were necessary and sufficient for high HPV vaccine initiation among adolescents, with National Immunization Survey-Teen data. RESULTS: No single policy was necessary or sufficient for high HPV vaccine uptake; however, 1 set of policies had consistently high HPV vaccine uptake: adoption of all policies except parental education mandates (girls: consistency = 1.00, coverage = 0.07; boys: consistency = 0.99, coverage = 0.08). CONCLUSIONS: We identified a set of polices related to high HPV vaccine uptake. Future studies should examine how these policies and others, individually and in combination, are associated with HPV vaccine uptake. Public Health Implications. This study provides insight into what sets of policies are consistently related to high HPV vaccine uptake.

Patterns of cancer-related health behaviors among middle-aged and older adults: Individual- and area-level socioeconomic disparities.

Multiple health behaviors could have greater impact on chronic diseases than single behaviors, but correlates of behavioral clusters are relatively understudied. Using data from NIH-AARP Diet and Health Study (initiated in 1995) for 324,522 participants from the U.S. (age 50-71), we conducted exploratory factor analysis to identify clusters of adherence to eight cancer prevention behaviors. Poisson regressions examined associations between cluster scores and neighborhood socioeconomic deprivation, measured with census block group (1) poverty and (2) low education. Four clusters emerged: Movement (adequate physical activity/less TV); Abstinence (never smoked/less alcohol); Weight control (healthy body mass index/high fruits and vegetables); and Other (adequate sleep/receiving cancer screenings). Scores on all clusters were lower for participants in neighborhoods with the highest poverty (most deprived quintile versus least deprived: relative risk [RR] = 0.95 (95% confidence interval [CI] = 0.94-0.96) for Movement, 0.98 (95% CI = 0.97-0.99) for Abstinence, 0.94 (95% CI = 0.92-0.95) for Weight control, and 0.94 (95% CI = 0.93-0.95) for Other; all p < 0.001). Scores on three clusters were lower for participants in neighborhoods with the lowest education (RR = 0.88 (95% CI = 0.87-0.89) for Movement, 0.89 (95% CI = 0.88-0.90) for Weight control, and 0.90 (95% CI = 0.89-0.91) for Other; all p < .001). Health behaviors among older adults demonstrated four clusters. Neighborhood deprivation was associated with lower scores on clusters, suggesting that interventions to reduce concentrated deprivation may be an efficient approach for improving multiple behaviors simultaneously.

State Prevalence and Ranks of Adolescent Substance Use: Implications for Cancer Prevention.

INTRODUCTION: This study statistically ranked states' performance on adolescent substance use related to cancer risk (past-month cigarette smoking, binge alcohol drinking, and marijuana use). METHODS: Data came from 69,200 adolescent participants (50 states and the District of Columbia) in the National Survey on Drug Use and Health (NSDUH) and 450,050 adolescent participants (47 states) in the Youth Risk Behavior Surveillance System (YRBSS). Adolescents were aged 14 to 17 years. For 2011-2015, we estimated and ranked states' prevalence of adolescent substance use. We calculated the ranks' 95% confidence intervals (CIs) using a Monte Carlo method with 100,000 simulations. Spearman correlations examined consistency of ranks. RESULTS: Across states, the prevalence of cigarette smoking was 4.5% to 14.3% in NSDUH and 4.7% to 18.5% in YRBSS. Utah had the lowest prevalence (NSDUH: rank = 51 [95% CI, 47-51]; YRBSS: rank = 47 [95% CI, 46-47]), and states' ranks across surveys were correlated (r = 0.66, P < .001). The prevalence of binge alcohol drinking was 5.9% to 14.3% (NSDUH) and 7.1% to 21.7% (YRBSS). Utah had the lowest prevalence (NSDUH: rank = 50 [95% CI, 40-51]; YRBSS: rank = 47 [95% CI, 47-47]), but ranks across surveys were weakly correlated (r = 0.38, P = .01). The prevalence of marijuana use was 6.3% to 18.7% (NSDUH) and 8.2% to 27.1% (YRBSS). Utah had the lowest prevalence of marijuana use (NSDUH: rank = 50 [95% CI = 33-51]; YRBSS: rank= 46 [95% CI, 46-46]), and ranks across surveys were correlated (r = 0.70, P < .001). Wide CIs for states ranked in the middle of each distribution obscured statistical differences among them. CONCLUSION: Variability emerged across adolescent substance use behaviors and surveys (perhaps because of administration differences). Most states showed statistically equivalent performance on adolescent substance use. Adolescents in all states would benefit from efforts to reduce substance use, to prevent against lifelong morbidity.

Break-induced ATR and Ddb1-Cul4(Cdt)² ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast.

Nucleotide synthesis is a universal response to DNA damage, but how this response facilitates DNA repair and cell survival is unclear. Here we establish a role for DNA damage-induced nucleotide synthesis in homologous recombination (HR) repair in fission yeast. Using a genetic screen, we found the Ddb1-Cul4(Cdt)² ubiquitin ligase complex and ribonucleotide reductase (RNR) to be required for HR repair of a DNA double-strand break (DSB). The Ddb1-Cul4(Cdt)² ubiquitin ligase complex is required for degradation of Spd1, an inhibitor of RNR in fission yeast. Accordingly, deleting spd1(+) suppressed the DNA damage sensitivity and the reduced HR efficiency associated with loss of ddb1(+) or cdt2(+). Furthermore, we demonstrate a role for nucleotide synthesis in postsynaptic gap filling of resected ssDNA ends during HR repair. Finally, we define a role for Rad3 (ATR) in nucleotide synthesis and HR through increasing Cdt2 nuclear levels in response to DNA damage. Our findings support a model in which break-induced Rad3 and Ddb1-Cul4(Cdt)² ubiquitin ligase-dependent Spd1 degradation and RNR activation promotes postsynaptic ssDNA gap filling during HR repair.

Comparing percentages and ranks of adolescent weight-related outcomes among U.S. states: Implications for intervention development.

Understanding statistical differences in states' percentages and ranks of adolescents meeting health behavior guidelines can guide policymaking. Data came from 531,777 adolescents (grades 9-12) who completed the Youth Risk Behavior Surveillance System survey in 2011, 2013, or 2015. We measured the percentage of adolescents in each state that met guidelines for physical activity, fruit and vegetable (F&V) consumption, and healthy weight status. Then we ranked states and calculated the ranks' 95% CI's using a Monte Carlo method with 100,000 simulations. We repeated these analyses stratified by sex (female or male) or race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic/Latino, or other). Pearson's and Spearman's correlation coefficients examined consistency in the percentages and ranks (respectively) across behaviors and subgroups. Meeting the physical activity and F&V consumption guidelines was relatively rare among adolescents (25.8% [95% CI=25.2%-26.4%] and 8.0% [95% CI=7.6%-8.3%], respectively), while meeting the healthy weight guideline was common (71.5% [95% CI=70.7%-72.3%]). At the state level, percentages of adolescents meeting these guidelines were statistically similar; states' ranks had wide CI's, resulting in considerable overlap (i.e., statistical equivalence). For each behavior, states' percentages and ranks were moderately to highly correlated across adolescent subgroups (Pearson's r=0.33-0.96; Spearman's r=0.42-0.96), but across behaviors, only F&V consumption and healthy weight were correlated (Pearson's r=0.34; Spearman's r=0.37). Adolescents in all states could benefit from initiatives to support cancer prevention behaviors, especially physical activity and F&V consumption. Programs in states that ranked highly on all assessed health behaviors could be adapted for dissemination in lower-performing states.

Correlates of human papillomavirus vaccine coverage: a state-level analysis.

BACKGROUND: We tested the hypothesis that states with higher rates of cancers associated with human papillomavirus (HPV) would have lower HPV vaccine coverage. METHODS: We gathered state-level data on HPV-related cancer rates and HPV vaccine initiation coverage for girls and boys, separately, and HPV vaccine follow-through (i.e., receipt of 3 doses among those initiating the series) for girls only. In addition, we gathered state-level data on demographic composition and contact with the health care system. We calculated Pearson correlations for these ecological relationships. RESULTS: Human papillomavirus vaccine initiation among girls was lower in states with higher levels of cervical cancer incidence and mortality (r = -0.29 and -0.46, respectively). In addition, vaccine follow-through among girls was lower in states with higher levels of cervical cancer mortality (r = -0.30). Other cancer rates were associated with HPV vaccine initiation and follow-through among girls, but not among boys. Human papillomavirus vaccine initiation among girls was lower in states with higher proportions of non-Hispanic black residents and lower proportions of higher-income residents. Human papillomavirus vaccine follow-through was higher in states with greater levels of adolescents' contact with the health care system. CONCLUSIONS: Human papillomavirus vaccine coverage for girls was lower in states with higher HPV-related cancer rates. Public health efforts should concentrate on geographic areas with higher cancer rates. Strengthening adolescent preventive health care use may be particularly important to increase vaccine follow-through. Cost-effectiveness analyses may overestimate the benefits of current vaccination coverage and underestimate the benefits of increasing coverage.