Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting.

A synthetic lethal relationship exists between disruption of polymerase theta (Polθ), and loss of either 53BP1 or homologous recombination (HR) proteins, including BRCA1; however, the mechanistic basis of these observations are unclear. Here we reveal two distinct mechanisms of Polθ synthetic lethality, identifying dual influences of 1) whether Polθ is lost or inhibited, and 2) the underlying susceptible genotype. Firstly, we find that the sensitivity of BRCA1/2- and 53BP1-deficient cells to Polθ loss, and 53BP1-deficient cells to Polθ inhibition (ART558) requires RAD52, and appropriate reduction of RAD52 can ameliorate these phenotypes. We show that in the absence of Polθ, RAD52 accumulations suppress ssDNA gap-filling in G2/M and encourage MRE11 nuclease accumulation. In contrast, the survival of BRCA1-deficient cells treated with Polθ inhibitor are not restored by RAD52 suppression, and ssDNA gap-filling is prevented by the chemically inhibited polymerase itself. These data define an additional role for Polθ, reveal the mechanism underlying synthetic lethality between 53BP1, BRCA1/2 and Polθ loss, and indicate genotype-dependent Polθ inhibitor mechanisms.

Identification of the interleukin-8 (CXCL-8) pathway in feline oral squamous cell carcinoma - A pilot study.

The purpose of this pilot study was to detect the presence of interleukin-8 (IL-8) and the potential downstream effects of IL-8 receptor activation in 2 previously characterized feline oral squamous cell carcinoma cell lines (SCCF1 and SCCF2). Interleukin-8 messenger RNA (mRNA) was initially detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A previously validated and commercially available enzyme-linked immunosorbent assay (ELISA) test was used to measure IL-8 production in the supernatant of the 2 cell lines. Western blot was used to detect phosphorylation of proteins (AKT, ERK1/2, JAK2, STAT3, and Src), known to be downstream of interleukin-8 receptor activation. The IL-8 receptor-specific antagonists, Reparixin and SCH527123, were used to identify effects on phosphorylation of these proteins. Interleukin-8 mRNA and protein were detected in both SCCF1 and SCCF2 by RT-PCR and ELISA, respectively. Phosphorylation of ERK1/2, STAT3, and Src was detected in both cell lines. Inhibition of the IL-8 receptor led to a decrease in phosphorylation of Src, but not ERK1/2 or STAT3. In conclusion, feline squamous cell carcinoma cell lines can produce IL-8. Phosphorylation of Src seems, at least in part, a consequence of IL-8 receptor activation. The phosphorylation of ERK1/2 and STAT3, although present, seems independent of IL-8 receptor activation. Due to its potential effects on the tumor microenvironment, in addition to its autocrine effects on Src phosphorylation, the inhibition of the IL-8 receptor may become a beneficial therapeutic tool. Evaluation of the presence of both IL-8 and Src in many cases should elucidate their importance.

Le but de cette étude pilote était de détecter la présence d'interleukine-8 (IL-8) et les effets potentiels en aval de l'activation du récepteur IL-8 dans deux lignées cellulaires de carcinome épidermoïde oral félin (SCCF1 et SCCF2) précédemment caractérisées. L'ARN messager de l'interleukine-8 (ARNm) a été initialement détecté par amplification en chaîne par la polymérase à transcription inverse quantitative (qRT-PCR). Un test immuno-enzymatique ELISA précédemment validé et disponible dans le commerce a été utilisé pour mesurer la production d'IL-8 dans le surnageant des deux lignées cellulaires. L'immunobuvardage a été utilisé pour détecter la phosphorylation des protéines (AKT, ERK1/2, JAK2, STAT3 et Src), connues pour être en aval de l'activation du récepteur de l'interleukine-8. Les antagonistes spécifiques du récepteur IL-8, Reparixin et SCH527123, ont été utilisés pour identifier les effets sur la phosphorylation de ces protéines. L'ARNm et la protéine de l'interleukine-8 ont été détectés dans SCCF1 et SCCF2 par RT-PCR et ELISA, respectivement. La phosphorylation de ERK1/2, STAT3 et Src a été détectée dans les deux lignées cellulaires. L'inhibition du récepteur IL-8 a conduit à une diminution de la phosphorylation de Src, mais pas ERK1/2 ou STAT3. En conclusion, les lignées cellulaires de carcinome épidermoïde félin sont capables de produire de l'IL-8. La phosphorylation de Src semble, au moins en partie, une conséquence de l'activation du récepteur IL-8. La phosphorylation de ERK1/2 et STAT3, bien que présente, semble indépendante de l'activation du récepteur IL-8. En raison de ses effets potentiels sur le micro-environnement tumoral, en plus de ses effets autocrines sur la phosphorylation de Src, l'inhibition du récepteur IL-8 peut devenir un outil thérapeutique bénéfique. L'évaluation de la présence à la fois d'IL-8 et de Src dans un grand nombre de cas devrait élucider leur importance.(Traduit par Docteur Serge Messier).

Examining the Causal Impact of Prenatal Home Visiting on Birth Outcomes: A Propensity Score Analysis.

OBJECTIVES: In Ohio, African American babies die at 2.5-3 times the rate of White babies. Preterm birth and low birth weight are the leading causes of infant mortality. Home visiting is an evidence-based strategy for serving low-income pregnant women; however, there are relatively few rigorous studies examining its effect on birth outcomes. METHODS: This study uses a propensity score technique to estimate the causal effect of participation in home visiting on prematurity and low birth weight among a low-income, predominantly African American sample (N = 26,814). RESULTS: We found that participation in home visiting significantly reduced the odds of experiencing both adverse birth events, with a larger program effect for the low birth weight outcome. CONCLUSIONS FOR PRACTICE: Results suggest that selective prevention strategies must be accompanied by universal attempts to improve the health and life circumstances of low income and minority women.

Metallodrugs are unique: opportunities and challenges of discovery and development.

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.

Assessing the Deployment of Home Visiting: Learning from a State-Wide Survey of Home Visiting Programs.

OBJECTIVES: Large-scale planning for health and human services programming is required to inform effective public policy as well as deliver services to meet community needs. The present study demonstrates the value of collecting data directly from deliverers of home visiting programs across a state. This study was conducted in response to the Patient Protection and Affordable Care Act, which requires states to conduct a needs assessment of home visiting programs for pregnant women and young children to receive federal funding. In this paper, we provide a descriptive analysis of a needs assessment of home visiting programs in Ohio. METHODS: All programs in the state that met the federal definition of home visiting were included in this study. Program staff completed a web-based survey with open- and close-ended questions covering program management, content, goals, and characteristics of the families served. RESULTS: Consistent with the research literature, program representatives reported great diversity with regard to program management, reach, eligibility, goals, content, and services delivered, yet consistently conveyed great need for home visiting services across the state. CONCLUSIONS: Results demonstrate quantitative and qualitative assessments of need have direct implications for public policy. Given the lack of consistency highlighted in Ohio, other states are encouraged to conduct a similar needs assessment to facilitate cross-program and cross-state comparisons. Data could be used to outline a capacity-building and technical assistance agenda to ensure states can effectively meet the need for home visiting in their state.

Perceived control and communication about sex: a study of South African families.

Caregiver-youth communication about sex protects youth against HIV/AIDS, and caregivers who believe that sex knowledge is important are more likely to talk to their youth about sex. However, caregivers who experience barriers to communication about sex may not talk to their youth about sex even if the caregiver believes that sex education is important. The Theory of Planned Behaviour predicts that an actor has perceived control is necessary for behavioural change. This study therefore hypothesised that caregivers' perceived control moderates the relationship between caregiver attitudes about youth sex knowledge and caregiver-youth communication about sex. Results from a sample of 99 female South African caregivers of adolescent (10-14 year old) youth supported our hypothesis, indicating that caregiver attitudes about providing youth with sex knowledge positively predict communication about sex only when caregivers have perceived control. This finding illustrates the importance of perceived control in predicting caregiver-youth communication, and therefore has implications for family-based interventions aimed at improving caregiver-youth communication about sex.

Caregiver-youth communication about sex in South Africa: the role of maternal child sexual abuse history.

Much of the research on child sexual abuse focuses on negative outcomes. This brief report explores a potentially protective parenting behavior among black South African female caregivers with and without a child sexual abuse history. Using cross-sectional baseline data, we hypothesized that caregiver child sexual abuse history would be positively associated with caregiver-youth sex communication and this relationship would be strongest for girls. Youth whose caregiver experienced child sexual abuse were more likely to report communicating with their caregiver about sex than youth whose caregivers did not experience child sexual abuse; however, this relation did not hold for caregiver reported communication. Child sexual abuse survivors' ability and decision to discuss sex with their youth has the potential to protect youth from sexual risk and demonstrates resilience among a group rarely acknowledged for positive parenting practices.

Preliminary results from a family-based HIV prevention intervention for South African youth.

OBJECTIVES: Approximately 5.6 million South Africans are living with human immunodeficiency virus (HIV; UNAIDS, 2010). Prevalence among Black adolescents and young adults is particularly alarming. This pilot study of an HIV preventive intervention targeting South African youth contributes to the growing body of research on culturally competent family-based interventions. METHOD: A total of 99 parent-child dyads were enrolled in an experimental repeated measures study, using a wait-list control group. Our 6-session intervention targeted general parenting (relationship quality, parental monitoring, and involvement), gender roles, and parent-youth communication about sex (content and quality). Parents and youth were assessed at baseline, postintervention, and 6-month follow-up. Eligibility included being the primary female caregiver of a 10- to 14-year-old child with whom they spent at least 4 nights a week and being able to participate in English or Xhosa. RESULTS: Effect sizes with this small sample met or exceeded those of other family-based HIV interventions for youth in the United States and South Africa (e.g., Bell et al., 2008; Forehand et al., 2007). Parents' reports at postintervention indicated larger effect sizes for general parenting than youths' reports indicated. Parents' reports showed medium to large effects for all sex communication outcomes at postintervention and the 6-month follow-up. Youth reports demonstrated small to medium effects for most communication variables and these effects lasted through the 6-month follow-up period. CONCLUSIONS: Intergenerational social networks (e.g., families) hold promise for HIV prevention among South African youth. A full efficacy trial with longer-term follow-up and attention to maintenance of effects is warranted.

Perceived Control and Communication about Sex: A Study of South African Families

Caregiver-youth communication about sex protects youth against HIV/AIDS; and caregivers who believe that sex knowledge is important are more likely to talk to their youth about sex. However; caregivers who experience barriers to communication about sex may not talk to their youth about sex even if the caregiver believes that sex education is important. The Theory of Planned Behaviour predicts that an actor has perceived control is necessary for behavioural change. This study therefore hypothesised that caregivers' perceived control moderates the relationship between caregiver attitudes about youth sex knowledge and caregiver-youth communication about sex. Results from a sample of 99 female South African caregivers of adolescent (10-14 year old) youth supported our hypothesis; indicating that caregiver attitudes about providing youth with sex knowledge positively predict communication about sex only when caregivers have perceived control. This finding illustrates the importance of perceived control in predicting caregiver-youth communication; and therefore has implications for family-based interventions aimed at improving caregiver-youth communication about sex

Teacher-student relationship climate and school outcomes: implications for educational policy initiatives.

In recent discussions regarding concerns about the academic achievement of US students, educational policy makers have suggested the implementation of certain teacher policies. To address the limited empirical research on the putative educational impact of such policies, this study used multilevel structural equation models to investigate the longitudinal associations between teacher evaluation and reward policies, and student mathematics achievement and dropout with a national sample of students (n = 7,779) attending one of 431 public high schools. The student sample included an equal number of boys and girls averaging 16 years of age, and included a White (53%) majority. This study examined whether associations between teacher policies and student achievement were mediated by the teacher-student relationship climate. Results of this study were threefold. First, teacher evaluation policies that allowed students to evaluate their teachers were associated with more positive student reports of the classroom teaching climate. Second, schools with teacher reward policies that included assigning higher performing teachers with higher performing students had a negative association with student perceptions of the teaching climate. Lastly, schools with better student perceptions of the teaching climate were associated with lower student dropout rates by students' senior year. These findings are discussed in light of their educational policy implications.

Investigating the effects of trauma-related research on well-being.

Using an experimental design, we investigated the impact of participation in trauma-related research on well-being in a sample of 219 higher education students. We created five conditions that exposed participants to questions about life events. A sixth condition represented a control condition. Exposure conditions varied according to whether they contained yes/no questions about events that entailed stress, stigma, trauma, or sexual violation. We operationalized well-being by measuring positive and negative affect, state anxiety, and positive reactions to research. Across exposure conditions, participants reported low levels of negative affect and generally positive reactions immediately after participation. The most negative and least positive responses followed exposure conditions that contained questions about stressful events and sexual violation. We discuss implications of our findings for ethics review board practices.

Early intervention for substance abuse among youth and young adults with mental health conditions: an exploration of community mental health practices.

This mixed method study examined current practices and barriers for screening and assessing substance use among youth/young adults in community mental health systems. Substance use rates remain high among youth/young adults in the general population and substance use disorders are prevalent among young people involved in public service systems such as mental health. In an effort to understand the dynamics for early intervention, 64 case managers and/or clinical directors from children's mental health systems in two states participated in an online survey or focus group in fall 2008. Quantitative survey questions and qualitative focus group questions explored attitudes and perspectives about screening and early intervention for substance use among youth/young adults involved in the mental health system and current agency practices. Mixed method results suggest a number of barriers to substance use screening and early intervention and point to innovations that could be more effectively supported.

Lay theories of bipolar disorder: the causes, manifestations and cures for perceived bipolar disorder.

This study aimed to investigate lay theories of the cause and treatment of bipolar disorder, and the recognition of its symptoms. This questionnaire-based study included vignette descriptions of mental disorders and 70 items relating to bipolar disorder. It was completed by 173 participants. Bipolar disorder was recognized less than depression but at the same rate as schizophrenia. Contrary to previous research, analysis showed that lay beliefs of the causes of bipolar disorder generally concur with scientific academic theories. Drug treatment was favoured as a cure rather than psychotherapy. Theories of cause and treatment were logically correlated. Overall, the results suggest that lay people have reasonably informed beliefs about the causes and treatments of bipolar disorder, however recognition of the symptoms is poor.

Assessing elder mistreatment: instrument development and implications for adult protective services.

Assessment of elder mistreatment is hindered by a myriad of factors, including inconsistent definitions, divergent and untested theories of causation, and limited research attention to the problem. In addition to these difficulties, professionals encounter complex situations requiring considerable clinical assessment skills and decision-making capacity. Adult Protective Services (APS) workers, as well as mandated reporters such as healthcare providers and social workers, need an assessment tool that can reliably and accurately assess for elder mistreatment. Based on a structured review of screening and assessment instruments, this article discusses the psychometric properties of 15 instruments and the relevance to APS. Implications of the findings for future research, practice, and policy are discussed.

Development of a risk and resilience-based out-of-school time program for children and youths.

Out-of-school time (OST) programs offer a unique opportunity to provide educational supports to high-risk children and youths.The authors describe the utility of applying principles of risk and resilience to the development and evaluation of an OST program. Academic outcomes among participants at the Bridge Project, an OST program located in three urban public housing communities, are presented to illustrate a risk and resilience approach to service delivery. Implications for practice and research are delineated.

Assessing child and youth well-being: implications for child welfare practice.

The measurement of child well-being has become increasingly important in child welfare practice in the past ten years with the federal emphasis on measuring positive outcomes for children and families. Practical and methodological barriers to evaluating well-being exist alongside positive developments in the field. This article reviews the research literature related to child and youth well-being, providing a context for the discussion of measurement issues in child welfare settings. Based on a structured review of the literature, the article discusses instruments that appear to be most appropriate for use in a child welfare setting. Instruments are presented within stages of development, including (1) Infancy and Early Childhood, (2) Middle Childhood, and (3) Adolescence. Implications for the design and use of child well-being instruments in child welfare practice are discussed.