Background

Alterations of hypothalamic-pituitary-adrenal (HPA) function are well-established in adults with current depression. HPA alterations may persist into remission and confer increased risk for recurrence.

Methods

A modified version of the Trier Social Stress Test (TSST) was administered at baseline to 32 young adults with remitted major depressive disorder and 36 never-depressed controls. Participants were randomly assigned to either a 'high-stress' condition involving social evaluation or a 'low-stress' control condition. Cortisol concentrations were measured in saliva samples throughout the TSST. Participants were assessed again after 6 months for the occurrence of stressful life events and depressive symptoms/disorders during the follow-up period.

Results

Participants who exhibited enhanced cortisol reactivity in the low-stress condition showed increases in depressive symptoms over follow-up, after controlling for stressful life events during the follow-up period. Anticipatory stress cortisol and cortisol reactivity each interacted with history of depressive episodes to predict depression trajectories.

Limitations

The single TSST administration limits conclusions about whether alterations of cortisol reactivity represent trait-like vulnerability factors or consequences ("scars') of past depression.

Conclusions

These results extend previous findings on stress sensitivity in depression and suggest that altered HPA function during remission could reflect an endophenotype for vulnerability to depression recurrence. Findings support interactive models of risk for depression recurrence implicating HPA function, depression history, and sensitivity to minor stressors. Results may have implications for interventions that match treatment approaches to profiles of HPA function.

This study examined cortisol and affective reactivity to a psychosocial stress task in 102 young adults who varied in risk for depression (56 remitted depressed, 46 never depressed). Participants were randomly assigned to either a stress (i.e., social-evaluative threat) or control (i.e., no social-evaluative threat) condition. For never-depressed individuals, cortisol responses were significantly greater in the stress compared to the control condition. Moreover, cortisol responses were significantly greater for never-depressed than remitted-depressed individuals in the stress condition. For individuals with a history of depression, cortisol responses did not differ significantly between the stress and control conditions. Negative affective reactivity also was higher for never depressed, but not remitted depressed, individuals in the stress compared to the control condition. Moreover, cortisol responses were inversely related to negative affect during the recovery phase in both stress and control conditions. Findings indicate the lack of a robust cortisol response to social evaluation stress among remitted-depressed individuals as compared to that of never-depressed controls. Future studies should investigate unique and interactive links between these hypothalamic-pituitary-adrenal and affective reactivity alterations and risk for subsequent depressive episodes.

Objectives

This prospective study investigated whether within-individual relations between depression vulnerability factors (childhood trauma, dysfunctional attitudes, maladaptive coping) and depressive symptom trajectories varied as a function of the number of prior major depressive episodes (MDEs) experienced in their lifetime.

Design

Participants were 68 young adults who varied with regard to their history of depression; 32 were remitted depressed and 36 were never depressed.

Methods

Depressive symptoms and disorders were assessed using semi-structured psychiatric interviews conducted twice over a 6-month period; interviews yielded weekly ratings of depressive symptoms during the follow-up interval. Childhood trauma, dysfunctional attitudes and coping were assessed with self-report measures. Data analyses were conducted using time-lagged multilevel models.

Results

Individuals with more previous MDEs who reported greater childhood trauma exposure, more dysfunctional attitudes, or greater use of maladaptive coping strategies experienced more rapid increases in depressive symptoms during the follow-up period. A significant interaction of coping, number of previous MDEs, and time was found indicating that among individuals with less adaptive coping (i.e., lower primary or lower secondary control coping scores), depressive symptoms rating (DSR) increased significantly in relation to number of prior depressive episodes; no change in DSR was observed for never-depressed individuals. Among individuals with higher primary control coping scores, significant increases in DSR scores were observed for individuals with ≥3 prior MDEs only.

Conclusions

Findings highlight the need for treatment and prevention programmes that target stress reactivity and coping strategies early in the course of depression.

Statins have the potential to reduce breast cancer incidence and recurrence as shown in both epidemiologic and laboratory studies. The purpose of this study was to evaluate the effect of a lipophilic statin, atorvastatin, on breast cancer biomarkers of risk [mammographic density (MD) and insulin growth factor 1 (IGF-1)] in high-risk premenopausal women.Premenopausal women at increased risk for breast cancer received either 40 mg of atorvastatin or placebo for 1 year. Biomarker assessment was performed prior to initiation and at completion of study medication. MD was determined using both Breast Imaging Reporting and Data System and the visual analogue scale. Serum IGF-1 was determined by ELISA assay at the end of the study.Sixty-three women were enrolled between December 2005 and May 2010. Sixteen (25%) women withdrew. The mean age of participants was 43 (range, 35-50), 100% were white, and the average body mass index (BMI) was 26.4. The statin group demonstrated a significant decrease in cholesterol and low-density lipoprotein (LDL), suggesting compliance with study medication. After accounting for BMI, there was no difference in change in MD between groups. There was a significant increase in serum IGF-1 in the statin group.In this multi-institutional randomized prospective clinical trial of premenopausal women at increased risk for breast cancer, we did not see an effect of atorvastatin on MD. Further investigation of statins may be warranted; however, design of prior trials and potential mechanism of action of the agent need to be considered in the design of future trials. Cancer Prev Res; 9(5); 379-84. ©2016 AACR.

Abstract: Background: TSECs were developed to treat menopausal symptoms after progesterone containing hormone replacement therapy was found to significantly increase the risk of invasive breast cancer (IBC). The first of this class of agents combines conjugated estrogens (CE), a collection of steroidal estrogens that collectively have both estrogen receptor (ERα) agonistic and antagonistic activity, and bazedoxifene (BZA), a third generation selective estrogen receptor modulator that does not stimulate the mammary gland or endometrium. The FDA approved CE/BZA for treatment of menopausal symptoms and osteoporosis after five randomized placebo controlled trials demonstrated the safety, efficacy and tolerability of CE/BZA in healthy postmenopausal women. Since then, a substantial body of evidence has emerged suggesting that CE/BZA may have additional therapeutic benefits in women. It is widely accepted that progression to IBC occurs through both epithelial and stromal mechanisms. Recent in vitro and in vivo data provide support that CE/BZA prevents progression to IBC through its effects on both epithelium and stroma. In epithelial cells, CE/BZA antagonizes estrogen-induced proliferation and expression of markers of ERα activity and also degrades ERα protein. In the stroma, CE/BZA increases expression of the scavenger receptor CD36 and consequently, reduces expression of extracellular matrix proteins (ECM) and pro-inflammatory cytokines that have been shown to contribute to the development of pro-tumorigenic microenvironment. Based on these preliminary data, we hypothesized that CE/BZA will have an anti-tumorigenic effect in the breast. Our ultimate objective is to provide postmenopausal women diagnosed with DCIS a novel and safe therapeutic option to prevent progression to IBC. Specific Aims: Aim 1: To assess epithelial contributions by determining if a short intervention of CE/BZA will have antagonistic activity in breast epithelium of postmenopausal women with ER + DCIS. Aim 2: To assess stromal contributions by determining if a short intervention of CE/BZA will alter expression of stromal markers of progression in breast tissue of postmenopausal women with ER + DCIS. Aim 3: To determine if a short intervention of CE/BZA is well tolerated and safe in postmenopausal women with ER + DCIS. Trial Design: We are currently conducting a multicenter randomized placebo controlled window of opportunity trial with CE/BZA in post-menopausal women with DCIS, a non-obligate precursor to IBC. The duration of intervention is 28 ± 7 days prior to surgical resection to enable comparison of CE/BZA on the breast using the diagnostic core biopsy and surgical sample. To date 33/166 women have enrolled in the trial. Eligibility Criteria: Post-menopausal women between 18-79 years of age diagnosed with ER (+) DCIS (>1cm on imaging) undergoing surgery are eligible. Women must not be on current hormonal therapy, have a current or past diagnosis of IBC, other ER sensitive tumors or have recurrent DCIS. Statistics: Results will be compared between diagnostic biopsy and surgical resection specimens and contrasted between the CE/BZA intervention group and placebo group using Fisher’s exact test for categorical variables and independent sample t-tests, or rank sum tests for continuous data. For RNAseq data, transcripts that have >1.5-fold expression change (at 20% FDR) between control and experimental samples will be used for downstream analysis, such as to plot heat maps, pathway and gene ontology analysis. Summary: At the conclusion of this study, we will have the first direct evidence of the potential benefits of CE/BZA therapy on DCIS lesions in the human breast, along with an initial assessment of symptoms and pharmacogenomics that will inform the design of future studies. Citation Format: Swati A. Kulkarni, Geoffrey Greene, Thea Tlsty, Luis Blanco, Judy Garber, Al George, Fred Rademaker, Seema A Khan, Nora Hansen, Kevin Bethke, Rebecca Aft, Julia Tchou. A large-scale multicenter phase II study evaluating the protective effect of a tissue selective estrogen complex (TSEC) in women with newly diagnosed ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-09-02.

Rates of substantiated child abuse and neglect vary significantly across counties. Despite strong cross-sectional support for links between social-contextual characteristics and abuse and neglect, few longitudinal studies have tested relations between these risk factors and substantiated rates of abuse/neglect. The goal of this study was to identify county-level socioeconomic and crime factors associated with substantiated abuse/neglect rates over 13 years (2004-2016). Annual county-level data for Tennessee, obtained from the KIDS COUNT Data Center, included rates of substantiated child abuse and neglect, children's race and ethnicity, births to unmarried women, teen birth rate, children in families receiving Supplemental Nutrition Assistance Program (SNAP) benefits, and children in families receiving Temporary Assistance for Needy Families. Annual county-level crime report data, obtained from the Tennessee Incident Based Reporting System, included sexual offenses, non-sexual assaults, stalking incidents, thefts, property damage, and drug-related offenses. Bayesian spatio-temporal models indicated that substantiated child abuse and neglect rates were independently and positively associated with teen birth rates, percentages of births to unmarried mothers, drug-related offenses, and percentages of children receiving SNAP benefits. In contrast, substantiated child abuse and neglect rates were negatively associated with percentages of African-American youth. The findings highlighted distinct demographic, socioeconomic, and crime factors associated with substantiated child abuse and neglect rates and have the potential to enhance identification of high-risk counties that could benefit from targeted abuse and neglect prevention efforts.

Rates of substantiated child abuse and neglect vary significantly across counties. Despite strong cross-sectional support for links between social-contextual characteristics and abuse and neglect, few longitudinal studies have tested relations between these risk factors and substantiated rates of abuse/neglect. The goal of this study was to identify county-level socioeconomic and crime factors associated with substantiated abuse/neglect rates over 13 years (2004-2016). Annual county-level data for Tennessee, obtained from the KIDS COUNT Data Center, included rates of substantiated child abuse and neglect, children's race and ethnicity, births to unmarried women, teen birth rate, children in families receiving Supplemental Nutrition Assistance Program (SNAP) benefits, and children in families receiving Temporary Assistance for Needy Families. Annual county-level crime report data, obtained from the Tennessee Incident Based Reporting System, included sexual offenses, non-sexual assaults, stalking incidents, thefts, property damage, and drug-related offenses. Bayesian spatio-temporal models indicated that substantiated child abuse and neglect rates were independently and positively associated with teen birth rates, percentages of births to unmarried mothers, drug-related offenses, and percentages of children receiving SNAP benefits. In contrast, substantiated child abuse and neglect rates were negatively associated with percentages of African-American youth. The findings highlighted distinct demographic, socioeconomic, and crime factors associated with substantiated child abuse and neglect rates and have the potential to enhance identification of high-risk counties that could benefit from targeted abuse and neglect prevention efforts.

Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system's ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative.

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.