Sarah O. Meadows

Gene expression signatures that predict radiation exposure in mice and humans.

Background The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation. Methods and Findings We have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans. Conclusions We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.

Marital Trajectories and Mortality Among US Adults

More than a century of empirical evidence links marital status to mortality. However, the hazards of dying associated with long-term marital trajectories and contributing risk factors are largely unknown. The authors used 1992-2006 prospective data from a cohort of US adults to investigate the impact of current marital status, marriage timing, divorce and widow transitions, and marital durations on mortality. Multivariate hazard ratios were significantly higher for adults currently divorced and widowed, married at young ages (< or =18 years), who accumulated divorce and widow transitions (among women), and who were divorced for 1-4 years. Results also showed significantly lower risks of mortality for men married after age 25 years compared with on time (ages 19-25 years) and among women experiencing > or =10 years of divorce and > or =5 years of widowhood relative to those without exposure to these statuses. For both sexes, accumulation of marriage duration was the most robust predictor of survival. Results from risk-adjusted models indicated that socioeconomic resources, health behaviors, and health status attenuated the associations in different ways for men and women. The study demonstrates that traditional measures oversimplify the relation between marital status and mortality and that sex differences are related to a nexus of marital experiences and associated health risks.

Race-Ethnic Inequality and Psychological Distress: Depressive Symptoms from Adolescence to Young Adulthood.

Social inequality is well established in the mental health of race-ethnic groups, but little is known about this disparity from adolescence to young adulthood. This study examined differences in trajectories of depressive symptoms across 4 race-ethnic groups (Whites, Blacks, Hispanics, and Asians) using 3 waves of the National Longitudinal Study of Adolescent Health. Latent trajectory analyses showed race-ethnic variations among both females and males. Stressors were significantly related to depressive symptoms for all study members, but they accounted for symptom trajectories only among Black males and minority females. Persistent differences in trajectories for Blacks and Whites showed parallel slopes that did not converge over time. Neither background characteristics nor social resources (i.e., social support) altered this gap. However, social support represents a potential equalizer of these race-ethnic differences, owing to the ubiquitous nature of its protective effects.

Disaggregating the Effects of Marital Trajectories on Health

Recent studies linking marital status and health increasingly focus on marital trajectories to examine the relationship from a life course perspective. However, research has been slow to bridge the theoretical concept of a marital trajectory with its measurement. This study uses retrospective and prospective data to model the age-dependent effects of marital sequences, timing, transitions, and durations on physical health. Results indicate that marriage duration is associated with lower rates of disease for men and women; however, the effect is time dependent and contingent on other trajectory components. For females, marriage timing and the cumulative number of divorce transitions are also important for health. For males, divorce duration and widowhood transitions play an integral role in this process. The authors also find that marital typologies have no effect when the number of transitions is taken into account.

Family Structure and Fathers' Well-Being: Trajectories of Mental Health and Self-Rated Health*

The association between marital status and health among men has been well documented, but few studies track health trajectories following family structure transitions among unmarried fathers. Using the Fragile Families and Child Wellbeing Study this article examines trajectories of paternal mental health and self-rated health, focusing on transitions into and out of residential relationships with the childs biological mother or a new partner during a five-year post-birth period (N = 4,331). Continuously married fathers report higher time-specific self-rated health and fewer mental health problems than continuously single fathers, controlling for underlying health trajectories. The disparity, however, does not increase over time, providing little support for the marital resource model during these years. Static group differences suggest that resources fathers carry with them into unions may buffer them from the negative effects of union dissolution. The implications of these findings for cohabitation, as well as selection and causation arguments, are also discussed.

Is It There When You Need It? Mismatch in Perception of Future Availability and Subsequent Receipt of Instrumental Social Support

Little is known about the effect of incongruity between perception of, or belief in, the availability of support and actual receipt of support during a time of need. This article examines associations between belief in the future availability of instrumental support (e.g., child care, temporary housing, and financial assistance), subsequent reception of inadequate support, and depression in a socioeconomically diverse sample of new mothers. Receipt of support is associated with increased odds of experiencing a major depressive episode (MDE), whereas belief in the availability of future support appears to be protective of mental health. Mothers who experience a negative mismatch between support perception and adequate receipt of support have increased odds of experiencing an MDE compared with mothers who either receive adequate support or who have no support needs; however, their susceptibility is no greater than that of mothers who simply have unmet instrumental needs.

The Association Between Perceptions of Social Support and Maternal Mental Health: A Cumulative Perspective

The question of how to best measure family processes so that longitudinal experiences within the family are accurately captured has become an important issue for family scholars. Using the Fragile Families and Child Wellbeing Study (N = 2,158), this article focuses on the association between trajectories of perceived supportiveness from biological fathers and mothers’ mental health problems 5 years after a birth. The relationship status between mothers and biological fathers is significantly related to her perceptions of his supportiveness, with married mothers reporting the highest levels of supportiveness followed by mothers in cohabiting unions, romantic non-coresidential unions, and, finally, mothers not in a romantic relationship. Controlling for both time-varying and time-invariant maternal and relationship characteristics, a positive slope of perceived supportiveness from biological fathers is associated with fewer subsequent mental health problems 5 years after the birth. The discussion calls attention to alternate modeling strategies for longitudinal family experiences.

Pharmacological Manipulation of the RAR/RXR Signaling Pathway Maintains the Repopulating Capacity of Hematopoietic Stem Cells in Culture

The retinoid X receptor (RXR) contributes to the regulation of diverse biological pathways via its role as a heterodimeric partner of several nuclear receptors. However, RXR has no established role in the regulation of hematopoietic stem cell (HSC) fate. In this study, we sought to determine whether direct modulation of RXR signaling could impact human HSC self-renewal or differentiation. Treatment of human CD34(+)CD38(-)lin(-) cells with LG1506, a selective RXR modulator, inhibited the differentiation of HSCs in culture and maintained long-term repopulating HSCs in culture that were otherwise lost in response to cytokine treatment. Further studies revealed that LG1506 had a distinct mechanism of action in that it facilitated the recruitment of corepressors to the retinoic acid receptor (RAR)/RXR complex at target gene promoters, suggesting that this molecule was functioning as an inverse agonist in the context of this heterodimer. Interestingly, using combinatorial peptide phage display, we identified unique surfaces presented on RXR when occupied by LG1506 and demonstrated that other modulators that exhibited these properties functioned similarly at both a mechanistic and biological level. These data indicate that the RAR/RXR heterodimer is a critical regulator of human HSC differentiation, and pharmacological modulation of RXR signaling prevents the loss of human HSCs that otherwise occurs in short-term culture.

The CWI and Its Components: Empirical Studies and Findings

Chapter 2 described the conceptual and methodological foundations of the Child and Youth Well-Being Index (CWI). The question now becomes: What can the CWI and its component time series tell us about the well-being of America’s children and its changes (improvements and deteriorations) over time? Related to this are questions, such as what are the properties of the CWI?, how robust is it?, how does it relate to data on the subjective well-being of children and youth? and how can the CWI be used to study and anticipate changes in well-being? This chapter addresses these questions.

Abstract 2673: Idelalisib has activity at clinically achievable drug concentrations in a subset of ABC and GCB diffuse large B-cell lymphoma and transformed follicular lymphoma cell lines

Diffuse large B-cell lymphoma (DLBCL) is the largest lymphoma subtype representing approximately one-third of all cases of non-Hodgkin9s lymphoma. Gene expression profiling showed that DLBCL can be stratified into activated B-cell (ABC) or germinal center B-cell (GCB) subtypes (Alizadeh et al., Nature 2000). The overall five year survival rate is only approximately 50% (Shaffer et al., Annu. Rev. Immunol. 2012), thus a medical need exits for the treatment of this disease, particularly for patients who relapse after the first line chemoimmunotherapy regimen. Idelalisib is an investigational, highly selective oral inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) delta isoform. PI3K delta signaling is required for B lymphocyte activation, proliferation and survival and is dysregulated in several B-cell malignancies. We investigated the activity of idelalisib and ibrutinib, an inhibitor of Bruton9s tyrosine kinase, on the inhibition of proliferation against a panel of 22 DLBCL (9 ABC, 13 GCB) and 3 transformed follicular lymphoma cell lines. Idelalisib has potent activity (EC50 Citation Format: Jia Y. Liu, Tom Kenney, Leslie Butterworth, Adam Kashishian, Sarah Meadows, Peng Yue, Li Li, Kathleen Keegan, Christophe Queva, Stacey Tannheimer. Idelalisib has activity at clinically achievable drug concentrations in a subset of ABC and GCB diffuse large B-cell lymphoma and transformed follicular lymphoma cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2673. doi:10.1158/1538-7445.AM2015-2673