Mechanisms of action and resistance in histone methylation-targeted therapy.

Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated1-7. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2-compound interface result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.

Risk and protective family factors during childhood on youth violence among African American males: The role of mothers and nonresident fathers.

African American male youth experience disproportionately higher levels of violence. We examined parental depression among African American mothers and nonresident fathers on parenting stress and school involvement in their adolescent sons' school connectedness and violent behaviors. Using a longitudinal study design, parent factors were assessed when sons were 9 years old on youth outcomes at age 15. We found that maternal depression was associated with maternal stress, and maternal stress was indirectly associated with sons' violent behaviors through school connectedness. School involvement among nonresident fathers was positively associated with sons' school connectedness, which was linked to less youth violent behaviors. Maternal stress and nonresident fathers' school involvement are influential for understanding youth violence. Future interventions should incorporate a more nuanced approach when including family factors.

The Effects of Multiple Dimensions of Risk and Protective Factors on Depressive Symptoms Among Nonresident African American Fathers.

Compared to other groups, African American men experience proportionately greater adverse social and economic circumstances, which have been linked to poor mental health. A growing body of literature has begun to examine depressive symptoms among African American men; however, limited literature has examined the concurrent contributions of risk and protective factors among nonresident African American fathers. This study examined the relative contribution of perceived financial strain, perceived neighborhood characteristics, and interpersonal stress on depressive symptoms among 347 nonresident African American fathers. Social support was examined as a protective factor for depressive symptoms. Results from hierarchical regression analyses indicated interpersonal stress was associated with depressive symptoms even after controlling for perceived financial strain, perceived neighborhood characteristics, and specific sociodemographic factors. Additionally, among fathers with high interpersonal stress, having more social support buffered the negative effect of interpersonal stress on depressive symptoms. Findings suggest experiencing strain from multiple dimensions can increase the risk of depressive symptoms among nonresident African American fathers. We also found that interpersonal stress was especially harmful for mental health. Family service providers and mental health professionals should incorporate stress management techniques to reduce stressful interpersonal relationships as a way to lower depressive symptoms among nonresident African American fathers.

Catalytic Leadership in Food & Fitness Community Partnerships.

Catalytic leadership is a type of multidimensional leadership that facilitates cross-sector collaboration to enact systems and policy changes within communities. Catalytic leaders provide opportunities for stakeholders to partner and merge their efforts to create new opportunities for their work. Catalytic leaders are individuals, organizations, and collaborative partnerships that stimulate partnership alliances. Additionally, catalytic partnerships facilitate the process of collaboration through encouraging and supporting stakeholders to work together effectively and successfully. This article provides examples of catalytic leadership roles that emerged from the Food & Fitness community partnerships. These partnerships were funded by the W.K. Kellogg Foundation to increase access to locally grown food and safe places to play for children and families through systems and policy changes in communities throughout the United States. Key strategies and types of support (i.e., informational and instrumental support) provided through Food & Fitness catalytic leadership that sustained the work of these partnerships was discussed. Based on catalytic leadership strategies identified and types of support provided, outcomes that emerged from this work were also described. We conclude with key recommendations for community partnerships interested in serving as catalytic leaders for large-scale initiatives in their communities.

The long-term consequences of school suspension and expulsion on depressive symptoms.

Exposure to exclusionary discipline has been tied to several deleterious outcomes in adulthood, including contact with the criminal legal system. While this work provides interesting insight into the long-term consequences tied to this form of school punishment, few have attempted to consider whether and how, exclusionary discipline practices, in particular, school suspension and expulsion shape mental health patterning over the life course. Using panel data from the National Longitudinal Study of Adolescent to Adult Health, we contribute to this body of literature by examining whether exposure to school suspension or expulsion shapes depressive symptom trajectories from adolescence to adulthood. Results from our mixed-effects linear growth curve models demonstrate both forms of exclusionary discipline play a significant role in depressive symptom trajectories. We find suspended and expelled youth exhibit significantly higher depressive symptoms in adolescence when compared to their counterparts with no history of suspension or expulsion. Results also show age variation in depressive symptom trajectories by history of exposure to exclusionary discipline. Specifically, results show the depressive symptoms gap between disciplined and non-disciplined youth slightly dissipates as youth age into early adulthood, but as individuals begin to transition out of this stage of the life course, the gap in depressive symptoms widens substantially. Results carry implications for how punitive disciplinary practices in schools shape mental health from adolescence to adulthood.

Loneliness and Psychological Distress Among Older Californians: The Moderating Roles of Citizenship Status and English Proficiency.

OBJECTIVES: Guided by the theory of stress proliferation, our study examined whether loneliness, citizenship status, and English proficiency were associated with psychological distress among older adults, and if citizenship status and English proficiency moderated these relationships. METHODS: Using the older adult subsample (65+ years) of the 2019-2020 California Health Interview Survey (N = 15,210), we assessed cross-sectional associations between loneliness, citizenship status, and English proficiency on psychological distress by conducting multivariable linear regression models. Interaction terms were included in subsequent models to determine if citizenship status and English proficiency moderated the relationship between loneliness and psychological distress. RESULTS: In unadjusted models, greater loneliness was associated with higher distress. Both naturalized citizens and noncitizens, and those with limited English proficiency (LEP) exhibited greater distress than US born citizens and those who speak English only (EO). After adjusting for sociodemographic and health covariables, loneliness remained significant for distress although the relationships between citizenship status and English proficiency became attenuated. With the inclusion of interactions, the magnitude of the relationship between loneliness and distress was stronger for naturalized citizens and those with LEP than native-born citizens and those who speak EO, respectively. DISCUSSION: Loneliness was the most consistent stressor affecting multiple life domains. However, our findings demonstrate that stress proliferation is occurring among older immigrant adults and the interplay between loneliness, citizenship status, and English proficiency is contributing to heightened distress. Further attention is needed in understanding the role of multiple stressors influencing mental health among immigrant older adults.

Social Isolation, Self-Rated Health, and Self-Rated Oral Health among African Americans.

Social isolation is associated with worse health; however, few studies have examined the health effects of isolation among African Americans. The purpose of this study is to evaluate associations between social isolation and self-rated physical and oral health from the National Survey of American Life, a nationally representative sample of African Americans. Social isolation was operationalized to reflect both objective isolation (lack of contact) and subjective isolation (lack of emotional closeness). Self-rated physical and oral health were regressed on objective and subjective isolation while controlling for marital status, gender, age, family income, education, and health behaviors. Poorer self-rated physical health was associated with objective isolation, while poorer self-rated oral health was associated with subjective isolation. This study contributes to the small literature of the impact of social isolation on health among African Americans; furthermore, it is the first to examine the relationship between isolation and self-rated oral health in this population.

Racial/Ethnic Differences in Loneliness Among Older Adults: The Role of Income and Education as Mediators.

Background and Objectives: Loneliness is a major public health concern; however, limited research has examined the mechanisms contributing to racial/ethnic inequities in loneliness. Race/ethnicity has been hypothesized to be a distal factor influencing loneliness, and racial/ethnic inequities in loneliness may be attributable to socioeconomic factors (e.g., income and education). Our study seeks to confirm these hypotheses by examining mechanisms that contribute to racial/ethnic inequities in loneliness. In other words, if racial/ethnic differences in loneliness among older adults are mediated by income and education. Research Design and Methods: Data came from the Health and Retirement Study Leave-Behind Questionnaire, 2014-2016. Loneliness was measured by the UCLA 3-item loneliness scale. Race/ethnicity categories were White, Black, and Hispanic/Latino. The mediator variables were household income and education. Multivariable linear regression models were used to determine differences in loneliness by race/ethnicity. The Karlson-Holm-Breen (KHB) mediation method was used to determine if income and education mediated racial/ethnic differences in loneliness. Results: In models examining income and education together, a complete mediation was found between White and Black older adults, in that income and education completely mediated differences in loneliness between these groups. A partial mediation was found between White and Hispanic, and Black and Hispanic older adults. When examining income and education separately, we found that income solely accounted for racial/ethnic differences in loneliness compared to education. Discussion and Implications: Our study is the first to explicitly determine if socioeconomic factors mediate race/ethnicity differences in loneliness among a national sample of older adults. These findings illustrate that income may have greater proximate effects for loneliness among older adults in comparison to education. Additionally, these findings can inform evidence-based interventions to reduce loneliness among older adults. Interventions that enhance quality of life and provide opportunities for socialization for racialized low-income older adults may help decrease racial/ethnic inequities in loneliness.

Paternal Incarceration, Race and Ethnicity, and Maternal Health.

BACKGROUND: Although increased attention has been placed on the potential deleterious consequences of paternal incarceration on maternal health, little empirical research has attempted to understand the physiological processes that might underlie this relationship. Moreover, exposure to incarceration and access to resources that shape family incarceration patterns are unequally distributed across racial and ethnic lines, yet few studies utilize analytic frameworks that account for this social reality. Using a within race/ethnicity analytic framework, the present study addresses these gaps by examining relationships between paternal incarceration and telomere length for Black, Latina/o, and White mothers. METHODS: Data were drawn from the Fragile Families and Child Wellbeing Study, a longitudinal, stratified multistage probability sample of couples and children in 20 large U.S. cities. The final analytic sample consisted of 2174 mothers that were followed from pregnancy to age 9 of the focal child. RESULTS: Findings revealed exposure to paternal incarceration was negatively associated with telomere length for Black mothers, but not for Latina/o and White mothers. Mediation analysis also showed paternal incarceration-telomere length relationships did not operate through secondary stressors, such as economic instability, poor mental health, and parenting stress. CONCLUSION: Overall, results demonstrated that the detrimental physiological consequences of paternal incarceration for mothers depended on racial and ethnic background. Findings from this study can provide a foundation upon which health scholars and criminal justice stakeholders may better understand whether and how paternal incarceration shapes deleterious health patterns for the mothers who remain to care for the children of those incarcerated.

The co-occurrence of adverse childhood experiences and mental health among Latina/o adults: A latent class analysis approach.

Adverse childhood experiences (ACEs) have been linked to poor mental health among Latina/os. Few studies, however, have attempted to understand the extent to which ACEs co-occur and whether different forms of ACE co-occurrence differentially shape poor mental health patterns among Latina/os. The present study begins to address this gap by (1) identifying latent classes of ACEs and (2) determining whether and how different ACE classes shape high depressive symptoms among Latina/o adults. Data were drawn from two waves of the Hispanic Community Health Study/Study of Latinos, a longitudinal, community-based sample of Latina/os living in four urban communities. Latent Class Analysis (LCA) was used to identify subgroups of Latina/os who were exposed to co-occurring forms of maltreatment. Results from the LCA revealed four classes: (1) high ACEs, (2) emotional and physical abuse, (3) low ACEs, and (4) household alcohol/drug use and parental separation/divorce. Regression analyses indicate, when compared to the low ACEs class, Latina/os in the high ACEs class and emotional/physical abuse class were more likely to report high depressive symptoms. Findings from this study demonstrate ACEs co-occur in distinct classes of maltreatment and different combinations of ACEs uniquely shape the risk of poor mental health among Latina/os. Results from this study can help inform tailored mental health interventions for Latina/os that have a history of ACE exposure.

Sociodemographic Factors and Neighborhood/Environmental Conditions Associated with Social Isolation Among Black Older Adults.

Objectives: To investigate sociodemographic factors and neighborhood/environmental conditions associated with social isolation (SI) among Black older adults. Methods: We utilized data from the 2014 and 2016 Leave-Behind Questionnaire from the Health and Retirement Study (HRS LBQ) among those who self-identified as Black (N = 2.323). Outcome variables for our study included SI from adult children, other family members, friends, disengagement from social participation and religious services, being unmarried, and living alone. These indicators were also combined into an overall SI index. Critical predictors included gender, age, household income, education, employment status, neighborhood cohesion, neighborhood disorder, urbanicity, and region of residence. Results: Sociodemographic factors of gender, education and household income were significantly associated with SI indicators. Additionally, some neighborhood/environmental conditions were associated with SI indicators. Discussion: SI was found to be patterned by sociodemographic factors. These results can be used to develop effective interventions to mitigate SI among Black older adults.

Visa type and financial strain on depressive symptoms among Filipino migrants to the United States.

Migrants have been theorized to be healthier than their non-migrant counterparts; however, there is limited examination of health selection using binational data and how selection occurs, particularly for mental health outcomes. This study examines the role of visa status and financial strain as critical factors for mental health selection among Filipino migrants to the U.S. and non-migrants who remain in the Philippines. We used the baseline data from the Health of Philippine Emigrants Study (HoPES; n = 1631) to compare depressive symptoms between non-migrants and migrants who were both surveyed prior to their departure to the U.S. We assessed depressive symptoms using linear regression by migration status, financial strain, and by visa categories including fiancée/marriage, unlimited family reunification, limited family reunification, and employment. Overall, all migrants reported lower depressive symptoms than non-migrants; however, depressive symptoms varied by visa type. Fiancée/marriage migrants had lower depressive symptoms than compared to limited family reunification migrants. Additionally, those who reported financial strain had higher depressive symptoms than those without any financial strain. We find that migrants were positively selected for mental health using a unique sample of Filipino migrants before they left for the U.S.

Perceived Racial/Ethnic Discrimination, Citizenship Status, and Self-Rated Health Among Immigrant Young Adults.

Both racial/ethnic discrimination and citizenship status are manifestations of racism. Few empirical studies have examined the role of multiple stressors and how both stressors are interlinked to influence health among immigrant young adults. Informed by the theory of stress proliferation, the current study seeks to examine the interplay between perceived racial/ethnic discrimination and citizenship status on health. We used the third wave of the Children of Immigrants Longitudinal Study (CILS) to examine the influence of perceived racial/ethnic discrimination and citizenship status on self-rated health (SRH) among immigrant young adults (N = 3344). Perceived racial/ethnic discrimination was initially associated with SRH. After adjusting for both predictors, those experiencing perceived racial/ethnic discrimination and non-citizen youth were less likely to report better health than youth who did not report perceived racial/ethnic discrimination or citizen youth. In fully adjusted multivariate regression models, racial/ethnic discrimination remained significant, while citizenship status was no longer associated with SRH. To test stress proliferation, an interaction term was included to assess whether the relationship between perceived racial/ethnic discrimination and SRH varied by citizenship status. The interaction term was significant; non-citizen young adults who experienced racial/ethnic discrimination were less likely to report better health in comparison to citizen young adults and those who did not report perceived racial/ethnic discrimination. Results suggest that the interplay between perceived racial/ethnic discrimination and citizenship status may be influential for health among immigrant young adults. These findings underscore the need for further assessment of the role of stress proliferation on immigrant young adults' health.

Crimmigrating Narratives: Examining Third-Party Observations of US Detained Immigration Court.

Examining what we call "crimmigrating narratives," we show that US immigration court criminalizes non-citizens, cements forms of social control, and dispenses punishment in a non-punitive legal setting. Building on theories of crimmigration and a sociology of narrative, we code, categorize, and describe third-party observations of detained immigration court hearings conducted in Fort Snelling, Minnesota, from July 2018 to June 2019. We identify and investigate structural factors of three key crimmigrating narratives in the courtroom: one based on threats (stories of the non-citizen's criminal history and perceived danger to society), a second involving deservingness (stories of the non-citizen's social ties, hardship, and belonging in the United States), and a third pertaining to their status as "impossible subjects" (stories rendering non-citizens "illegal," categorically excludable, and contradictory to the law). Findings demonstrate that the courts' prioritization of these three narratives disconnects detainees from their own socially organized experience and prevents them from fully engaging in the immigration court process. In closing, we discuss the potential implications of crimmigrating narratives for the US immigration legal system and non-citizen status.

Perceived structural vulnerabilities among detained noncitizen immigrants in Minnesota.

Across several decades there has been an unprecedented increase in immigration enforcement including detention and deportation. Immigration detention profoundly impacts those experiencing detention and their family members. An emerging area of research has found that immigrants experience a number of challenges which constrain and limit their decisions, choices, and options for security and integration in the United States due to social, political and structural determinants. These determinants lead to greater structural vulnerabilities among immigrants. The purpose of the current study was to illuminate the perceived vulnerabilities of detained noncitizen immigrants as they are raised and described while attending case hearings at the Bloomington, Minnesota immigration court. Through conducting a thematic analysis of notes derived from third party immigration court observers, three areas of perceived vulnerability were identified. These perceived vulnerabilities include 1) migration and motivations to migrate, 2) structural vulnerabilities (e.g., discrimination, financial insecurity, social ties and family support, stable or fixed residence, English language proficiency, health and mental health) in the US, and 3) challenges in navigating immigration detention. These findings demonstrate that noncitizen immigrants who are undergoing immigration detention are experiencing multiple intersecting vulnerabilities which profoundly impact their lives. Collaborative efforts across sectors are needed to work towards comprehensive immigration reforms including both short-term and long-term solutions to address pressing issues for noncitizens undergoing immigration detention.

Multiple financial stressors and serious psychological distress among adults in the USA.

OBJECTIVES: Financial stress has adverse consequences for health. However, the association between individual and cumulative associations of multiple financial stressors and serious psychological distress (SPD) is unclear. METHODS: Using data from the 2017 National Health Interview Survey, we examined cross-sectional associations between perceived financial worries, healthcare insecurity, food insecurity, and SPD among 23,317 US adults. Associations were examined using logistic regression. RESULTS: Among US adults in 2017, the overall prevalence of SPD was 3.6%. Among those with SPD, 85.5% were financially worried, 50.3% were food insecure, and 51.2% were healthcare insecure. Financial worries (OR 4.27; CI 3.31, 5.52), food insecurity (OR 2.34; CI 1.92, 2.85), and healthcare insecurity (OR 2.26; CI 1.85, 2.76) were each associated with higher odds of SPD. A dose-response association was found between the number of stressors and SPD. CONCLUSIONS: Each financial stressor was adversely associated with SPD both individually and cumulatively, indicating the adverse effects of the accumulation of these stressors. Additional studies are needed to understand the longitudinal effects of multiple financial stressors on mental health outcomes.