Inheritance in Contemporary America

With the baby boom generation on the cusp of retirement, life expectancies on the rise, and the nation’s cultural makeup in flux, the United States is faced with social and policy quandaries that demand attention. How are elders to balance the competing claims of helping family members during their lifetime, saving for old age, and planning estates? What roles should the state, family, and individuals play in supporting people during later life? Are new familial gift-giving trends sustainable, and, if so, what effects might they have on future generations?Inheritance in Contemporary America tackles the complex legal, policy, and emotional issues that surround bequests and inheritances in an era of increasing longevity, broadening ethnicity, and unraveling social safety nets. Through empirical analyses, case studies, interviews, and anecdotes, Jacqueline L. Angel explains the historical nature of familial giving and how it is changing as the nation’s demographics shift. She explores the legal, personal, and policy complexities involved in passing wealth down through generations and provides a cross-disciplinary context for exploring the indelible effects that newly unfolding inheritance practices will have on various societal cohorts and the nation in general.From nuclear and extended families to the state and nongovernmental bodies, Angel’s engaging study explores how attitudes toward giving are evolving and confronts in stark terms the legacy that these shifts in attitude will leave. This book will be a vital tool for scholars and practitioners in gerontology, sociology, psychology, anthropology, economics, political science, and public policy

Acculturation, Gender, and Active Life Expectancy in the Mexican-Origin Population

Objective—This study examines the potential effects of nativity and acculturation on active life expectancy (ALE) among Mexican-origin elders. Method—We employ 17 years of data from the Hispanic Established Population for the Epidemiologic Study of the Elderly to calculate ALE at age 65 with and without disabilities. Results—Native-born males and foreign-born females spend a larger fraction of their elderly years with activities of daily living (ADL) disability. Conversely, both foreign-born males and females spend a larger fraction of their remaining years with instrumental activities of daily life (IADL) disability than the native-born. In descriptive analysis, women with low acculturation report higher ADL and IADL disability. Men manifest similar patterns for IADLs. Discussion—Although foreign-born elders live slightly longer lives, they do so with more years spent in a disabled state. Given the rapid aging of the Mexican-origin population, the prevention and treatment of disabilities, particularly among the foreign born, should be a major public health priority

Living Arrangements and Dementia Among the Oldest Old: A Comparison of Mexicans and Mexican Americans

Background and Objectives The growing population of adults surviving past age 85 in the United States and Mexico raises questions about the living arrangements of the oldest old and those living with dementia. This study compares Mexican and Mexican American individuals aged 85 and older to identify associations with cognitive status and living arrangements in Mexico and the United States. Research Design and Methods This study includes 419 Mexican Americans in 5 southwestern states (Hispanic Established Population for the Epidemiologic Studies of the Elderly) and 687 Mexicans from a nationally representative sample (Mexican Health and Aging Study). It examines characteristics associated with living alone using logistic regression and describes the living arrangements of older adults with probable dementia in each country. Results Older adults with dementia were significantly less likely to live alone than with others in the United States while there were no relationships between dementia and living arrangements in Mexico. However, a substantial proportion of older adults with dementia lived alone in both nations: 22% in the United States and 21% in Mexico. Among Mexican Americans with dementia, those living alone were more likely to be women, childless, reside in assisted living facilities, and less likely to own their homes. Similarly, Mexican individuals with dementia who lived alone were also less likely to be homeowners than those living with others. Discussion and Implications Contextual differences in living arrangements and housing between the United States and Mexico pose different challenges for aging populations with a high prevalence of dementia

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

HIVToolbox, an Integrated Web Application for Investigating HIV

Many bioinformatic databases and applications focus on a limited domain of knowledge federating links to information in other databases. This segregated data structure likely limits our ability to investigate and understand complex biological systems. To facilitate research, therefore, we have built HIVToolbox, which integrates much of the knowledge about HIV proteins and allows virologists and structural biologists to access sequence, structure, and functional relationships in an intuitive web application. HIV-1 integrase protein was used as a case study to show the utility of this application. We show how data integration facilitates identification of new questions and hypotheses much more rapid and convenient than current approaches using isolated repositories. Several new hypotheses for integrase were created as an example, and we experimentally confirmed a predicted CK2 phosphorylation site. Weblink: [http://hivtoolbox.bio-toolkit.com