Characterizing Relationships between T-cell Inflammation and Outcomes in Patients with High-Risk Neuroblastoma According to Mesenchymal and Adrenergic Signatures.

Unlabelled: Recent insights have identified adrenergic (ADRN) and mesenchymal (MES) cell lineages as distinct biologic cell types and T-cell inflammation as a prognostic marker in neuroblastoma. We hypothesized that elucidating unique and overlapping aspects of these biologic features could serve as novel biomarkers for informing ongoing efforts to improve therapeutic approaches for children with high-risk neuroblastoma. We identified lineage-specific, single-stranded super-enhancers to define ADRN and MES specific genes.

Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation.

The N-methyladenosine (mA) RNA modification is an important regulator of gene expression. mA is deposited by a methyltransferase complex that includes methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14). High levels of METTL3/METTL14 drive the growth of many types of adult cancer, and METTL3/METTL14 inhibitors are emerging as new anticancer agents.

5-Hydroxymethylcytosine Profiling of Cell-Free DNA Identifies Bivalent Genes That Are Prognostic of Survival in High-Risk Neuroblastoma.

Purpose: Neuroblastoma is the most common extracranial solid tumor in childhood. We previously showed that circulating cell-free DNA (cfDNA) and tumor biopsy derived 5-hydroxymethylcytosime (5-hmC) profiles identified patients with neuroblastoma who experienced subsequent relapse. Here, we hypothesized that 5-hmC modifications selectively enriched in cfDNA compared with tumor biopsy samples would identify epigenetic changes associated with aggressive tumor behavior and identify novel biomarkers of outcome in patients with high-risk neuroblastoma.

Adrenergic and mesenchymal signatures are identifiable in cell-free DNA and correlate with metastatic disease burden in children with neuroblastoma.

Background: Cell-free DNA (cfDNA) profiles of 5-hydroxymethylcytosine (5-hmC), an epigenetic marker of open chromatin and active gene expression, are correlated with metastatic disease burden in patients with neuroblastoma. Neuroblastoma tumors are comprised of adrenergic (ADRN) and mesenchymal (MES) cells, and the relative abundance of each in tumor biopsies has prognostic implications. We hypothesized that ADRN and MES-specific signatures could be quantified in cfDNA 5-hmC profiles and would augment the detection of metastatic burden in patients with neuroblastoma.

5-hydroxymethylcytosine profiling of cell-free DNA identifies bivalent genes that are prognostic of survival in high-risk neuroblastoma.

Neuroblastoma is the most common extra-cranial solid tumor in childhood and epigenetic dysregulation is a key driver of this embryonal disease. In cell-free DNA from neuroblastoma patients with high-risk disease, we found increased 5-hydroxymethylcytosine (5-hmC) deposition on Polycomb Repressive Complex 2 (PRC2) target genes, a finding previously described in the context of bivalent genes. As bivalent genes, defined as genes bearing both activating (H3K4me3) and repressive (H3K27me3) chromatin modifications, have been shown to play an important role in development and cancer, we investigated the potential role of bivalent genes in maintaining a de-differentiated state in neuroblastoma and their potential use as a biomarker.

Neighborhood Socioeconomic Status Affects Patient-Reported Outcome 2 Years After ACL Reconstruction.

Background: Lower socioeconomic status (SES) is associated with worse patient-reported outcome (PRO) after orthopaedic procedures. In patients with anterior cruciate ligament (ACL) reconstruction, evaluating SES by use of traditional measures such as years of education or occupation is problematic because this group has a large proportion of younger patients. We hypothesized that lower education level and lower values for SES would predict worse PRO at 2 years after ACL reconstruction and that the effect of education level would vary with patient age.

The "Good Times" Cohort in Later-Life.

Race differences in midlife circumstances explain much of the disability gap in older adulthood, but questions remain about whether early life selection processes are race invariant. To address this, we (1) isolate the 1930s cohort to explore potential race-specific life courses and (2) utilize a two-stage estimation procedure to examine the role of early-to-midlife selection in shaping later-life functional limitations. Using data on Black and White adults born 1931-1941 from the Health and Retirement Study (W2-W9), we estimate trajectories of later-life functional limitations after modeling midlife income and comorbidity as a function of early life factors.

Intraindividual Variability in Late-Life Functional Limitations Among White, Black, and Hispanic Older Adults.

Consistent with the weathering hypothesis, many studies have captured racial/ethnic disparities in average functional health trajectories. The same mechanisms of social inequality that contribute to worse average health among minority adults may also contribute to greater fluctuations in their physical function at upper ages. Using panel data from the Health and Retirement Study, we examine patterns of intraindividual variability over time in trajectories of functional limitations for White, Black, and Hispanic older adults.

The Continued Eclipse of Heterogeneity in Gerontological Research.

Objectives: After a long history of neglect, diversity among older people and increasing heterogeneity with age are now familiar ideas in gerontological discourse. We take up the question of whether this increased attention is translating into the domain of empirical research. We replicate Nelson and Dannefer's (1992) review of the treatment of age-based variability in gerontological research, the most recent known assessment of the issue.

Do Local Social Hierarchies Matter for Mental Health? A Study of Neighborhood Social Status and Depressive Symptoms in Older Adults.

Objectives: Despite a well-established association between relative social position and health, stratification at smaller levels of social organization has received scant attention. Neighborhood is a localized context that has increasing relevance for adults as they age, thus one's relative position within this type of mesolevel group may have an effect on mental health, independent of absolute level of social and economic resources. We examine the relationship between an older adult's relative rank within their neighborhoods on two criteria and depressive symptoms.

From Noise to Signal: The Age and Social Patterning of Intra-Individual Variability in Late-Life Health.

Objectives: Despite a long tradition of attending to issues of intra-individual variability in the gerontological literature, large-scale panel studies on late-life health disparities have primarily relied on average health trajectories, relegating intra-individual variability over time to random error terms, or "noise." This article reintegrates the systematic study of intra-individual variability back into standard growth curve modeling and investigates the age and social patterning of intra-individual variability in health trajectories.

Method: Using panel data from the Health and Retirement Study, we estimate multilevel growth curves of functional limitations and cognitive impairment and examine whether intra-individual variability in these two health outcomes varies by age, gender, race/ethnicity, and socioeconomic status, using level-1 residuals extracted from the adjusted growth curve models.

The social context of disablement among older adults: does marital quality matter for loneliness?

Prior research has not adequately considered that disablement occurs within a web of relationships that provides socioemotional resources to and/or places demands on older adults. Drawing on the stress process and life course perspectives, we considered the social context of disablement by examining the influence of marital quality on the association between disability and loneliness among married older adults. Using data from the National Social Life, Health, and Aging Project, we found (1) functional limitations were associated with higher levels of loneliness; (2) neither positive nor negative marital quality mediated this association, contrary to the stress-deterioration hypothesis; and (3) positive (but not negative) marital quality moderated this association, consistent with the stress-buffering hypothesis.

Proactive aging: a longitudinal study of stress, resources, agency, and well-being in late life.

Objectives: Using the Proactivity Model of Successful Aging, we examined how internal and external resources contribute to the maintenance of psychological well-being and social activities among older adults who experience normative stressors of aging. Outcome variables in this study are collectively referred to as quality of life (QOL). We also examined the mediating role of proactive adaptations between internal and external resources and QOL indicators.

Utility of routine nurse assessment of the risk of chemotherapy-induced febrile neutropenia.

Evidence-based guidelines recommend that patients at high risk (> or = 20%) for febrile neutropenia (FN) should receive prophylactic colony-stimulating factors (Aapro et al., 2006; Kouroukis et al., 2008; National Comprehensive Cancer Network [NCCN], 2008; Smith et al.

Toward advocacy in cancer care for older adults: survivors have cautious personal actions but bold advice for others.

Objectives: To examine narratives of personal coping with the cancer experience and compare them with narratives of advice offered to other cancer patients by community-dwelling elderly cancer survivors.

Design: Qualitative and quantitative mixed methods.

Setting: Community.

The AIM Higher Initiative: new procedures implemented for assessment, information, and management of chemotherapy toxicities in community oncology clinics.

Chemotherapy-related toxicities are common and often undertreated in routine cancer care. Initiatives to improve toxicity management in practices may not always be effective. Quality improvement programs must engage multiple disciplines of the healthcare team and sustain efforts to institute and maintain procedures that address practice needs.

4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.

A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate.

Baseline evaluation of the AIM Higher Initiative: establishing the mark from which to measure.

Purpose/objectives: To collect baseline measurements before the implementation of interventions associated with the AIM (Assessment Information Management) Higher Initiative--a quality improvement program intended to improve symptom assessment, management, and information distribution for five chemotherapy-related symptom groups: anemia, neutropenia, diarrhea and constipation, nausea and vomiting, and depression and anxiety.

Design: Subject telephone interviews and chart reviews.

Setting: 15 community oncology clinics in the United States.

The color of hospitalization over the adult life course: cumulative disadvantage in black and white?

Objectives: Drawing from cumulative disadvantage theory, this research addresses the following questions: Do hospital admission and discharge rates differ for White and Black adults? If yes, do the differences amplify in later life?

Methods: This study made use of hospital records abstracted from a long-term prospective study of adults in the National Health and Nutrition Examination Survey I: Epidemiologic Follow-up Study (N = 6,833). Semi-Markov models were specified to examine the likelihood of hospital admission and discharge for Black and White adults aged 25 to 74 years old at baseline.

Results: Black adults were less likely than White adults to be admitted to the hospital, but they had longer lengths of stay.

Assessing racial health inequality in older adulthood: comparisons from mixed-mode panel interviews.

Objectives: Estimates of the extent of health disparities among Black and White older adults are not consistent across studies. The purpose of this study was to systematically compare responses from Black and White older adults in telephone and face-to-face interviews in order to determine whether estimates of racial health inequality vary by survey interview mode.

Methods: By using data from a mixed-mode panel study, I compared estimates of changing health inequality for Black and White older adults collected from face-to-face and telephone interviews.

When do older adults become "disabled"? Social and health antecedents of perceived disability in a panel study of the oldest old.

Disability carries negative social meaning, and little is known about when (or if), in the process of health decline, persons identify themselves as "disabled." We examine the social and health criteria that older adults use to subjectively rate their own disability status. Using a panel study of older adults (ages 72+), we estimate ordered probit and growth curve models of perceived disability over time.