Background: Social determinants of health (SDoH) are known to influence an individual’s risk for CVD. Childhood is a vulnerable period during which the influences of SDoH may have a stronger impact on future health outcomes. Little is known about early life SDoH and associations with cardiovascular health (CVH) in early adulthood. Methods: In 1998-2000, the Future of Families and Child Wellbeing Study (FFCWS) enrolled 4898 mother-baby dyads from large cities across the US. Births to unmarried mothers were oversampled. When the offspring were 22 yrs, they completed an in-person exam for CVH metrics. SDoH at birth included maternal and paternal education, mother living in a public housing project, having income within the past year from public assistance/welfare/food stamps. Life’s Essential 8 (LE8) Score (without sleep) was assessed at age 22. Linear regression models examined the association of individual SDoH measures with LE8 score adjusting for age, gender and race/ethnicity. Results: This study included 1211 participants, mean age 22 yrs (55% female; 51% Black, 25% Hispanic, 20% White, 4% Other). Adverse SDoH were common with 10% living in a public housing project at birth and 36.7% of mothers having received public assistance within the past year. Adjusted CVH scores were 3.0 (95% CI 1.2-4.8) pts lower for individuals whose mother reported having received public assistance in the past year. Compared to mothers with a college or graduate degree, those with less than high school, high school, and some college had 8.0 (5.0-10.9), 7.1 (4.2-10.0) and 3.2 (0.3-6.1) lower scores CVH scores. Findings were similar for paternal education. No significant associations were observed with living in a public housing project. Conclusion: SDoH at the time of birth have long lasting influence on the CVH of offspring. Interventions to promote CVH within children and families experiencing adverse SDoH are critical to promote health equity and break the inter-generational cycle of CVD.
<div>Abstract<p>Because Notch signaling is implicated in colon cancer tumorigenesis and protects cells from apoptosis by inducing prosurvival targets, it was hypothesized that inhibition of Notch signaling with γ-secretase inhibitors (GSI) may enhance the chemosensitivity of colon cancer cells. We first show that the Notch-1 receptor, as well as its downstream target Hes-1, is up-regulated with colon cancer progression, similar to other genes involved in chemoresistance. We then report that chemotherapy induces Notch-1, as oxaliplatin, 5-fluorouracil (5-FU), or SN-38 (the active metabolite of irinotecan) induced Notch-1 intracellular domain (NICD) protein and activated Hes-1. Induction of NICD by oxaliplatin was caused by an increase in the activity and expression of γ-secretase complex, as suppression of the protein subunit nicastrin with small interfering RNA (siRNA) prevented NICD induction after oxaliplatin. Subsequent inhibition of Notch-1 signaling with a sulfonamide GSI (GSI34) prevented the induction of NICD by chemotherapy and blunted Hes-1 activation. Blocking the activation of Notch signaling with GSI34 sensitized cells to chemotherapy and was synergistic with oxaliplatin, 5-FU, and SN-38. This chemosensitization was mediated by Notch-1, as inhibition of Notch-1 with siRNA enhanced chemosensitivity whereas overexpression of NICD increased chemoresistance. Down-regulation of Notch signaling also prevented the induction of prosurvival pathways, most notably phosphoinositide kinase-3/Akt, after oxaliplatin. In summary, colon cancer cells may up-regulate Notch-1 as a protective mechanism in response to chemotherapy. Therefore, combining GSIs with chemotherapy may represent a novel approach for treating metastatic colon cancers by mitigating the development of chemoresistance. [Cancer Res 2009;69(2):573–82]</p></div>
Children who are socioeconomically disadvantaged are at increased risk for high body mass index (BMI) and multiple diseases in adulthood. The developmental origins of health and disease hypothesis proposes that early life conditions affect later-life health in a manner that is only partially modifiable by later-life experiences. Epigenetic mechanisms may regulate the influence of early life conditions on later life health. Recent epigenetic studies of adult blood samples have identified DNA-methylation sites associated with higher BMI and worse health (epigenetic-BMI). Here, we used longitudinal and twin study designs to examine whether epigenetic predictors of BMI developed in adults are valid biomarkers of child BMI and are sensitive to early life social determinants of health. Salivary epigenetic-BMI was calculated from two samples: (1) N=1,183 8-to-19-year-olds (609 female,
OBJECTIVES: To describe family healthcare burden and health resource utilization in pediatric survivors of acute respiratory distress syndrome (ARDS) at 3 and 9 months. DESIGN: Secondary analysis of a prospective multisite cohort study. SETTING: Eight academic PICUs in the United States (2019–2020). PATIENTS: Critically ill children with ARDS and follow-up survey data collected at 3 and/or 9 months after the event. INTERVENTIONS: None. METHODS AND MEASUREMENT: We evaluated family healthcare burden, a measure of healthcare provided by families at home, and child health resource use including medication use and emergency department (ED) and hospital readmissions during the initial 3- and 9-month post-ARDS using proxy-report. Using multivariable logistic regression, we evaluated patient characteristics associated with family healthcare burden at 3 months. MAIN RESULTS: Of 109 eligible patients, 74 (68%) and 63 patients (58%) had follow-up at 3- and 9-month post-ARDS. At 3 months, 46 families (62%) reported healthcare burden including (22%) with unmet care coordination needs. At 9 months, 33 families (52%) reported healthcare burden including 10 families (16%) with unmet care coordination needs. At month 3, 61 patients (82%) required prescription medications, 13 patients (18%) had ED visits and 16 patients (22%) required hospital readmission. At month 9, 41 patients (65%) required prescription medications, 19 patients (30%) had ED visits, and 16 (25%) required hospital readmission were reported. Medication use was associated with family healthcare burden at both 3 and 9 months. In a multivariable analysis, preillness functional status and chronic conditions were associated with healthcare burden at month 3 but illness characteristics were not. CONCLUSIONS: Pediatric ARDS survivors report high rates of healthcare burden and health resource utilization at 3- and 9-month post-ARDS. Future studies should assess the impact of improved care coordination to simplify care (e.g., medication management) and improve family burden.
The transcription factor p63 is critical for many biological processes, including development and maintenance of epidermal tissues and tumorigenesis. Here, we report that the TAp63 isoforms regulate cell metabolism through the induction of the mitochondrial glutaminase 2 (GLS2) gene both in primary cells and tumor cell lines. By ChIP analysis and luciferase assay, we confirmed that TAp63 binds directly to the p53/p63 consensus DNA binding sequence within the GLS2 promoter region. Given the critical role of p63 in epidermal differentiation, we have investigated the regulation of GLS2 expression during this process. GLS2 and TAp63 expression increases during the in vitro differentiation of primary human keratinocytes, and depletion of GLS2 inhibits skin differentiation both at molecular and cellular levels. We found that GLS2 and TAp63 expression are concomitantly induced in cancer cells exposed to oxidative stresses. siRNA-mediated depletion of GLS2 sensitizes cells to ROS-induced apoptosis, suggesting that the TAp63/GLS2 axis can be functionally important as a cellular antioxidant pathway in the absence of p53. Accordingly, we found that GLS2 is upregulated in colon adenocarcinoma. Altogether, our findings demonstrate that GLS2 is a bona fide TAp63 target gene, and that the TAp63-dependent regulation of GLS2 is important for both physiological and pathological processes.
Abstract About half of cancers sustain mutations in the TP53 gene, whereas the other half maintain a wild-type p53 (wtp53) but may compromise the p53 response because of other alterations. Homeodomain-interacting protein kinase-2 (HIPK2) is a positive regulator of p53 oncosuppressor function. Here, we show, by microarray analysis, that wtp53 lost the target gene activation following stable knockdown of HIPK2 (HIPK2i) in colon cancer cell line. Our data show that the stable knockdown of HIPK2 led to wtp53 misfolding, as detected by p53 immunoprecipitation with conformation-specific antibodies, and that p53 protein misfolding impaired p53 DNA binding and transcription of target genes. We present evidence that zinc supplementation to HIPK2i cells increased p53 reactivity to conformation-sensitive PAb1620 (wild-type conformation) antibody and restored p53 sequence-specific DNA binding in vivo and transcription of target genes in response to Adriamycin treatment. Finally, combination of zinc and Adriamycin suppressed tumor growth in vivo and activated misfolded p53 that induced its target genes in nude mice tumor xenografts derived from HIPK2i cells. Bioinformatics analysis of microarray data from colon cancer patients showed significant association of poor survival with low HIPK2 expression only in tumors expressing wtp53. These results show a critical role of HIPK2 in maintaining the transactivation activity of wtp53 and further suggest that low expression of HIPK2 may impair the p53 function in tumors harboring wtp53. [Cancer Res 2008;68(10):3707–13]
Background: Lower respiratory tract infections (LRTI) are a leading cause of mortality in children with critical illness. Despite this, the pathogenic microbes in this vulnerable demographic frequently remain unknown. Metagenomic next generation sequencing (mNGS) can complement traditional diagnostics in epidemiologic surveillance studies by providing broad-range pathogen detection.Methods: We conducted a prospective, multicenter cohort study of critically ill children ages 31 days to 17 years with respiratory failure requiring prolonged mechanical ventilation. Using a combination of clinically-ordered testing and tracheal aspirate mNGS we determined the prevalence, seasonal variation, and genetic relatedness of respiratory pathogens in children with clinically adjudicated LRTI (n=276) or no LRTI (n=121).Findings: A presumptive microbiologic etiology was identified in 92% of children, with RSV (46%), Haemophilus influenzae (25%) and Moraxella catarrhalis (24%) being most common. mNGS identified uncommon pathogens including Ureaplasma parvum (<1%) and Bocavirus (3%). Co-detection of viral and bacterial pathogens occurred in 52% of cases. Incidental carriage of potentially pathogenic microbes was observed in 68% of children without LRTI, with rhinovirus (25%) most prevalent. RSV, H. influenzae and M. catarrhalis were statistically more prevalent in children under five. Both viral and bacterial LRTI occurred predominantly during winter months, and RSV infection was characterized by seasonal and geographic clusters of related strains.Interpretation: The combination of clinical diagnostics and mNGS enabled comprehensive pathogen surveillance in critically ill children with LRTI. RSV, H. influenzae , and M. catarrhalis were disproportionately represented. Carriage of potentially pathogenic microbes was common in children without LRTI.Funding Statement: NIH, Chan Zuckerberg BiohubDeclaration of Interests: All authors declare no competing interests.Ethics Approval Statement: The study was approved by a central IRB at the University ofUtah.
