Circuit change in neonatal and pediatric extracorporeal membrane oxygenation is associated with adverse outcomes.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) circuits may be changed during the run for multiple reasons; however, these circuit changes may be associated with adverse events. Predictors for undergoing a circuit change (CC) and their outcomes remain unclear. We hypothesized that neonatal and pediatric CC correlates with increased morbidity and mortality. METHODS: Pediatric and neonatal patients who underwent one ECMO run lasting <30 days at a tertiary children's hospital from 2011 through 2017 were retrospectively reviewed. Bivariate regression analysis evaluated factors associated with ECMO mortality and morbidity. LASSO logistic regression models identified independent risk factors for undergoing a CC. p < .05 was significant. RESULTS: One hundred 85 patients were included; 137 (74%) underwent no CC, while 48 (26%) underwent one or more. Undergoing a CC was associated with longer ECMO duration (p < .001), higher blood transfusion volumes (p < .001), increased hemorrhagic complications (p < .001) and increased mortality (p = .002). Increased platelet (p = .001) and FFP (p = .016) transfusion volumes at any time while on ECMO were independent factors associated with undergoing a CC. CONCLUSIONS: Changing the circuit during the ECMO run occurs frequently and may be associated with poorer outcomes. Understanding the outcomes and predictors for CC may guide management protocols for more efficient circuit changes given its important association with overall outcomes.

Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage.

The critical cellular hydride donor NADPH is produced through various means, including the oxidative pentose phosphate pathway (oxPPP), folate metabolism and malic enzyme. In growing cells, it is efficient to produce NADPH via the oxPPP and folate metabolism, which also make nucleotide precursors. In nonproliferating adipocytes, a metabolic cycle involving malic enzyme holds the potential to make both NADPH and two-carbon units for fat synthesis. Recently developed deuterium ((2)H) tracer methods have enabled direct measurement of NADPH production by the oxPPP and folate metabolism. Here we enable tracking of NADPH production by malic enzyme with [2,2,3,3-(2)H]dimethyl-succinate and [4-(2)H]glucose. Using these tracers, we show that most NADPH in differentiating 3T3-L1 mouse adipocytes is made by malic enzyme. The associated metabolic cycle is disrupted by hypoxia, which switches the main adipocyte NADPH source to the oxPPP. Thus, (2)H-labeled tracers enable dissection of NADPH production routes across cell types and environmental conditions.

Obesity, cancer, and acetyl-CoA metabolism.

As rates of obesity soar in the Unites States and around the world, cancer attributed to obesity has emerged as major threat to public health. The link between obesity and cancer can be attributed in part to the state of chronic inflammation that develops in obesity. Acetyl-CoA production and protein acetylation patterns are highly sensitive to metabolic state and are significantly altered in obesity. In this article, we explore the potential role of nutrient-sensitive lysine acetylation in regulating inflammatory processes in obesity-linked cancer.

2,2-bis(4-chlorophenyl)-1,1-dichloroethylene stimulates androgen independence in prostate cancer cells through combinatorial activation of mutant androgen receptor and mitogen-activated protein kinase pathways.

Therapy resistance represents a major clinical challenge in disseminated prostate cancer for which only palliative treatment is available. One phenotype of therapy-resistant tumors is the expression of somatic, gain-of-function mutations of the androgen receptor (AR). Such mutant receptors can use noncanonical endogenous ligands (e.g., estrogen) as agonists, thereby promoting recurrent tumor formation. Additionally, selected AR mutants are sensitized to the estrogenic endocrine-disrupting compound (EDC) bisphenol A, present in the environment. Herein, screening of additional EDCs revealed that multiple tumor-derived AR mutants (including T877A, H874Y, L701H, and V715M) are sensitized to activation by the pesticide 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE), thus indicating that this agent may impinge on AR signaling in cancer cells. Further investigation showed that DDE induced mutant AR recruitment to the prostate-specific antigen regulatory region, concomitant with an enhancement of target gene expression, and androgen-independent proliferation. By contrast, neither AR activation nor altered cellular proliferation was observed in cells expressing wild-type AR. Activation of signal transduction pathways was also observed based on rapid phosphorylation of mitogen-activated protein kinase (MAPK) and vasodilator-stimulated phosphoprotein, although only MAPK activation was associated with DDE-induced cellular proliferation. Functional analyses showed that both mutant AR and MAPK pathways contribute to the proliferative action of DDE, as evidenced through selective abrogation of each pathway. Together, these data show that exposure to environmentally relevant doses of EDCs can promote androgen-independent cellular proliferation in tumor cells expressing mutant AR and that DDE uses both mutant AR and MAPK pathways to exert its mitogenic activity.

Comparison of respiratory parameters in participants with and without chronic low back pain.

BACKGROUND: Individuals with chronic low back pain (CLBP) may lack coordination between the stabilising and respiratory functions of trunk muscles. The trunk stabilisers compromise breathing to maintain spinal stability, leading to breathing dysfunctions. Maximal voluntary ventilation (MVV) is indicative of the respiratory muscle endurance and strength whereas end-tidal carbon dioxide (PETCO2) gives an estimate of breathing patterns that closely reflect the arterial measurement of CO2. CLBP has been shown to have a significant effect on respiratory functions. However, the impact has not yet been quantified. Further, there is a dearth of literature comparingrespiratory functions between CLBP and healthy individuals. This study investigates respiratory functions in participants with and without CLBP. METHODS: The study compared the respiratory functions of maximal voluntary ventilation (MVV) and End-Tidal Carbon Dioxide (PETCO2) between 14 participants with CLBP and 14 healthy individuals. Participants in both groups were matched for age, height, weight and body surface area. The assessment of MVV and PETCO2 were performed sitting, standing on a stable surface, and on an unstable surface (BOSU ball). RESULTS: The mean of measured MVV (L/min) was found to be lower (p < 0.05) in the CLBP group when compared to the healthy group. Mean PETCO2 and respiratory rate was found to be higher in CLBP group when compared to the healthy group in all three positions, although this was not found to be statistically significant. CONCLUSION: The findings of this study demonstrated sub-optimal respiratory parameters in participants with chronic low back pain. However, when adjusted for gender, the difference was not found to be significant between the two groups.

Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer.

CONTEXT.­: Regulatory approval of pembrolizumab for treatment of gastric and gastroesophageal junction (G/GEJ) adenocarcinoma required a reproducible scoring method for use of programmed death ligand-1 (PD-L1) protein expression as a companion diagnostic to identify likely responders to therapy. OBJECTIVE.­: To develop an immunohistochemical scoring algorithm that includes PD-L1 expression for tumor and immune cells, that is, the combined positive score. DESIGN.­: Four previously treated tumor types in the KEYNOTE-012 and KEYNOTE-028 studies were analyzed descriptively with a version of the PD-L1 immunohistochemical 22C3 pharmDx assay labeled for investigational use only to determine the relative importance of PD-L1 expression in tumor versus immune cells as a biomarker for pembrolizumab response. A combined positive score was developed as a novel scoring method and was compared with the tumor proportion score in cohort 1 from the KEYNOTE-059 study (G/GEJ cancer). External reproducibility was assessed. RESULTS.­: Per combined positive score cutoff of 1 or more, the prevalence of PD-L1 expression in patients with G/GEJ cancer was 57.6% (148 of 257 patients), with reasonable enrichment of responses (odds ratio, 2.8). Per tumor proportion score cutoff of 1% or more, prevalence was 12.5% (32 of 257 patients), with minimal enrichment (odds ratio, 1.4). External reproducibility assessments demonstrated interpathologist overall agreement of 96.6% (591 of 612; 95% CI, 94.0%-98.7%) and intrapathologist overall agreement of 97.2% (595 of 612; 95% CI, 95.3%-98.9%). CONCLUSIONS.­: Combined positive score is a robust, reproducible PD-L1 scoring method that predicts response to pembrolizumab in patients with G/GEJ cancer. This novel scoring method supported US Food and Drug Administration approval of pembrolizumab as third-line therapy for G/GEJ cancer and has facilitated investigation in other indications.

Legal themes concerning obesity regulation in the United States: Theory and practice.

Despite national health objectives to reduce the incidence of obesity to 15% of the population by 2010, public health data suggest that the incidence of obesity in the United States is actually increasing. The U.S. recognizes that it (like other industrialized countries) faces an epidemic of obesity and related health conditions. How can U.S. jurisdictions (federal, state, and local) and the private sector respond to this epidemic through laws and policies that are directly or indirectly designed to address obesity? This article analyzes the theoretical and practical roles of law as a tool to curb obesity in the U.S. It proffers ten major legal themes to address obesity among the U.S. population, including: (1) use of incentives to encourage healthier behaviors; (2) use of financial disincentives to discourage unhealthy behaviors; (3) requirements to improve food quality, diversity, or availability; (4) compensation for injured persons seeking recourse; (5) restriction of access to unhealthy foods; (6) regulations aimed at influencing consumer choices; (7) control of marketing and advertising; (8) creation of communities that support healthy lifestyles; (9) physical education/fitness requirements; and (10) insurance coverage mandates.

Fibrocartilaginous emboli in the pediatric population: The role of rehabilitation in facilitating functional recovery.

A 12 year-old female presented to the emergency department with a right hemiparesis, headache, and neck pain. Initial neural imaging studies were unremarkable. However, a repeat MRI of the cervical spine during her acute hospitalization showed an acute spinal infarct. Neurological workup was consistent with fibrocartilaginous embolism (FCE) as the etiology. After several weeks of intensive inpatient rehabilitation, the patient demonstrated remarkable functional progress. This case report reviews the comprehensive pediatric literature on FCE with focus on the mechanism of injury, role of imaging studies, treatment options and prognosis. Awareness of the typical clinical history, as well as the signs and symptoms characteristic of FCE will improve the identification of this rare cause of abrupt weakness and potentially facilitate functional recovery.

Bisphenol A facilitates bypass of androgen ablation therapy in prostate cancer.

Prostatic adenocarcinomas depend on androgen for growth and survival. First line treatment of disseminated disease exploits this dependence by specifically targeting androgen receptor function. Clinical evidence has shown that androgen receptor is reactivated in recurrent tumors despite the continuance of androgen deprivation therapy. Several factors have been shown to restore androgen receptor activity under these conditions, including somatic mutation of the androgen receptor ligand-binding domain. We have shown previously that select tumor-derived mutants of the androgen receptor are receptive to activation by bisphenol A (BPA), an endocrine-disrupting compound that is leached from polycarbonate plastics and epoxy resins into the human food supply. Moreover, we have shown that BPA can promote cell cycle progression in cultured prostate cancer cells under conditions of androgen deprivation. Here, we challenged the effect of BPA on the therapeutic response in a xenograft model system of prostate cancer containing the endogenous BPA-responsive AR-T877A mutant protein. We show that after androgen deprivation, BPA enhanced both cellular proliferation rates and tumor growth. These effects were mediated, at least in part, through androgen receptor activity, as prostate-specific antigen levels rose with accelerated kinetics in BPA-exposed animals. Thus, at levels relevant to human exposure, BPA can modulate tumor cell growth and advance biochemical recurrence in tumors expressing the AR-T877A mutation.

Transitioning from pediatric to adult health care with familial hypercholesterolemia: Listening to young adult and parent voices.

BACKGROUND: Young adults with familial hypercholesterolemia (FH) are at a critical period for establishing behaviors to promote future cardiovascular health. OBJECTIVE: To examine challenges transitioning to adult care for young adults with FH and parents of FH-affected young adults in the context of 2 developmental tasks, transitioning from childhood to early adulthood and assuming responsibility for self-management of a chronic disorder. METHODS: Semistructured, qualitative interviews were conducted with 12 young adults with FH and 12 parents of affected young adults from a pediatric subspecialty preventive cardiology program in a northeastern academic medical center. Analyses were conducted using a modified grounded theory framework. RESULTS: Respondents identified 5 challenges: (1) recognizing oneself as a decision maker, (2) navigating emerging independence, (3) prioritizing treatment for a chronic disorder with limited signs and symptoms, (4) managing social implications of FH, and (5) finding credible resources for guidance. Both young adults and parents proposed similar recommendations for addressing these challenges, including the need for family and peer involvement to establish and maintain diet and exercise routines and to provide medication reminders. Systems-level recommendations included early engagement of adolescents in shared decision-making with health care team; providing credible, educational resources regarding FH; and using blood tests to track treatment efficacy. CONCLUSION: Young adults with FH transitioning to adult care may benefit from explicit interventions to address challenges to establishing healthy lifestyle behaviors and medication adherence as they move toward being responsible for their medical care. Further research should explore the efficacy of recommended interventions.

Young adult and parent stakeholder perspectives on participation in patient-centered comparative effectiveness research.

AIM: Explore perspectives of adolescent and young adult (AYA) and parent stakeholders regarding their engagement in comparative effectiveness research (CER) evaluating cholesterol screening and treatment strategies for 17-21 year olds. METHODS: All nine AYAs and parent stakeholders participating in a 20-member panel of AYAs, parents and professionals (i.e., clinicians, researchers, policy makers, payers), completed a quantitative survey and a semistructured interview at the completion of the core CER study. RESULTS & CONCLUSION: AYAs and parents stakeholders emphasized the role of power differentials regarding shared knowledge, relationships and trust, and logistics. To mitigate power differentials, stakeholders recommended more materials, clearer definition of roles and in-person meetings. Perceived positive outcomes included diversity of perspectives provided, better understanding their own health and decision-making and improving CER.

Adolescent Perceptions of Cholesterol Screening Results: "Young Invincibles" or Developing Adults?

PURPOSE: Guidelines recommend cholesterol screening for all adolescents and young adults (AYAs) ages 17-21 years. Little is known about how screening results impact perceptions of AYA health. METHODS: We recruited 37 AYAs and 35 parents of AYAs with differing risk for abnormal cholesterol results: (1) familial hypercholesterolemia; (2) obesity; and (3) generally healthy. Participants completed quantitative health status ratings using visual analog scales (VASs) and semistructured interviews regarding three hypothetical cholesterol screening scenarios: (1) high likelihood of cardiovascular disease (CVD) before age 40 years ("high risk"); (2) some risk of CVD before age 70 years ("moderate risk"); and (3) low risk for CVD despite a strong family history of CVD ("low risk"). We analyzed VAS data with logistic regression and qualitative data with a priori and emergent coding using multiple coders. RESULTS: Each group perceived all three cholesterol screening scenarios as comparatively less than perfect health; the high-risk result fell furthest from perfect health. Although there was no significant difference between AYAs and parents in VAS ratings, qualitative analyses revealed AYAs were more likely than parents to discount the impact of moderate-risk results because of longer length of time before predicted CVD. CONCLUSIONS: AYAs' and parents' perceptions of the impact of cholesterol screening results on AYA health varied by presented scenario, ranging from mild to significant decreases in perceptions of AYA health. As universal cholesterol screening continues to be adopted in this age group, further studies of the real-life impact on AYA risk perceptions and subsequent behavior are warranted.

Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism.

The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels. When combined with an AR antagonist, ACLY inhibition in CRPC cells promotes energetic stress and AMPK activation, resulting in further suppression of AR levels and target gene expression, inhibition of proliferation, and apoptosis. Supplying exogenous fatty acids can restore energetic homeostasis; however, this rescue does not occur through increased ß-oxidation to support mitochondrial ATP production. Instead, concurrent inhibition of ACLY and AR may drive excess ATP consumption as cells attempt to cope with endoplasmic reticulum (ER) stress, which is prevented by fatty acid supplementation. Thus, fatty acid metabolism plays a key role in coordinating ER and energetic homeostasis in CRPC cells, thereby sustaining AR action and promoting proliferation. Consistent with a role for fatty acid metabolism in sustaining AR levels in prostate cancer in vivo, AR mRNA levels in human prostate tumors correlate positively with expression of ACLY and other fatty acid synthesis genes. The ACLY-AMPK-AR network can be exploited to sensitize CRPC cells to AR antagonism, suggesting novel therapeutic opportunities for prostate cancer.

A cancerous web: signaling, metabolism, and the epigenome.

Histone acetylation is sensitive to the availability of acetyl-CoA. However, the extent to which metabolic alterations in cancer cells impact tumor histone acetylation has been unclear. Here, we discuss our recent findings that oncogenic AKT1 activation regulates histone acetylation levels in tumors through regulation of acetyl-CoA metabolism.

Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation.

Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.

Targeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression.

Nuclear receptors and pioneer factors drive the development and progression of prostate cancer. In this disease, aggressive disease phenotypes and hormone therapy failures result from resurgent activity of androgen receptor (AR) and the upregulation of coactivator protein p300 and pioneer factors (e.g., GATA2 and FOXA1). Thus, a major emphasis in the field is to identify mechanisms by which castrate-resistant AR activity and pioneer factor function can be combinatorially suppressed. Here we show that the turmeric spice isoflavone curcumin suppresses p300 and CBP occupancy at sites of AR function. Curcumin reduced the association of histone acetylation and pioneer factors, thereby suppressing AR residence and downstream target gene expression. Histone deacetylase inhibitors reversed the effects of curcumin on AR activity, further underscoring the impact of curcumin on altering the chromatin landscape. These functions precluded pioneer factor occupancy, leading ultimately to a suppression of ligand-dependent and ligand-independent AR residence on chromatin. Moreover, these functions were conserved even in cells with heightened pioneer factor activity, thus identifying a potential strategy to manage this subclass of tumors. Biological relevance was further identified using in vivo xenograft models mimicking disease progression. Curcumin cooperated in vivo with androgen deprivation as indicated by a reduction in tumor growth and delay to the onset of castrate-resistant disease. Together, our results show the combinatorial impact of targeting AR and histone modification in prostate cancer, thus setting the stage for further development of curcumin as a novel agent to target AR signaling.