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2.
Circ Heart Fail ; 12(11): e006214, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31658831

RESUMO

BACKGROUND: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality. RESULTS: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84-0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72-0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race. CONCLUSIONS: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.

3.
Clin Pharmacol Ther ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31502253

RESUMO

In randomized clinical trials (RCTs), it is assumed that nonspecific effects beyond action of pharmacological agents are roughly equivalent in drug and placebo treatment groups. Hence, since the inception of RCTs, drug efficacy is determined by comparing outcomes in active to those in placebo control arms. However, quantitation of efficacy is based on an unproven assumption, that drug and placebo responses are always additive. Response to treatment in RCTs can be differentially influenced by the perturbing effects of patient expectations, side effects, and pharmacogenomic interactions in both drug and placebo arms. Ability to control for these effects requires understanding of when and where they arise, how to mitigate, analyze, and even leverage their impact. Here, we examine three factors that influence additivity: expectation, side effects, and pharmacogenomics. Furthermore, to provide novel insights into nonadditivity and solutions for managing it, we introduce systems pharmacogenomics, a network approach to integrating and analyzing the effects of the numerous interacting perturbations to which a patient is exposed in RCTs.

4.
Nat Biotechnol ; 37(11): 1287-1293, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31548726

RESUMO

Fluorescent RNAs (FRs), aptamers that bind and activate fluorescent dyes, have been used to image abundant cellular RNA species. However, limitations such as low brightness and limited availability of dye/aptamer combinations with different spectral characteristics have limited use of these tools in live mammalian cells and in vivo. Here, we develop Peppers, a series of monomeric, bright and stable FRs with a broad range of emission maxima spanning from cyan to red. Peppers allow simple and robust imaging of diverse RNA species in live cells with minimal perturbation of the target RNA's transcription, localization and translation. Quantification of the levels of proteins and their messenger RNAs in single cells suggests that translation is governed by normal enzyme kinetics but with marked heterogeneity. We further show that Peppers can be used for imaging genomic loci with CRISPR display, for real-time tracking of protein-RNA tethering, and for super-resolution imaging. We believe these FRs will be useful tools for live imaging of cellular RNAs.

5.
J Genet Couns ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31478310

RESUMO

BACKGROUND: Despite growing evidence of diagnostic yield and clinical utility of whole exome sequencing (WES) in patients with undiagnosed diseases, there remain significant cost and reimbursement barriers limiting access to such testing. The diagnostic yield and resulting clinical actions of WES for patients who previously faced insurance coverage barriers have not yet been explored. METHODS: We performed a retrospective descriptive analysis of clinical WES outcomes for patients facing insurance coverage barriers prior to clinical WES and who subsequently enrolled in the Undiagnosed Diseases Network (UDN). Clinical WES was completed as a result of participation in the UDN. Payer type, molecular diagnostic yield, and resulting clinical actions were evaluated. RESULTS: Sixty-six patients in the UDN faced insurance coverage barriers to WES at the time of enrollment (67% public payer, 26% private payer). Forty-two of 66 (64%) received insurance denial for clinician-ordered WES, 19/66 (29%) had health insurance through a payer known not to cover WES, and 5/66 (8%) had previous payer denial of other genetic tests. Clinical WES results yielded a molecular diagnosis in 23 of 66 patients (35% [78% pediatric, 65% neurologic indication]). Molecular diagnosis resulted in clinical actions in 14 of 23 patients (61%). CONCLUSIONS: These data demonstrate that a substantial proportion of patients who encountered insurance coverage barriers to WES had a clinically actionable molecular diagnosis, supporting the notion that WES has value as a covered benefit for patients who remain undiagnosed despite objective clinical findings.

6.
Nat Commun ; 10(1): 3476, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375661

RESUMO

Recent advances in DNA/RNA sequencing have made it possible to identify new targets rapidly and to repurpose approved drugs for treating heterogeneous diseases by the 'precise' targeting of individualized disease modules. In this study, we develop a Genome-wide Positioning Systems network (GPSnet) algorithm for drug repurposing by specifically targeting disease modules derived from individual patient's DNA and RNA sequencing profiles mapped to the human protein-protein interactome network. We investigate whole-exome sequencing and transcriptome profiles from ~5,000 patients across 15 cancer types from The Cancer Genome Atlas. We show that GPSnet-predicted disease modules can predict drug responses and prioritize new indications for 140 approved drugs. Importantly, we experimentally validate that an approved cardiac arrhythmia and heart failure drug, ouabain, shows potential antitumor activities in lung adenocarcinoma by uniquely targeting a HIF1α/LEO1-mediated cell metabolism pathway. In summary, GPSnet offers a network-based, in silico drug repurposing framework for more efficacious therapeutic selections.

7.
Circ Res ; 125(7): 707-719, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412728

RESUMO

RATIONALE: PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1α) represents an attractive target interfering bioenergetics and mitochondrial homeostasis, yet multiple attempts have failed to upregulate PGC1α expression as a therapy, for instance, causing cardiomyopathy. OBJECTIVE: To determine whether a fine-tuning of PGC1α expression is essential for cardiac homeostasis in a context-dependent manner. METHODS AND RESULTS: Moderate cardiac-specific PGC1α overexpression through a ROSA26 locus knock-in strategy was utilized in WT (wild type) mice and in G3Terc-/- (third generation of telomerase deficient; hereafter as G3) mouse model, respectively. Ultrastructure, mitochondrial stress, echocardiographic, and a variety of biological approaches were applied to assess mitochondrial physiology and cardiac function. While WT mice showed a relatively consistent PGC1α expression from 3 to 12 months old, age-matched G3 mice exhibited declined PGC1α expression and compromised mitochondrial function. Cardiac-specific overexpression of PGC1α (PGC1αOE) promoted mitochondrial and cardiac function in 3-month-old WT mice but accelerated cardiac aging and significantly shortened life span in 12-month-old WT mice because of increased mitochondrial damage and reactive oxygen species insult. In contrast, cardiac-specific PGC1α knock in in G3 (G3 PGC1αOE) mice restored mitochondrial homeostasis and attenuated senescence-associated secretory phenotypes, thereby preserving cardiac performance with age and extending health span. Mechanistically, age-dependent defect in mitophagy is associated with accumulation of damaged mitochondria that leads to cardiac impairment and premature death in 12-month-old WT PGC1αOE mice. In the context of telomere dysfunction, PGC1α induction replenished energy supply through restoring the compromised mitochondrial biogenesis and thus is beneficial to old G3 heart. CONCLUSIONS: Fine-tuning the expression of PGC1α is crucial for the cardiac homeostasis because the balance between mitochondrial biogenesis and clearance is vital for regulating mitochondrial function and homeostasis. These results reinforce the importance of carefully evaluating the PGC1α-boosting strategies in a context-dependent manner to facilitate clinical translation of novel cardioprotective therapies.

8.
Endocrine ; 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31410748

RESUMO

Understanding the genomic basis of type 2 diabetes mellitus is a major challenge. Simple genome-wide association studies (GWAS) have identified ~250 loci that link to the phenotype; however, the great majority have tiny effect size of uncertain mechanistic significance. Polygenic risk score strategies do nothing more than integrate these statistical association into a single scalar parameter, again offering limited mechanistic insight. The new discipline of network medicine offers an approach by which to provide useful mechanistic information from GWAS and other omic data sets. To understand disease in the network context requires using a predefined comprehensive network-in our case the protein-protein interaction network, or interactome-as a template upon which to map loci from GWAS or other data sources. These loci have been shown to cluster in a subnetwork in the interactome (as is the case for most diseases), exploration of which identifies novel pathways that regulate disease pathogenesis and uncovers novel targets for therapeutic intervention. Such an approach is essential for utilizing the growing pool of omic data in a mechanistically rational way as we move increasingly towards precision medicine for this highly prevalent disorder.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31218894

RESUMO

Significance: Reducing equivalents (NAD(P)H and glutathione [GSH]) are essential for maintaining cellular redox homeostasis and for modulating cellular metabolism. Reductive stress induced by excessive levels of reduced NAD+ (NADH), reduced NADP+ (NADPH), and GSH is as harmful as oxidative stress and is implicated in many pathological processes. Recent Advances: Reductive stress broadens our view of the importance of cellular redox homeostasis and the influences of an imbalanced redox niche on biological functions, including cell metabolism. Critical Issues: The distribution of cellular NAD(H), NADP(H), and GSH/GSH disulfide is highly compartmentalized. Understanding how cells coordinate different pools of redox couples under unstressed and stressed conditions is critical for a comprehensive view of redox homeostasis and stress. It is also critical to explore the underlying mechanisms of reductive stress and its biological consequences, including effects on energy metabolism. Future Directions: Future studies are needed to investigate how reductive stress affects cell metabolism and how cells adapt their metabolism to reductive stress. Whether or not NADH shuttles and mitochondrial nicotinamide nucleotide transhydrogenase enzyme can regulate hypoxia-induced reductive stress is also a worthy pursuit. Developing strategies (e.g., antireductant approaches) to counteract reductive stress and its related adverse biological consequences also requires extensive future efforts.

12.
Pharmacogenomics ; 20(7): 529-551, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31124409

RESUMO

Disease, drugs and the placebos used as comparators are inextricably linked in the methodology of the double-blind, randomized controlled trial. Nonetheless, pharmacogenomics, the study of how individuals respond to drugs based on genetic substrate, focuses primarily on the link between genes and drugs, while the link between genes and disease is often overlooked and the link between genes and placebos is largely ignored. Herein, we use the example of the enzyme catechol-O-methyltransferase to examine the hypothesis that genes can function as pharmacogenomic hubs across system-wide regulatory processes that, if perturbed in andomized controlled trials, can have primary and combinatorial effects on drug and placebo responses.

13.
Am J Pathol ; 189(7): 1311-1326, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31014954

RESUMO

The past decade has witnessed exponential growth in the generation of high-throughput human data across almost all known dimensions of biological systems. The discipline of network medicine has rapidly evolved in parallel, providing an unbiased, comprehensive biological framework through which to interrogate and integrate systematically these large-scale, multi-omic data to enhance our understanding of disease mechanisms and to design drugs that reflect a deep knowledge of molecular pathobiology. In this review, we discuss the key principles of network medicine and the human disease network and explore the latest applications of network medicine in this multi-omic era. We also highlight the current conceptual and technological challenges, which serve as exciting opportunities by which to improve and expand the network-based applications beyond the artificial boundaries of the current state of human pathobiology.

14.
J Am Coll Cardiol ; 73(15): 1978-1986, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31000001

RESUMO

Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. However, limitations of this hypothesis suggest that sarcomere mutations alone do not adequately explain all HCM clinical and pathobiological features. Disease-causing sarcomere mutations are absent in ∼70% of patients with established disease, and sarcomere gene carriers can live to advanced ages without developing HCM. Some features of HCM are also inconsistent with the single sarcomere gene hypothesis, such as regional left ventricular hypertrophy and myocardial fibrosis, as well as structurally abnormal elongated mitral valve leaflets and remodeled intramural coronary arterioles, which involve tissue types that do not express cardiomyocyte sarcomere proteins. It is timely to expand the HCM research focus beyond a single molecular event toward more inclusive models to explain this disease in its entirety. The authors chart paths forward addressing this knowledge gap using novel analytical approaches, particularly network medicine, to unravel the pathobiological complexity of HCM.

18.
Circ Res ; 124(7): 987-989, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30920923
19.
Am J Med Genet A ; 179(6): 958-965, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30903737

RESUMO

The Undiagnosed Diseases Network (UDN) aims to achieve a unifying etiologic diagnosis for patients with mysterious conditions. Although the UDN has focused on the identification of genetic determinants, environmental etiologies may be causative or modifying agents that interact with predisposing genes. We developed and implemented a screening questionnaire to assess environmental exposures in UDN patients. We hypothesized that patients with potentially adverse environmental exposures would be less likely to have a genetic basis for their undiagnosed disease. Among seven postnatal environmental exposure categories assessed in 269 UDN participants, patients with a confirmed or strong candidate genetic diagnosis were significantly less likely to report exposures to metals, dust, or chemicals (p < 0.05). A composite variable of the seven exposure categories was substantially more common (40%) in patients without a genetic diagnosis than in those with a genetic diagnosis (18.4%) (p = 0.004). In multivariable analysis adjusting for age and sex, the composite variable of any positive environmental exposure was associated with a reduced odds of finding a genetic diagnosis (OR 0.41, 95% CI 0.18-0.96, p = 0.04). These results were generally robust to exclusion of patients with early life disease onset. Our results suggest a possible approach to increase the yield of genetic etiologies for adult undiagnosed diseases by first focusing on patients without significant environmental exposures. Still, there is ample reason to expect cases in which specific environmental exposures impact the risk of clinically evident genetic disease. Our findings emphasize the importance of systematic investigations of potential environmental risk factors for undiagnosed diseases.

20.
Arterioscler Thromb Vasc Biol ; 39(4): 653-664, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30727752

RESUMO

In pulmonary arterial hypertension (PAH), the Warburg effect (glycolytic shift) and mitochondrial fission are determinants of phenotype alterations characteristic of the disease, such as proliferation, apoptosis resistance, migration, endothelial-mesenchymal transition, and extracellular matrix stiffness. Current therapies, focusing largely on vasodilation and antithrombotic protection, do not restore these aberrant phenotypes suggesting that additional pathways need be targeted. The multifactorial nature of PAH suggests epigenetic changes as potential determinants of vascular remodeling. Transgenerational epigenetic changes induced by hypoxia can result in permanent changes early in fetal development increasing PAH risk in adulthood. Unlike genetic mutations, epigenetic changes are pharmacologically reversible, making them an attractive target as therapeutic strategies for PAH. This review offers a landscape of the most current clinical, epigenetic-sensitive changes contributing to PAH vascular remodeling both in early and later life, with a focus on a network medicine strategy. Furthermore, we discuss the importance of the application (from morphogenesis to disease onset) of molecular network-based algorithms to dissect PAH molecular pathobiology. Additionally, we suggest an integrated network-based program for clinical disease gene discovery that may reveal novel biomarkers and novel disease targets, thus offering a truly innovative path toward redefining and treating PAH, as well as facilitating the trajectory of a comprehensive precision medicine approach to PAH.

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