RESUMO
PURPOSE OF REVIEW: The goal of this review is to summarize current understanding of pharmacogenetics and pharmacogenomics in chemotherapy-induced cardiotoxicity. RECENT FINDINGS: Most of the studies rely on in vitro cytotoxic assays. There have been several smaller scale candidate gene approaches and a handful of genome-wide studies linking genetic variation to susceptibility to chemotherapy-induced cardiotoxicity. Currently, pharmacogenomic testing of all childhood cancer patients with an indication for doxorubicin or daunorubicin therapy for RARG rs2229774, SLC28A3 rs7853758, and UGT1A6*4 rs17863783 variants is recommended. There is no recommendation regarding testing in adults. There is clear evidence pointing to the role of pharmacogenetics and pharmacogenomics in cardiotoxicity susceptibility to chemotherapeutic agents. Larger scale studies are needed to further identify susceptibility markers and to develop pharmacogenomics-based risk profiling to improve quality of life and life expectancy in cancer survivors.
Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/genética , Farmacogenética/métodos , Animais , Antineoplásicos/uso terapêutico , Cardiotoxicidade/etiologia , Daunorrubicina/efeitos adversos , Daunorrubicina/farmacologia , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Testes Genéticos , Humanos , Camundongos , Polimorfismo de Nucleotídeo Único , Receptores do Ácido Retinoico/genética , Receptor gama de Ácido RetinoicoRESUMO
Cardiac failure has been widely associated with an increase in glucose utilization. The aim of our study was to identify factors that mechanistically bridge this link between hyperglycemia and heart failure. Here, we screened the Hybrid Mouse Diversity Panel (HMDP) for substrate-specific cardiomyocyte candidates based on heart transcriptional profile and circulating nutrients. Next, we utilized an in vitro model of rat cardiomyocytes to demonstrate that the gene expression changes were in direct response to substrate abundance. After overlaying candidates of interest with a separate HMDP study evaluating isoproterenol-induced heart failure, we chose to focus on the gene Trp53inp2 as a cardiomyocyte glucose utilization-specific factor. Trp53inp2 gene knockdown in rat cardiomyocytes reduced expression and protein abundance of key glycolytic enzymes. This resulted in reduction of both glucose uptake and glycogen content in cardiomyocytes stimulated with isoproterenol. Furthermore, this reduction effectively blunted the capacity of glucose and isoprotereonol to synergistically induce hypertrophic gene expression and cell size expansion. We conclude that Trp53inp2 serves as regulator of cardiomyocyte glycolytic activity and can consequently regulate hypertrophic response in the context of elevated glucose content.NEW & NOTEWORTHY Here, we apply a novel method for screening transcripts based on a substrate-specific expression pattern to identify Trp53inp2 as an induced cardiomyocyte glucose utilization factor. We further show that reducing expression of the gene could effectively blunt hypertrophic response in the context of elevated glucose content.
Assuntos
Cardiomegalia/genética , Cardiomegalia/metabolismo , Glucose/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/genética , Animais , Cardiomegalia/induzido quimicamente , Cardiotônicos , Tamanho Celular , Células Cultivadas , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Glicogênio/metabolismo , Glicólise/genética , Técnicas In Vitro , Isoproterenol , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , RNA Interferente Pequeno , Ratos , Especificidade por SubstratoRESUMO
Expression of a cohort of disease-associated genes, some of which are active in fetal myocardium, is considered a hallmark of transcriptional change in cardiac hypertrophy models. How this transcriptome remodeling is affected by the common genetic variation present in populations is unknown. We examined the role of genetics, as well as contributions of chromatin proteins, to regulate cardiac gene expression and heart failure susceptibility. We examined gene expression in 84 genetically distinct inbred strains of control and isoproterenol-treated mice, which exhibited varying degrees of disease. Unexpectedly, fetal gene expression was not correlated with hypertrophic phenotypes. Unbiased modeling identified 74 predictors of heart mass after isoproterenol-induced stress, but these predictors did not enrich for any cardiac pathways. However, expanded analysis of fetal genes and chromatin remodelers as groups correlated significantly with individual systemic phenotypes. Yet, cardiac transcription factors and genes shown by gain-/loss-of-function studies to contribute to hypertrophic signaling did not correlate with cardiac mass or function in disease. Because the relationship between gene expression and phenotype was strain specific, we examined genetic contribution to expression. Strikingly, strains with similar transcriptomes in the basal heart did not cluster together in the isoproterenol state, providing comprehensive evidence that there are different genetic contributors to physiological and pathological gene expression. Furthermore, the divergence in transcriptome similarity versus genetic similarity between strains is organ specific and genome-wide, suggesting chromatin is a critical buffer between genetics and gene expression.
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Cardiomegalia/genética , Cromatina/genética , Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Variação Genética/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Feminino , Coração/fisiologia , Camundongos , Fenótipo , Transdução de Sinais/genética , Fatores de Transcrição/genéticaAssuntos
Doenças Cardiovasculares/terapia , Atenção à Saúde/tendências , Participação do Paciente/tendências , Medicina de Precisão/tendências , Terapias em Estudo/tendências , Doenças Cardiovasculares/genética , Ensaios Clínicos como Assunto/métodos , Atenção à Saúde/métodos , Genômica/métodos , Genômica/tendências , Humanos , Participação do Paciente/métodos , Medicina de Precisão/métodos , Terapias em Estudo/métodosRESUMO
BACKGROUND: Unbalanced translocations can cause developmental delay (DD), intellectual disability (ID), growth problems, dysmorphic features, and congenital anomalies. They may arise de novo or may be inherited from a parent carrying a balanced rearrangement. It is estimated that 1/500 people is a balanced translocation carrier. The outcomes of different chromosomal rearrangements have the potential to reveal the functional consequences of partial trisomy or partial monosomy and can help guide genetic counseling for balanced carriers, and other young patients diagnosed with similar imbalances. METHODS: We performed clinical phenotyping and cytogenetic analyses of two siblings with a history of developmental delay (DD), intellectual disability (ID) and dysmorphic features. RESULTS: The proband, a 38-year-old female, has a history of short stature, dysmorphic features and aortic coarctation. She underwent chromosomal microarray analysis, which identified partial monosomy of 4q and partial trisomy of 10p. Her brother, a 37-year-old male, has a history of more severe DD, behavioral problems, dysmorphic features, and congenital anomalies. Subsequently, karyotype confirmed two different unbalanced translocations in the siblings: 46,XX,der(4)t(4;10)(q33;p15.1) and 46,XY,der(10)t(4;10)(q33;p15.1), respectively. These chromosomal rearrangements represent two possible outcomes from a parent who is a carrier for a balanced translocation 46,XX,t(4;10)(q33;p15.1). CONCLUSION: To our knowledge, this 4q and 10p translocation has not been described in literature. In this report we compare clinical features due to the composite effects of partial monosomy 4q with partial trisomy 10p and partial trisomy 4q with partial monosomy 10p. These findings speak to the relevance of old and new genomic testing, the viability of these segregation outcomes, and need for genetic counseling.
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Transtornos Cromossômicos , Deficiência Intelectual , Humanos , Masculino , Feminino , Adulto , Deleção Cromossômica , Trissomia/genética , Deficiência Intelectual/genética , Transtornos Cromossômicos/genética , Translocação Genética , Aberrações CromossômicasRESUMO
Importance: College students in the US have been heavily affected by the COVID-19 pandemic. In addition to increased rates of depression and anxiety, college students have faced unprecedented stressors, such as geographic relocation and abrupt conversion from in-person classes to online classes. Objective: To study the association between course delivery model and psychological distress among US college students. Design, Setting, and Participants: This cross-sectional analysis used national data from the American College Health Association-National College Health Assessment III data set. Data were gathered from a web-based survey administered from January to early June 2021 to full-time US college students attending 4-year programs. Exposure: Course delivery model was self-reported. Main Outcomes and Measures: Psychological distress was measured using the Kessler Screening Scale for Psychological Distress. Results: This study evaluated 59â¯250 full-time undergraduate students (68.1% women; 51.5% White students; mean [SD] age, 21.2 [4.3] years); 3.5% attended fully in-person classes, 61.2% attended fully online classes, and 35.3% attended a mixed format of in-person and online classes. Students who attended classes fully online reported higher levels of psychological distress than those who attended a mix of online and in-person classes (b = 0.76 [99% CI, 0.64-0.88]; P < .001). This association remained significant after controlling for geographic region, year in school, gender, race and ethnicity, food security, current anxiety and/or depressive disorders, COVID-19 concerns, and residence (living on campus, off campus with family, or other off-campus arrangements) (b = 0.18 [99% CI, 0.04-0.31]; P = .001), as well as time spent socializing with friends (b = 0.13 [99% CI, 0.002-0.26]; P = .009). Conclusions and Relevance: The findings of this study suggest that mental health professionals may wish to consider the association of course delivery models with mental health outcomes when working with college students. Colleges should be aware of the mental health burden associated with attending fully online classes and consider possible in-person components and supports for students.
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COVID-19 , Angústia Psicológica , Humanos , Feminino , Adulto Jovem , Adulto , Masculino , COVID-19/epidemiologia , Estudos Transversais , Pandemias , UniversidadesRESUMO
Isoproterenol (ISO), is a non-selective beta-adrenergic agonist, that is used widely to induce cardiac injury in mice. While the acute model mimics stress-induced cardiomyopathy, the chronic model, administered through an osmotic pump, mimics advanced heart failure in humans. The purpose of the described protocol is to create the chronic ISO-induced heart failure model in mice using an implanted mini-pump. This protocol has been used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation are described in detail and may be relevant to anyone interested in creating a heart failure model in mice. In addition, the weekly cardiac remodeling changes based on echocardiographic parameters for each strain and expected time to model development are presented. In summary, the method is simple and reproducible. Continuous ISO administered via the implanted mini-pump over 3 to 4 weeks is sufficient to induce cardiac remodeling. Finally, the success for ISO model creation may be assessed in vivo by serial echocardiography demonstrating hypertrophy, ventricular dilation, and dysfunction.
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Insuficiência Cardíaca/induzido quimicamente , Isoproterenol/administração & dosagem , Implantação de Prótese , Agonistas Adrenérgicos beta/farmacologia , Anestesia , Animais , Modelos Animais de Doenças , Ecocardiografia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Masculino , Camundongos , OsmoseRESUMO
Isoproterenol is used widely for inducing heart failure in mice. Isoproterenol is a nonselective beta-adrenergic agonist. The acute model mimics stress-induced cardiomyopathy. The chronic model mimics advanced heart failure in humans. In this chapter, we describe a protocol that we used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation and echocardiography are described in detail. We also discuss the impact of drug dosage, duration, mortality, age, gender, and strain on cardiac remodeling responses. The success of model creation may be assessed by echocardiogram or molecular markers. This chapter may be relevant to those who are interested in using this heart failure model.
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Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/instrumentação , Insuficiência Cardíaca/induzido quimicamente , Isoproterenol , Animais , Ecocardiografia/métodos , Feminino , Insuficiência Cardíaca/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Miocárdio/patologia , Osmose , Remodelação Ventricular/efeitos dos fármacosRESUMO
A traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100 + strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). We find that genes whose expression fold-change correlates in a statistically significant way with the severity of the disease are either up or down-regulated across strains, and therefore missed by a traditional population-wide analysis of differential gene expression. Furthermore, those "fold-change" genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome. We validate our approach by showing that the knockdown of Hes1, predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80-90% in neonatal rat ventricular myocytes. Our results demonstrate that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies.
RESUMO
We describe a simple bioinformatics method for biomarker discovery that is based on the analysis of global transcript levels in a population of inbred mouse strains showing variation for disease-related traits. This method has advantages such as controlled environment and accessibility to heart and plasma tissue in the preclinical selection stage. We illustrate the approach by identifying candidate heart failure (HF) biomarkers by overlaying mouse transcriptome and clinical traits from 91 Hybrid Mouse Diversity Panel (HMDP) inbred strains and human HF transcriptome from the Myocardial Applied Genomics Network (MAGNet) consortium. We found that some of the top differentially expressed genes correlated with known human HF biomarkers, such as galectin-3 and tissue inhibitor of metalloproteinase 1. Using ELISA assays, we investigated one novel candidate, Glycoprotein NMB, in a mouse model of chronic ß-adrenergic stimulation by isoproterenol (ISO) induced HF. We observed significantly lower GPNMB plasma levels in the ISO model compared to the control group (p-value = 0.007). In addition, we assessed GPNMB plasma levels among 389 HF cases and controls from the METabolic Syndrome In Men (METSIM) study. Lower levels of GPNMB were also observed in patients with HF from the METSIM study compared to non-HF controls (p-value < 0.0001). In summary, we have identified several candidate biomarkers for HF using the cardiac transcriptome data in a population of mice that may be directly relevant and applicable to human populations.
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Proteínas do Olho/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/metabolismo , Idoso , Animais , Biomarcadores/metabolismo , Biologia Computacional , Modelos Animais de Doenças , Feminino , Galectina 3/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Inibidor Tecidual de Metaloproteinase-1/genética , TranscriptomaRESUMO
We previously reported a genetic analysis of heart failure traits in a population of inbred mouse strains treated with isoproterenol to mimic catecholamine-driven cardiac hypertrophy. Here, we apply a co-expression network algorithm, wMICA, to perform a systems-level analysis of left ventricular transcriptomes from these mice. We describe the features of the overall network but focus on a module identified in treated hearts that is strongly related to cardiac hypertrophy and pathological remodeling. Using the causal modeling algorithm NEO, we identified the gene Adamts2 as a putative regulator of this module and validated the predictive value of NEO using small interfering RNA-mediated knockdown in neonatal rat ventricular myocytes. Adamts2 silencing regulated the expression of the genes residing within the module and impaired isoproterenol-induced cellular hypertrophy. Our results provide a view of higher order interactions in heart failure with potential for diagnostic and therapeutic insights.
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Proteínas ADAMTS/genética , Cardiomegalia/genética , Biologia de Sistemas/métodos , Proteínas ADAMTS/fisiologia , Animais , Cardiomegalia/induzido quimicamente , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Cardiotônicos/efeitos adversos , Catecolaminas/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Insuficiência Cardíaca/genética , Ventrículos do Coração/metabolismo , Isoproterenol/farmacologia , Camundongos , Camundongos Endogâmicos/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Remodelação Ventricular/genéticaRESUMO
Histoplasmosis is an endemic disease in many regions of the United States. Physicians must be aware of the clinical syndromes and take advantage of epidemiologic clues when diagnosing histoplasmosis pericarditis. Clinicians must also be familiar with the uses and limitations of a battery of serologic and mycologic tests. Finally, further clinical trials are needed to study the role of antifungal therapy in the treatment of histoplasmosis pericarditis.