Showing papers by "Joseph Loscalzo published in 2014"

Keshan disease, selenium deficiency, and the selenoproteome.

Abstract: Investigation of a muscle disease in animals and a cluster of cases of cardiomyopathy in a region of China led to the elucidation of a central role for selenoproteins in human health.

Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series)

Abstract: Epigenetics refers to heritable traits that are not a consequence of DNA sequence. Three classes of epigenetic regulation exist: DNA methylation, histone modification, and noncoding RNA action. In the cardiovascular system, epigenetic regulation affects development, differentiation, and disease propensity or expression. Defining the determinants of epigenetic regulation offers opportunities for novel strategies for disease prevention and treatment.

DiseaseConnect: a comprehensive web server for mechanism-based disease–disease connections

Abstract: The DiseaseConnect (http://disease-connect.org )i s a web server for analysis and visualization of a comprehensive knowledge on mechanism-based disease connectivity. The traditional disease classification system groups diseases with similar clinical symptoms and phenotypic traits. Thus, diseases with entirely different pathologies could be grouped together, leading to a similar treatment design. Such problems could be avoided if diseases were classified based on their molecular mechanisms. Connecting diseases with similar pathological mechanisms could inspire novel strategies on the effective repositioning of existing drugs and therapies. Although there have been several studies attempting to generate disease connectivity networks, they have not yet utilized the enormous and rapidly growing public repositories of disease-related omics data and literature, two primary resources capable of providing insights into disease connections at an unprecedented level of detail. Our DiseaseConnect, the first public web server, integrates comprehensive omics and literature data, including a large amount of gene expression data, Genome-Wide Association Studies catalog, and text-mined knowledge, to discover disease–disease connectivity via common molecular mechanisms. Moreover, the clinical comorbidity data and a comprehensive compilation of known drug– disease relationships are additionally utilized for advancing the understanding of the disease landscape and for facilitating the mechanism-based development of new drug treatments.

Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis

Abstract: Background—The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension, suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in pulmonary arterial hypertension. Methods and Results—Patients with pulmonary arterial hypertension, rats with Sugen/hypoxia–pulmonary arterial hypertension, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia–StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldoste...

Plasma levels of the proinflammatory chitin-binding glycoprotein YKL-40, variation in the chitinase 3-like 1 gene (CHI3L1), and incident cardiovascular events.

Abstract: Background YKL-40, encoded by the chitinase 3-like 1 ( CHI3L1 ) gene, is a chitinase-like protein involved in innate immune function hypothesized to play a role in the progression of atherosclerosis that may have differential roles in myocardial infarction (MI), as compared to stroke. Methods and Results In a nested case-control study conducted within a prospective cohort of 23 294 initially healthy women of European ancestry, we (1) measured plasma concentration of YKL-40 among 359 participants who subsequently developed cardiovascular events and among 359 age-, smoking-, and hormone replacement therapy–matched participants who remained free of disease during 17 years of follow-up, (2) compared effects of YKL-40 on vascular risk to that associated with 3 alternative inflammatory biomarkers (high-sensitivity C-reactive protein) ([hsCRP], soluble intracellular adhesion molecule 1, and fibrinogen), and (3) evaluated the role of 41 single-nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 gene ( CHI3L1 ) as determinants of YKL-40 levels and incident vascular events. YKL-40 levels were higher in women with hypertension, diabetes, and obesity and correlated modestly with high-density lipoprotein cholesterol, triglycerides, and hsCRP, but not with low-density lipoprotein cholesterol. Baseline YKL-40 level was significantly associated with incident thromboembolic stroke with a magnitude of effect (a 40% per quartile increase in odds ratio [OR], P =0.019) comparable to that of hsCRP (a 52% per quartile increase in OR, P =0.006). By contrast, no significant association was observed between YKL-40 and incident MI. Genetic variation in CHI3L1 was strongly associated with YKL-40 levels; however, in this sample set, we did not observe a statistically significant association between genotype and future vascular events. Conclusions Among initially healthy U.S. women, plasma levels of the proinflammatory chitenase-like protein, YKL-40, were influenced by environmental as well as genetic factors and predicted incident thromboembolic stroke, but not MI, a differential effect consistent with limited previous data.

Analyzing networks of phenotypes in complex diseases: methodology and applications in COPD.

Abstract: The investigation of complex disease heterogeneity has been challenging. Here, we introduce a network-based approach, using partial correlations, that analyzes the relationships among multiple disease-related phenotypes. We applied this method to two large, well-characterized studies of chronic obstructive pulmonary disease (COPD). We also examined the associations between these COPD phenotypic networks and other factors, including case-control status, disease severity, and genetic variants. Using these phenotypic networks, we have detected novel relationships between phenotypes that would not have been observed using traditional epidemiological approaches. Phenotypic network analysis of complex diseases could provide novel insights into disease susceptibility, disease severity, and genetic mechanisms.

Polymorphisms in Catechol-O-Methyltransferase Modify Treatment Effects of Aspirin on Risk of Cardiovascular Disease

Abstract: Objective— Catechol- O -methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD. Approach and Results— We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women’s Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51–0.84]; P =0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P =2.4×10 −5 ). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05–3.25]; P =0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39–0.93]; P =0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83–2.70]; P =0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34–0.84]; P =0.006) women. Rs4818 results were similar. Conclusions— Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.

Hypoxamirs and mitochondrial metabolism.

Abstract: Significance: Chronic hypoxia can drive maladaptive responses in numerous organ systems, leading to a multitude of chronic mammalian diseases. Oxygen homeostasis is intimately linked with mitochondrial metabolism, and dysfunction in these systems can combine to form the backbone of hypoxic-ischemic injury in multiple tissue beds. Increased appreciation of the crucial roles of hypoxia-associated miRNA (hypoxamirs) in metabolism adds a new dimension to our understanding of the regulation of hypoxia-induced disease. Recent Advances: Myriad factors related to glycolysis (e.g., aldolase A and hexokinase II), tricarboxylic acid cycle function (e.g., glutaminase and iron-sulfur cluster assembly protein 1/2), and apoptosis (e.g., p53) have been recently implicated as targets of hypoxamirs. In addition, several hypoxamirs have been implicated in the regulation of the master transcription factor of hypoxia, hypoxia-inducible factor-1α, clarifying how the cellular program of hypoxia is sustained and resolve...

A Celebration of Failure

Abstract: > Every failure is a step to success. Every detection of what is false directs us toward what is true: every trial exhausts some tempting form of error. Not only so; but scarcely any attempt is entirely a failure; scarcely any theory, the result of steady thought, is altogether false; no tempting form of Error is without some latent charm derived from Truth. > > —W. Whewell1 Contemporary society cherishes success. Success defines the person, the organization, the culture. It is a clear goal for every initiative that has an outcome. It is a gauge by which one measures impact, influence, and consequence. Success is defined as much by tangible achievement of a predefined goal as it is by its polar opposite, failure. The commonly held view is that failure is to be avoided because success is to be achieved, and both cannot coexist. In this editorial, I will dwell on failure and make the case that failure has at least as important a role in our experience, education, and professional development as success, if we would only learn from it. We are first exposed to the concept of failure in elementary school, quickly realizing how it can affect our educational progress. My generation of students lived in fear of failing tests, subjects, and ultimately, grades, thereby being left behind to repeat the school year. This early, first experience with failure obviously colors our perception of the concept with great negativity. Defined in this way, failure is simply the opposite of success, a notion that sets the stage for the role of failure and its interpretation throughout one’s life. This is particularly true for physicians and scientists, who, as consummate overachievers, strive to succeed and implicitly strive to avoid failure with each challenge. Nothing but perfection will suffice because failure renders our …

Network-based association of hypoxia-responsive genes with cardiovascular diseases

Abstract: Molecular oxygen is indispensable for cellular viability and function. Hypoxia is a stress condition in which oxygen demand exceeds supply. Low cellular oxygen content induces a number of molecular changes to activate regulatory pathways responsible for increasing the oxygen supply and optimizing cellular metabolism under limited oxygen conditions. Hypoxia plays critical roles in the pathobiology of many diseases, such as cancer, heart failure, myocardial ischemia, stroke, and chronic lung diseases. Although the complicated associations between hypoxia and cardiovascular (and cerebrovascular) diseases (CVD) have been recognized for some time, there are few studies that investigate their biological link from a systems biology perspective. In this study, we integrate hypoxia genes, CVD genes, and the human protein interactome in order to explore the relationship between hypoxia and cardiovascular diseases at a systems level. We show that hypoxia genes are much closer to CVD genes in the human protein interactome than that expected by chance. We also find that hypoxia genes play significant bridging roles in connecting different cardiovascular diseases. We construct a hypoxia-CVD bipartite network and find several interesting hypoxia-CVD modules with significant gene ontology similarity. Finally, we show that hypoxia genes tend to have more CVD interactors in the human interactome than in random networks of matching topology. Based on these observations, we can predict novel genes that may be associated with CVD. This network-based association study gives us a broad view of the relationships between hypoxia and cardiovascular diseases and provides new insights into the role of hypoxia in cardiovascular biology.

A division of medical communications in an academic medical center's department of medicine.

Abstract: Excellent physician communication skills (physician-to-patient and patient-to-physician) have been found to have a positive impact on patient satisfaction and may positively affect patient health behaviors and health outcomes. Such skills are also essential for accurate, succinct, and clear peer-to-peer (physician-to-physician), physician-to-lay-public, and physician-to-media communications. These skills are not innate, however; they must be learned and practiced repeatedly. The Division of Medical Communications (DMC) was created within the Department of Medicine at Brigham and Women's Hospital as an intellectual home for physicians who desire to learn and teach the wide variety of skills needed for effective communication.In this Perspective, the authors provide an overview of the key types of medical communications and share the DMC model as an innovative approach to providing expert guidance to physicians and physicians-in-training as they develop, practice, and refine their communication skills. Current DMC projects and programs include a Volunteer Patient Teaching Corps, which provides feedback to medical students, residents, and faculty on communication skills; a controlled trial of a modified team-based learning method for attending rounds; expert coaching in preparation for presentations of all types (e.g., grand rounds; oral presentations or poster presentations on basic science, clinical, or medical education research); sessions on speaking to the media and running a meeting well; and courses on writing for publication. Objective assessment of the impact of each of these interventions is planned.

Clinical problem-solving. Out of the blue.

Abstract: Copyright © 2014 Massachusetts Medical Society. A 55-year-old man with a history of heart failure presented to the emergency department with pain and swelling in his right foot and leg. Three days before presentation, he noted a sudden onset of swelling in the right foot and calf, without any prior trauma. The swelling worsened progressively, extending to the upper leg, and was accompanied by pain in the foot and calf. He doubled his usual dose of torsemide, with no effect. On the day of presentation, he noted new dusky discoloration of the toes on his right foot.

Real-time assessment of the metabolic profile of living cells with genetically encoded NADH sensors.

Abstract: Redox metabolism plays a critical role in multiple pathophysiological settings, including oncogenesis and tumor progression. Until recently, however, our knowledge of key redox processes in living systems was limited by the lack of an adequate methodology to monitor redox potential. Nicotinamide adenine dinucleotide, in its reduced (NADH) and oxidized (NAD+) forms, is perhaps the most important small molecule in the redox metabolism of mammalian cells. We have previously developed a series of genetically encoded fluorescent sensors allowing for the quantification of intracellular NADH. Here, we present experimental components and considerations that are required to perform a standardized quantification of intracellular NADH based on these probes. Moreover, we present the initial calibration experiments necessary to obtain reliable data from this approach, we detail a protocol to measure intracellular NADH levels in steady-state kinetic experiments, and we provide consideration on the processing of data. Among various applications, this technique is suitable for the study of redox alterations in malignant cells.

Clinical problem-solving. Wasting away.

Abstract: Copyright © 2014 Massachusetts Medical Society. A 40-year-old woman presented to the emergency department with pain, weakness, and fatigue. During the 3 months before presentation, she noted the gradual onset of bilateral diffuse flank pain that spread to her lower back, abdomen, and both arms and legs. The pain was worse with movement, and she eventually became homebound. She had been unable to walk without assistance for the preceding 2 weeks. There were no other aggravating or relieving factors. The patient also reported poor appetite and reduced food intake and had lost approximately 4 kg. Nausea developed 2 days before presentation, and the patient became unable to take anything by mouth, which prompted her to seek evaluation. She reported no fevers, chills, vomiting, diarrhea, or other symptoms.

Quantitative imaging of selenoprotein with multi-isotope imaging mass spectrometry (MIMS)

Abstract: Multi-isotope imaging mass spectrometry (MIMS) allows high resolution quantitative imaging of protein and nucleic acid synthesis at the level of a single cell using stable isotope labels. We employed MIMS to determine the compartmental localization of selenoproteins tagged with stable isotope selenium compounds in human aortic endothelial cells (HAEC), and to compare the efficiency of labeling (to determine the ideal selenium source) from these compounds: [82Se]-selenite, [77Se]-seleno-methionine, and [76Se]-methyl-selenocysteine. We found that all three selenium sources appear to be localized in the nucleus as well as in the cytoplasm in HAEC. Seleno-methionine appears to be a better source for (seleno)protein synthesis. For MIMS detection, we compared freeze-drying to thin layer vs. thin sectioning for sample preparation. MIMS provides a unique and novel way to dissect selenoprotein synthesis in cells.

CLINICAL PROBLEM-SOLVING. A Man with Fever, Cough, and Rash.

Abstract: A 67-year-old man with hairy-cell leukemia presented to the clinic after 3 days of fevers, night sweats, arthralgias, and an erythematous vesicular-appearing rash on his back. He had not had headache, shortness of breath, bleeding episodes, vomiting, or diarrhea.

Against the Grain

Abstract: A 42-year-old man with a history of coronary artery disease presented to the emergency department with left-upper-quadrant abdominal pain that radiated to his back and along the subcostal margin. He also reported substernal chest pressure similar to his usual angina.

Stanching the Flow: The Evolution of Vertebrate Blood Clotting by Russell F. Doolittle (2012)

Abstract: Hemostasis is an essential physiological response to acute injury in organisms with a circulatory system. In the Darwinian struggle that drove early natural selection, only creatures that were capable of limiting blood loss could survive wounds or injuries that breeched a vessel. Vertebrates, from hagfish to primates, suffer acute injuries that would lead to exsanguination were adequate hemostasis not in place. The clotting of blood in response to injury is a primordial\\ but highly efficient and complex affair, the analysis of which remains a challenge.

A Tight Predicament

Abstract: A 27-year-old primigravid woman at 25 weeks 5 days of gestation presented to the emergency department in respiratory distress. One day earlier, a cough producing blood-tinged, frothy sputum had developed and worsened. She also noted shortness of breath and chest pain.

Clinical problem-solving. A chilly fever.

Abstract: Copyright © 2014 Massachusetts Medical Society. A 30-year-old graduate student presented to the emergency department in March reporting fevers associated with shaking chills and severe headaches. He had been well until 1 week before presentation, when he began to have daily fevers, with temperatures as high as 103.0°F (39.4°C) and with associated chills, nausea, and headaches. The fevers were most notable in the evening; by morning, the patient was afebrile and felt well enough to attend class. He had been taking acetaminophen, without symptom relief.