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| March 31,2006 | Inflammatory Biomarkers in Acute Coronary Syndromes | |||||||||
| Acute coronary syndromes (ACS) are multifactorial and occur in response to inflammation, plaque rupture and subsequent thrombosis, progressive mechanical obstruction, and dynamic obstruction.1 Patients with ACS span a large spectrum of risk that progresses from unstable angina (UA) to non–STelevation myocardial infarction (NSTEMI) to ST-elevation myocardial infarction (STEMI). ECG findings and markers of myocyte necrosis are used to define the type of ACS and guide reperfusion strategy in ST-elevation myocardial infarction. For patients with non–ST-elevation (NSTE) ACS, however, a large degree of uncertainty remains regarding long-term risk and optimal secondary prevention for the individual patient. | ||||||||||
| March 30,2006 | Information Technology and Cancer Prevention | |||||||||
| Information technology is rapidly advancing and making its way into many primary care settings. The technology may provide the means to increase the delivery of cancer preventive services. The aim of this systematic review is to examine the literature on information technology impacts on the delivery of cancer preventive services in primary care offices. Thirty studies met our selection criteria. Technology interventions studied to date have been limited to some type of reminder to either patients or providers. Patient reminders have been mailed before appointments, mailed unrelated to an appointment, mailed after a missed appointment, or given at the time of an appointment. Telephone call interventions have not used technology to automate the calls. Provider interventions have been primarily computer-generated reminders at the time of an appointment. | ||||||||||
| March 29,2006 | Mediators of Chronic Obstructive Pulmonary Disease | |||||||||
| Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem that is now a leading cause of death. COPD is associated with a chronic inflammatory response, predominantly in small airways and lung parenchyma, which is characterized by increased numbers of macrophages, neutrophils, and T lymphocytes. The inflammatory mediators involved in COPD have not been clearly defined, in contrast to asthma, but it is now apparent that many lipid mediators, inflammatory peptides, reactive oxygen and nitrogen species, chemokines, cytokines, and growth factors are involved in orchestrating the complex inflammatory process that results in small airway fibrosis and alveolar destruction. | ||||||||||
| March 28,2006 | Cardiac Neurobiology of Nitric Oxide Synthases | |||||||||
| Nitric oxide (NO) is a potent modulator of cardiac and vascular regulation. Its role in cardiac-autonomic neural signaling has received much attention over the last decade because of the ability of NO to alter cardiac sympathovagal balance to favor more anti-arrhythmic states. Complexity and controversy have arisen, however, because of the numerous sources of NO in the brain, peripheral nerves, and cardiomyocytes, all of which are potential regulators of cardiac excitability and calcium signaling. This review addresses the integrative role of NO as a relatively ubiquitous signaling molecule with respect to cardiac neurobiology. The present idea, that divergent NO-signaling pathways from multiple sources within the heart and nervous system converge to modulate cardiac excitability and impact on morbidity and mortality in health and disease, is discussed. | ||||||||||
| March 27,2006 | Longevity Determinant Genes | |||||||||
| An idea I had for many years is the general concept that there might be specific genes that are important to govern an aging rate. That is, in spite of the vast complexity of the aging process itself, there may be a few key genes that play an important role in governing how fast the aging process itself takes place. Some data generated over the last few years seems to be consistent with the idea. But of course there is still a lot more work to be done. One of the questions is, how do we stand with that hypothesis? Of course, it would be great if it was true, because it would indicate it may not be too complicated to increase the expression of a few genes, like thyrodoxin genes or the expression of an ARE complex that really may play an important role. | ||||||||||
| March 26,2006 | Epigenetics and human disease: translating basic biology into clinical applications | |||||||||
| Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Research has shown that epigenetic mechanisms provide an "extra" layer of transcriptional control that regulates how genes are expressed. These mechanisms are critical components in the normal development and growth of cells. Epigenetic abnormalities have been found to be causative factors in cancer, genetic disorders and pediatric syndromes as well as contributing factors in autoimmune diseases and aging. In this review, we examine the basic principles of epigenetic mechanisms and their contribution to human health as well as the clinical consequences of epigenetic errors. In addition, we address the use of epigenetic pathways in new approaches to diagnosis and targeted treatments across the clinical spectrum. | ||||||||||
| March 25,2006 | Molecular Physiology of Cardiac Repolarization | |||||||||
| The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next impulse is generated. Myocardial action potentials reflect the sequential activation and inactivation of inward (Na+ and Ca2+) and outward (K+) current carrying ion channels. In different regions of the heart, action potential waveforms are distinct, owing to differences in Na+, Ca2+, and K+ channel expression, and these differences contribute to the normal, unidirectional propagation of activity and to the generation of normal cardiac rhythms. Changes in channel functioning, resulting from inherited or acquired disease, affect action potential repolarization and can lead to the generation of life-threatening arrhythmias. | ||||||||||
| March 24,2006 | Functional Genomics in Early Autoimmunity | |||||||||
| The molecular mechanisms initiating the autoimmune process in type 1 diabetes mellitus (T1DM) remain unknown, and studies aiming to address this question have been compromised by the difficulty of predicting the disease at an early age both in humans and in animal models. An additional hindrance in selecting individuals at an early age has been the complex genetic inheritance of autoimmune diabetes, implicating not only several genes but also environmental factors. We have previously demonstrated the predictive value of insulin autoantibodies (IAAs) at an early age, between three to five weeks in the NOD mouse. Animals positive for early appearance of IAAs (E-IAAs) develop autoimmune diabetes earlier. | ||||||||||
| March 23,2006 | MicroRNAs and endocrine biology | |||||||||
| microRNAs (miRNAs) are highly conserved, non-coding RNAs that powerfully regulate gene expression at the post-transcriptional level. These fascinating molecules play essential roles in many biological processes in mammals, including insulin secretion, B-cell development, and adipocyte differentiation. This review provides a general background regarding current knowledge about miRNA biogenesis and the potential contributions of these RNAs to endocrine function. | ||||||||||
| March 22,2006 | Vascular Endothelial Growth Factor and Angiogenesis | |||||||||
| Angiogenesis is a hallmark of wound healing, the menstrual cycle, cancer, and various ischemic and inflammatory diseases. A rich variety of proand antiangiogenic molecules have already been discovered. Vascular endothelial growth factor (VEGF) is an interesting inducer of angiogenesis and lymphangiogenesis, because it is a highly specific mitogen for endothelial cells. Signal transduction involves binding to tyrosine kinase receptors and results in endothelial cell proliferation, migration, and new vessel formation. In this article, the role of VEGF in physiological and pathological processes is reviewed. We also discuss how modulation of VEGF expression creates new therapeutic possibilities and describe recent developments in this field. | ||||||||||
| March 21,2006 | Lung Cancer Immunotherapy | |||||||||
| Recent insights into anti-tumor immunotherapy have led to a wave of clinical trials involving immunotherapy for lung cancer.Vaccines have evolved from nonspecific immune stimulants, like Bacillus Calmette-Guerin (BCG), to much more specific and potent strategies, some of which generate active immune responses against tumor-associated antigens. Understanding the mechanisms of anti-tumor immunity and identifying target antigens will likely improve these therapeutic strategies and provide them with a niche in the future of lung cancer therapy. | ||||||||||
| March 20,2006 | Stability Regulation of mRNA and the Control of Gene Expression | |||||||||
| Microarray technology has become highly valuable for identifying complex global changes in gene expression patterns. Standard techniques measure changes in total cellular poly(A) mRNA levels. The assumption that changes in gene expression as measured by these techniques are directly and well correlated with changes in rates of new gene synthesis form the basis of attempts to connect coordinated changes in gene expression with shared transcription regulatory elements. Yet systematic attempts at this approach remain difficult to demonstrate convincingly. One reason for this difficulty may result from the intricate convergence of both transcriptional and mRNA turnover events which, together, directly influence steady-state mRNA levels. | ||||||||||
| March 19,2006 | Multiple Stem Cell Populations Contribute to the Formation of the Myocardium | |||||||||
| Owing to the very rapid growth of the vertebrate embryo following fertilization, an efficient circulatory system needs to be established during the initial stages of development. For that reason, the first functional organ that develops in both the bird and mammalian embryo is the heart. Until recently, the narrative of cardiac development was portrayed in a straightforward manner, with all the myocardium in the mature heart being generated from the expansion of an original pool of myocardial cells present in the early gastrula. It is now known that the story of the developing myocardium is more dynamic, as it is comprises cellular components of multiple ancestries. The de novo addition of myocytes to the developing heart occurs at various points during embryogenesis, as cardiac muscle takes on new members by the absorption of cells that either reside in neighboring nonmuscle tissue or come into contact with the myocardium by entering the heart upon migration or via the circulation. | ||||||||||
| March 18,2006 | New imaging techniques for diagnosing coronary artery disease | |||||||||
| New tomographic cardiovascular imaging tests, such as intravascular ultrasonography (IVUS), coronary computed tomography (CT) angiography and magnetic resonance imaging (MRI), can be used to assess atherosclerotic plaques for the characterization and early staging of coronary artery disease (CAD). Although IVUS images have very high resolution capable of revealing very early preclinical CAD, it is an invasive technique used clinically only in conjunction with a coronary intervention. Multiple-slice coronary CT angiography, which is noninvasive, shows promise as a diagnostic method for CAD. New 64-slice cardiac CT technology has high accuracy for the detection of lesions obstructing more than 50% of the lumen, with sensitivity, specificity, and positive and negative predictive values all better than 90% in patients without known CAD. | ||||||||||
| March 17,2006 | Aging and Genome Maintenance | |||||||||
| Genomic instability in somatic cells has been implicated as a major stochastic mechanism of aging. Using a transgenic mouse model with chromosomally integrated lacZ mutational target genes, we found mutations to accumulate with age at an organ- and tissue-specific rate. Also the spectrum of age-accumulated mutations was found to differ greatly from organ to organ; while initially similar, mutation spectra of different tissues diverged significantly over the lifetime. To explain how genomic instability, which is inherently stochastic, can be a causal factor in aging, it is proposed that randomly induced mutations may adversely affect normal patterns of gene regulation, resulting in a mosaic of cells at various stages on a trajectory of degeneration, eventually resulting in cell death or neoplastic transformation. | ||||||||||
| March 16,2006 | New Approaches and Therapeutics Targeting Apoptosis in Disease | |||||||||
| Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. Presumably, even more important is a causative or contributing role of apoptosis to various human diseases. These include situations with unwanted cell accumulation (cancer) and failure to eradicate aberrant cells (autoimmune diseases) or disorders with an inappropriate loss of cells (heart failure, stroke, AIDS, neurodegenerative diseases, and liver injury). The past decade has witnessed a tremendous progress in the knowledge of the molecular mechanisms that regulate apoptosis and the mediators that either prevent or trigger cell death. | ||||||||||
| March 15,2006 | Heart Failure Disease Management | |||||||||
| Millions of dollars are being spent to identify new therapies to improve mortality and morbidity for the growing epidemic of patients sustaining heart failure. However, in clinical practice, these therapies are currently underused. To bridge the gap between proven therapies and clinical practice, the medical community has turned to disease management. Heart failure disease management interventions vary from vital-sign monitoring to multidisciplinary approaches involving a pharmacist, nutritionist, nurse practitioner, and physician. This review attempts to categorize these inventions based on location. We compared the published results from randomized, controlled trials of the following types of heart failure disease management interventions: inpatient, clinic visits, home visits, and telephone follow up. | ||||||||||
| March 14,2006 | Embryonic Stem Cells: Prospects for Developmental Biology and Cell Therapy | |||||||||
| Stem cells represent natural units of embryonic development and tissue regeneration. Embryonic stem (ES) cells, in particular, possess a nearly unlimited self-renewal capacity and developmental potential to differentiate into virtually any cell type of an organism. Mouse ES cells, which are established as permanent cell lines from early embryos, can be regarded as a versatile biological system that has led to major advances in cell and developmental biology. Human ES cell lines, which have recently been derived, may additionally serve as an unlimited source of cells for regenerative medicine. Before therapeutic applications can be realized, important problems must be resolved. | ||||||||||
| March 13,2006 | Targeted Genome Modification via Triple Helix Formation | |||||||||
| Triplex-forming oligonucleotides (TFOs) that can bind to duplex DNA in a sequence-specific manner are potential tools to achieve targeted gene modification. Initial studies demonstrated the ability of TFOs to deliver mutagenic agents in a DNA site-specific manner. It has also been found that TFOs can induce gene modification in chromosomal DNA via the effect of the triple helix itself. Gene modification with TFOs includes induced recombination between a DNA target and a donor DNA molecule, a process that allows a TFO to exert an effect at a distance from the third-strand binding site. | ||||||||||
| March 12,2006 | Metabolic Energetics and Genetics in the Heart | |||||||||
| From the first stages of differentiation in the embryo to the end of life, energy substrate metabolism and function are inextricably linked features of the heart. The principle of energy substrate metabolism is simple. For a given developmental stage and for a given environment, the heart oxidizes the most efficient fuel on the path to ATP. The “multitasking” of energy substrate metabolism in the heart entails more than the generation of reducing equivalents for oxidative phosphorylation of ADP in the respiratory chain. In the postnatal heart, substrate switching and metabolic flexibility are features of normal function. In the stressed heart, metabolic remodeling precedes, triggers, and sustains functional and structural remodeling. | ||||||||||
| March 11,2006 | Developmental Origins of the Metabolic Syndrome | |||||||||
| The “fetal” or “early” origins of adult disease hypothesis was originally put forward by David Barker and colleagues and stated that environmental factors, particularly nutrition, act in early life to program the risks for adverse health outcomes in adult life. This hypothesis has been supported by a worldwide series of epidemiological studies that have provided evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance, and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. It is also clear from experimental studies that a range of molecular, cellular, metabolic, neuroendocrine, and physiological adaptations to changes in the early nutritional environment result in a permanent alteration of the developmental pattern of cellular proliferation and differentiation in key tissue and organ systems that result in pathological consequences in adult life. | ||||||||||
| March 10,2006 | Src tyrosine kinase as a chemotherapeutic target | |||||||||
| Src tyrosine kinase was the first protooncogene described. It has been found to be overexpressed and activated in a large number of different cancers. Cellular Src has been shown to activate a number of different effectors that are involved in different aspects of cancer biology such as metastasis, cell cycle regulation and cell survival. Despite this, Src inhibitors have not entered the regular arsenal of chemotherapeutics. This article reviews some of the biology, rationale, in vitro and in vivo preclinical evidence, and some very early clinical trials demonstrating efficacy of Src inhibitors. | ||||||||||
| March 9,2006 | Immunoregulation of Dendritic Cells | |||||||||
| The paradigm of tolerogenic/immature versus inflammatory/mature dendritic cells has dominated the recent literature regarding the role of these antigen-presenting cells in mediating immune homeostasis or self-tolerance and response to pathogens, respectively. This issue is further complicated by the identification of distinct subtypes of dendritic cells that exhibit different antigen-presenting cell effector functions. The discovery of pathogen-associated molecular patterns and toll-like receptors provides the mechanistic basis for dendritic cell recognition of specific pathogens and induction of appropriate innate and adaptive immune responses. Only recently has insight been gained into how dendritic cells contribute to establishing and/or maintaining immunological tolerance to self. | ||||||||||
| March 8,2006 | Calcium Signaling in Cardiac Ventricular Myocytes | |||||||||
| Calcium (Ca) is a multifunctional regulator of diverse cellular functions. In cardiac muscle Ca is a direct central mediator of electrical activation, ion channel gating, and excitation–contraction (E-C) coupling that all occur on the millisecond time scale. The key amplification step in E-C coupling is under tight control of very local [Ca]. Ca also directly activates signaling via kinases and phosphatases (e.g., Ca-calmodulin-dependent protein kinase [CaMKII] and calcineurin) that occur over a longer time scale (seconds to minutes), and the co-localization of these Ca-dependent modulators to their targets and to Ca is also critical in distinct signaling pathways. | ||||||||||
| March 7,2006 | Screening for lung cancer | |||||||||
| Lung cancer remains the leading cause of cancer-related deaths in the world. At present, the only high rate of cure therapy is surgical resection at early stage of disease. Early detection could potentially decrease lung cancer mortality suggesting that this cancer should be a good candidate for screening. Results of trials involving chest X-ray, sputum cytology and low-dose computed tomography (CT) are discussed here. The latter tool offers advantages over chest X-ray, but final results from controlled well conducted trials are necessary before the real utility of CT mass screening can be determined. Further approaches to secondary prevention such as screening with positron emission tomography (PET), autofluorescence bronchoscopy and biomarkers hold great promise for the future. | ||||||||||
| March 6,2006 | balancing life and death — a new approach to cancer therapy | |||||||||
| IκB kinase/NF-κB (IKK/NF-κB) signaling pathways play critical roles in a variety of physiological and pathological processes. One function of NF-κB is promotion of cell survival through induction of target genes, whose products inhibit components of the apoptotic machinery in normal and cancerous cells. NF-κB can also prevent programmed necrosis by inducing genes encoding antioxidant proteins. Regardless of mechanism, many cancer cells, of either epithelial or hematopoietic origin, use NF-κB to achieve resistance to anticancer drugs, radiation, and death cytokines. Hence, inhibition of IKK-driven NF-κB activation offers a strategy for treatment of different malignancies and can convert inflammation-induced tumor growth to inflammation-induced tumor regression. | ||||||||||
| March 5,2006 | C-reactive protein comes of age | |||||||||
| Cardiovascular disease remains a leading cause of death throughout the world despite advances in its detection and treatment. Commonly used risk algorithms, such as the Framingham Risk Score fail to identify all affected individuals. Novel cardiovascular risk factors that identify these missed individuals would greatly improve overall care of patients. C-reactive protein (CRP), an inflammatory biomarker, has emerged as a leading candidate to fulfill this role. Based on the results of several prospective epidemiologic studies, CRP has emerged as one of the most powerful predictors of cardiovascular disease. This marker provides valuable information to clinicians in various clinical settings, ranging from overt cardiovascular disease, stable angina, presenting acute coronary syndromes and peripheral vascular disease, to the metabolic syndrome. | ||||||||||
| March 4,2006 | Engineering T cells for cancer therapy | |||||||||
| It is generally accepted that the immune system plays an important role in controlling tumour development. However, the interplay between tumour and immune system is complex, as demonstrated by the fact that tumours can successfully establish and develop despite the presence of T cells in tumour. An improved understanding of how tumours evade T-cell surveillance, coupled with technical developments allowing the culture and manipulation of T cells, has driven the exploration of therapeutic strategies based on the adoptive transfer of tumour-specific T cells. The isolation, expansion and re-infusion of large numbers of tumour-specific T cells generated from tumour biopsies has been shown to be feasible. Indeed, impressive clinical responses have been documented in melanoma patients treated with these T cells. | ||||||||||
| March 3,2006 | Selection of Biomarkers by a Multivariate Statistical Processing of Composite Metabonomic Data Sets Using Multiple Factor Analysis | |||||||||
| We introduce a statistical approach for integrating data from several analytical platforms. We illustrate this approach using 1H-13C Heteronuclear Multiple Bond Connectivity nuclear magnetic resonance spectroscopy (1H-13C HMBC NMR) and Pyrolysis Metastable Atom Bombardment Time-of-Flight mass spectrometry (Py-MAB-TOF-MS) to perform metabolic fingerprinting on cattle treated with anabolic steroids. Multiple factor analysis (MFA) integrates complementary aspects from NMR and MS data into a unique metabolic signature describing the biomarkers related to the dose-response. | ||||||||||
| March 2,2006 | Pharmacogenetics: the outlook for genetic testing in statin therapy | |||||||||
| High levels of LDL cholesterol and low levels of HDL cholesterol are major risk factors for atherosclerosis and are commonly managed by statins, drugs that inhibit HMG CoA reductase (3-hydroxy- 3- methylglutaryl coenzyme A; gene HMGCR). The primary consequence of statin therapy is diminished de novo synthesis of cholesterol, stimulating cholesterol uptake into the cell from the plasma, which leads to large reductions in LDL cholesterol and modest elevations in HDL cholesterol. Statins are believed to have other pleiotropic effects that independently decrease the risk of atherosclerotic plaque rupture and cardio vascular disease, such as the reduction of systemic inflammation by as yet unknown mechanisms. | ||||||||||
| March 1,2006 | The role of peroxisome proliferator-activated receptor-β/δ in epithelial cell growth and differentiation | |||||||||
| The physiological and pharmacological roles of peroxisome proliferator-activated receptor-β (PPARβ-also referred to as PPARδ) are just beginning to emerge. It has recently become clear that PPARβ has a function in epithelial tissues, but controversy exists due to inconsistencies in the literature. There is strong evidence that ligand activation of PPARβ can induce terminal differentiation of keratinocytes, with a concomitant inhibition of cell proliferation. However, the role of PPARβ in keratinocyte-specific apoptosis is less clear. Additionally, the role of PPARβ in colonic epithelium remains unclear due to conflicting evidence suggesting that ligand activation of PPARβ can potentiate, as well as attenuate, intestinal cancer. |
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