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| December 31, 2006 | Drugs, their targets and the nature and number of drug targets | |||||||||||||||||||
| What is a drug target? And how many such targets are there? Here, we consider the nature of drug targets, and by classifying known drug substances on the basis of the discussed principles we provide an estimation of the total number of current drug targets.Estimations of the total number of drug targets are presently dominated by analyses of the human genome, which are limited for various reasons, including the inability to infer the existence of splice variants or interactions between the encoded proteins from gene sequences alone, and the fact that the function of most of the DNA in the genome remains unclear. | ||||||||||||||||||||
| December 30, 2006 | PAI-1 and the Metabolic Syndrome | |||||||||||||||||||
| The link between plasminogen activator inhibitor (PAI)-1 and the metabolic syndrome with obesity was established many years ago. Increased PAI-1 level can be now considered a true component of the syndrome. The metabolic syndrome is associated with an increased risk of developing cardiovascular disease, and PAI-1 overexpression may participate in this process. The mechanisms of PAI-1 overexpression during obesity are complex, and it is conceivable that several inducers are involved at the same time at several sites of synthesis. Interestingly, recent in vitro and in vivo studies showed that besides its role in atherothrombosis, PAI-1 is also implicated in adipose tissue development and in the control of insulin signaling in adipocytes. | ||||||||||||||||||||
| December 29, 2006 | Natriuretic peptides in the diagnosis and management of heart failure | |||||||||||||||||||
| The natriurtic peptides are a family of related hormones that play a cruial role in cardiovascular homeostasis.They have recently emerged as potentially important clinical markers in heart failure.Recent data have suggested an important role for these markers in establishing the diagnosis of heart failure in patients with unexplained dyspnea in both acute care and ambulatory settings.Other clinical uses of the natriuretic peptides,such as screening for asymptomatic ventricular dyfunction,establishing prognsis or guiding titration of drug therapy,are under investigation but have not yet sufficiently been validated for widespread clinical use. | ||||||||||||||||||||
| December 28, 2006 | Leukocyte–endothelial cell interactions | |||||||||||||||||||
| Leukocytes constantly patrol the vascular system in order to react promptly to infections when and where it is necessary. To fulfil this task, the cells have to enter secondary lymphoid organs and to emigrate into inflamed tissues, which requires them to cross the barrier of endothelial cells that line blood vessels. Transendothelial migration into inflamed tissues is preceded by a sequence of leukocyte–endothelial cell interactions, generally referred to as the ‘multistep adhesion cascade’. The cascade is initiated by inflammatory signals that cause local activation of vascular endothelium. | ||||||||||||||||||||
| December 27, 2006 | FXR, a multipurpose nuclear receptor | |||||||||||||||||||
| The farnesoid X receptor (FXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. In the past six years, remarkable inroads have been made into determining the functional importance of FXR. This receptor has been shown to have crucial roles in controlling bile acid homeostasis, lipoprotein and glucose metabolism, hepatic regeneration, intestinal bacterial growth and the response to hepatotoxins. Thus, the development of FXR agonists might prove useful for the treatment of diabetes, cholesterol gallstones, and hepatic and intestinal toxicity. | ||||||||||||||||||||
| December 26, 2006 | Principles of microRNA regulation of a human cellular signaling network | |||||||||||||||||||
| MicroRNAs (miRNAs) are endogenous B22-nucleotide RNAs, which suppress gene expression by selectively binding to the 30-noncoding region of specific messenger RNAs through base-pairing. Given the diversity and abundance of miRNA targets, miRNAs appear to functionally interact with various components of many cellular networks. By analyzing the interactions between miRNAs and a human cellular signaling network, we found that miRNAs predominantly target positive regulatory motifs, highly connected scaffolds and most downstream network components such as signaling transcription factors, but less frequently target negative regulatory motifs, common components of basic cellular machines and most upstream network components such as ligands. | ||||||||||||||||||||
| December 25, 2006 | The pathophysiology of myocardial reperfusion: a pathologist’s perspective | |||||||||||||||||||
| Coronary artery thrombosis, caused either by fissuring or erosion of atherosclerotic plaques, is the usual cause of acute myocardial infarction.1 If a coronary occlusion persists for more than 30 minutes, irreversible damage to the myocardium occurs. Persistent coronary occlusion results in a progressive increase of the infarct size with a wave-front transmural extension from the endocardium towards the epicardium.2 3 Although reperfusion can occur spontaneously, thrombotic coronary artery occlusion persists in the majority of patients suffering an acute myocardial infarction. Thus, timely coronary artery recanalisation and myocardial reperfusion, either by thrombolytic therapy or primary angioplasty and/or stenting, represents the most effective way of restoring the balance between myocardial oxygen supply and demand. Prevention of myocardial cell necrosis by the restoration of blood flow depends on the severity and duration of pre-existing myocardial ischaemia. | ||||||||||||||||||||
| December 24, 2006 | Epidemiology and antibiotic treatment of infective endocarditis | |||||||||||||||||||
| The epidemiological profile of infective endocarditis (IE) has changed dramatically over the last few years.1 Once a disease affecting young adults with previously well-identified valve disease—mostly rheumatic disease—IE is now affecting older patients, a significant proportion of whom has no previously known valve disease and develop IE as the result of healthcare associated procedures.2 | ||||||||||||||||||||
| December 23, 2006 | Mechanism of homologous recombination: mediators and helicases take on regulatory functions | |||||||||||||||||||
| Homologous recombination (HR) is an important mechanism for the repair of damaged chromosomes, for preventing the demise of damaged replication forks, and for several other aspects of chromosome maintenance. As such, HR is indispensable for genome integrity, but it must be regulated to avoid deleterious events. Mutations in the tumoursuppressor protein BRCA2, which has a mediator function in HR, lead to cancer formation. DNA helicases, such as Bloom’s syndrome protein (BLM), regulate HR at several levels, in attenuating unwanted HR events and in determining the outcome of HR. Defects in BLM are also associated with the cancer phenotype. The past several years have witnessed dramatic advances in our understanding of the mechanism and regulation of HR. | ||||||||||||||||||||
| December 22, 2006 | Choices for Good Health: American Cancer Society Guidelines for Nutrition and Physical Activity for Cancer Prevention | |||||||||||||||||||
| And healthy communities can help us make the right choices. After reviewing the scientific evidence, the American Cancer Society (ACS) has confirmed that maintaining a healthy weight, being physically active, and eating a healthy diet can help prevent cancer. And you can start to eat smarter and be more active at any time—from childhood to old age. No matter when you start, you’ll begin to be healthier and reduce your cancer risk. This set of guidelines for nutrition, physical activity, and cancer prevention was developed to help you make choices that may reduce your risk of cancer, and to promote healthy changes where you live, work, and play. | ||||||||||||||||||||
| December 21, 2006 | Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis | |||||||||||||||||||
| Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodeling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. To study the direct consequences of VSMC apoptosis, we generated transgenic mice expressing the human diphtheria toxin receptor (hDTR, encoded by HBEGF) from a minimal Tagln promoter. Despite apoptosis inducing loss of 50–70% of VSMCs, normal arteries showed no inflammation, reactive proliferation, thrombosis, remodeling or aneurysm formation. | ||||||||||||||||||||
| December 20, 2006 | Cytokines and Hematopoietic Stem Cell Mobilization | |||||||||||||||||||
| Hematopoietic stem cell transplantation (HSCT) has become the standard of care for the treatment of many hematologic malignancies, chemotherapy sensitive relapsed acute leukemias or lymphomas, multiple myeloma; and for some non-malignant diseases such as aplastic anemia and immunodeficient states. The hematopoietic stem cell (HSC) resides in the bone marrow (BM). A number of chemokines and cytokines have been shown in vivo and in clinical trials to enhance trafficking of HSC into the peripheral blood. This process, termed stem cell mobilization, results in the collection of HSC via apheresis for both autologous and allogeneic transplantation. Enhanced understanding of HSC biology, processes involved in HSC microenvironmental interactions and the critical ligands, receptors and cellular proteases involved in HSC homing and mobilization, with an emphasis on G-CSF induced HSC mobilization, form the basis of this review. | ||||||||||||||||||||
| December 19, 2006 | Designing Nonviral Vectors for Efficient Gene Transfer and Long-Term Gene Expression | |||||||||||||||||||
| Although the genetic therapy of human diseases has been conceptually possible for many years we still lack a vector system that allows safe and reproducible genetic modification of eukaryotic cells and ensures faithful long-term expression of transgenes. There is increasing agreement that vectors that are based exclusively on chromosomal elements, which replicate autonomously in human cells, could fulfill these criteria. The rational construction of such vectors is still hindered by our limited knowledge of the factors that regulate chromatin function in eukaryotic cells. This review sets out to summarize how our current knowledge of nuclear organization can be applied to the design of extrachromosomal gene expression vectors that can be used for human gene therapy. | ||||||||||||||||||||
| December 18, 2006 | Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification | |||||||||||||||||||
| Vascular smooth muscle cells (VSMCs) exhibit an extraordinary capacity to undergo phenotypic change during development, in vitro and in association with disease. Unlike other muscle cells they do not terminally differentiate. Development and maintenance of the mature contractile phenotype is regulated by a number of interacting transcription factors.Iyemere VP, Proudfoot D, Weissberg PL, Shanahan CM. (University of Cambridge, UK). Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification (Review). | ||||||||||||||||||||
| December 17, 2006 | Molecular screening of gastric cancer by proteome analysis | |||||||||||||||||||
| Gastric cancer affects annually more than 800 000 individuals worldwide and remains a challenge for clinicians and oncologists. Most patients with gastric cancer are diagnosed in advanced stages, when a curative resection is impossible, which leads to an overall poor prognosis. Finding new diagnostic and treatment procedures is of paramount importance to improve patient prognosis, which will be improved most dramatically by techniques that allow the detection of gastric cancer in its early stages. So far the value of conventional tumour markers such as Ca72-4 or carcinoembryonic antigen is limited, and even markers developed from molecular biological studies on the carcinogenesis of gastric cancer, such as E-cadherin and others, have not proved to be of adequate sensitivity and specificity to allow the early detection of gastric cancer. | ||||||||||||||||||||
| December 16, 2006 | The genetics of the amyloidoses: interactions with immunity and inflammation | |||||||||||||||||||
| Historically, the amyloidoses have been associated with inflammation and the immune response. From Virchow’s original description in human pathologic inflammatory states through their identification in horses used to produce antitoxin to their frequent occurrence in the course of multiple myeloma and a somewhat abortive designation as ‘gammaloid’, the disorders were felt to have an inflammatory origin. These presumptive associations antedated the availability of a reliable method for tissue extraction that would allow chemical analysis of the major deposited molecules. With the identification of the multiple precursors and the realization that most were not intrinsic elements of immune/inflammatory pathways, the investigative emphasis shifted to the analysis of the biophysical events involved in aggregation and fibril formation. | ||||||||||||||||||||
| December 15, 2006 | Gene-Specific Mechanisms of p53 Transcriptional Control and Prospects for Cancer Therapy | |||||||||||||||||||
| The regulation of gene-specific activation is critical to the tumor suppressor function by p53. p53 is a wellcharacterized transcription factor that responds to DNA damage and other genotoxic stresses by the activation of downstream targets that are involved with repair, differentiation, senescence, growth arrest, and apoptosis. Sequencespecific binding to DNA, conformation, post-translational modifications, cofactor binding, stability, and subcellular localization all influence the performance of p53. The purpose of this review is to define features that play a key role in gene-specific activation and to show that these are often incapacitated in cancer cells. Using such knowledge to design selective strategies for the restoration of p53 wild-type function in cancer cells represents a promising cancer therapy. | ||||||||||||||||||||
| December 14, 2006 | Proteome analysis to study signal transduction of G protein-coupled receptors | |||||||||||||||||||
| G protein-coupled receptors (GPCR) play an important role in drug development. Although many classical signal transduction pathways have been elucidated, more and more cross-talk to other cascades, e.g. MAP-kinase have been reported. In order to identify the overall function of receptor stimulation in a specific cell type or under certain conditions proteome analysis has been shown to be a very successful and powerful approach. Here, we will summarize the current state of the art of proteome analysis applied to GPCR. | ||||||||||||||||||||
| December 13, 2006 | The genetics of health | |||||||||||||||||||
| Recent experience with several high-profile drugs demonstrates the great challenges in developing effective and safe therapeutics. A complementary approach to the popular paradigm of disease genetics is based on inherited factors that reduce the incidence and severity of disease among individuals who are genetically predisposed to disease. We propose testing specifically for modifier genes and protective alleles among at-risk individuals and studying the efficacy of therapeutics based on the genetics of health. | ||||||||||||||||||||
| December 12, 2006 | Tolerogenic Dendritic Cells: The Ins and Outs of Outcome | |||||||||||||||||||
| Recent studies point to an important role for dendritic cells (DCs) in the induction of peripheral tolerance, revealing that the maturation and/or activation state of DCs might be a control point for the induction of peripheral tolerance. Recent progress in our understanding of the mechanisms mediating immune tolerance indicates them to be far more complex than hitherto anticipated. Factors deciding the outcome of vaccination with autologous DCs to prevent and treat diseases with an autoimmune background include maturation state of DCs, their administration route, long-term effects, antigen loading, and in vivo microenvironment. DC vaccination, although promising, is far from standardized. | ||||||||||||||||||||
| December 11, 2006 | A review of homocysteine and heart failure | |||||||||||||||||||
| Chronic heart failure (CHF) is a major public health problem causing considerable morbidity and mortality. Recently, plasma homocysteine (HCY) has been suggested to be increased in CHF patients potentially representing a newly recognized risk marker. This manuscript reviews the existing literature regarding hyperhomocysteinemia (HHCY) and CHF. Clinical data indicate that HHCY is associated with an increased incidence of CHF as well as with the severity of the disease. Mechanistic studies of HHCY and CHF are rare. However, preliminary results suggest that HHCY causes adverse cardiac remodelling characterized by interstitial and perivascular fibrosis resulting in increased myocardial stiffness. | ||||||||||||||||||||
| December 10, 2006 | Neuronal RNA Granules: Movers and Makers | |||||||||||||||||||
| RNA localization contributes to cell polarity and synaptic plasticity. Evidence will be discussed that RNA transport and local translation in neurons may be more intimately linked than originally thought. Second, neuronal RNA granules, originally defined as intermediates involved in mRNA transport, are much more diverse in their composition and functions than previously anticipated. We focus on three classes of RNA granules that include transport RNPs, stress granules, and P bodies and discuss their potential functions in RNA localization, microRNA-mediated translational regulation, and mRNA degradation. | ||||||||||||||||||||
| December 9, 2006 | Reciprocal regulation between natural killer cells and autoreactive T cells | |||||||||||||||||||
| The initiation and the progression of autoimmune diseases stem from complex interactions that involve cells of both the innate and the adaptive immune system. As we discuss here, natural killer (NK) cells, which are components of the innate immune system, can inhibit or promote the activation of autoreactive T cells during the initiation of autoimmunity. After they have been activated, autoreactive T cells contribute to the homeostatic contraction of NK-cell populations. The dynamic interaction between NK cells and autoreactive T cells might indicate the transition from the innate immune triggering of autoimmunity to the progressive phase of the disease. Understanding the mechanisms and signals that control the reciprocal regulation of NK cells and autoreactive T cells could have important implications for treatment in the clinic. | ||||||||||||||||||||
| December 8, 2006 | Oxidative stress and atherosclerosis | |||||||||||||||||||
| Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. Its incidence has been increasing lately in developing countries. Several lines of evidence support a role for oxidative stress in atherogenesis. Growing evidence indicates that chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is integral in the development of cardiovascular diseases (CVD). ROS mediate various signaling pathways that underlie vascular inflammation in atherogenesis from the initiation of fatty streak development through lesion progression to ultimate plaque rupture. Various animal models of oxidative stress support the notion that ROS have a causal role in atherosclerosis and other cardiovascular diseases. Human investigations also support the oxidative stress hypothesis of atherosclerosis. | ||||||||||||||||||||
| December 7, 2006 | Immunoregulatory function of mesenchymal stem cells | |||||||||||||||||||
| Mesenchymal stem cells (MSC) are a rare subset of stem cells residing in the bone marrow where they closely interact with hematopoietic stem cells and support their growth and differentiation. MSC can differentiate into multiple mesenchymal and nonmesenchymal lineages, providing a promising tool for tissue repair. In addition, MSC suppress many T cell, B cell and NK cell functions and may affect also dendritic cell activities. Due to their limited immunogenicity, MSC are poorly recognized by HLAincompatible hosts. Based on these unique properties, MSC are currently under investigation for their possible use to treat immuno-mediated diseases. | ||||||||||||||||||||
| December 6, 2006 | siRNA and isRNA: Two Edges of One Sword | |||||||||||||||||||
| RNA interference mediated by small interfering RNAs (siRNA) has emerged as a powerful tool to target specific knockdown of gene expression in cell culture. siRNA is now the gold standard technique to study gene function, and expectations for the development of new target-specific drugs are high. In addition to the gene-silencing activity of siRNA, a number of recent studies have pointed to immunological effects of siRNAs, including the induction of proinflammatory cytokines and type I interferon. There is good evidence that gene silencing and immunostimulation are two independent functional characteristics of RNA oligonucleotides. Immunorecognition of RNA depends on certain molecular features such as length, double- versus single-strand configuration, sequence motifs, and nucleoside modifications such as triphosphate residues. | ||||||||||||||||||||
| December 5, 2006 | Dynamic clamp: a powerful tool in cardiac electrophysiology | |||||||||||||||||||
| Dynamic clamp is a collection of closely related techniques that have been employed in cardiac electrophysiology to provide direct answers to numerous research questions regarding basic cellular mechanisms of action potential formation, action potential transfer and action potential synchronization in health and disease. Building on traditional current clamp, dynamic clamp was initially used to create virtual gap junctions between isolated myocytes. More recent applications include the embedding of a real pacemaking myocyte in a simulated network of atrial or ventricular cells and the insertion of virtual ion channels, either simulated in real time or simultaneously recorded from an expression system, into the membrane of an isolated myocyte. | ||||||||||||||||||||
| December 4, 2006 | Spreading of silent chromatin: inaction at a distance | |||||||||||||||||||
| One of the oldest unsolved problems in genetics is the observation that gene silencing can ‘spread’ along a chromosome. Although spreading has been widely perceived as a process of long-range assembly of heterochromatin proteins, such ‘oozing’ might not apply in most cases. Rather, long-range silencing seems to be a dynamic process, involving local diffusion of histone-modifying enzymes from source binding sites to low-affinity sites nearby. Discontinuous silencing might reflect looping interactions, whereas the spreading of continuous silencing might be driven by the processive movement of RNA or DNA polymerases. We review the evidence for the spreading of silencing in many contexts and organisms and conclude that multiple mechanisms have evolved that silence genes at a distance. | ||||||||||||||||||||
| December 3, 2006 | Autoimmunity to protective molecules: is it the perpetuum mobile (vicious cycle) of autoimmune rheumatic diseases? | |||||||||||||||||||
| Apoptotic defects and impaired clearance of cellular debris are considered key events in the development of autoimmunity, as they can contribute to autoantigen overload and might be involved in the initiation of an autoimmune response. The C1q protein and mannose-binding lectin are activators of the complement system. The pentraxins are a group of highly conserved proteins including the short pentraxins, C-reactive protein and serum amyloid P, and the long pentraxin family member, pentraxin 3, all of which are involved in innate immunity and in acute-phase responses. In addition to their role in innate immunity and inflammation, each of these proteins participates in the removal of damaged and apoptotic cells. | ||||||||||||||||||||
| December 2, 2006 | Adipocytokines: mediators linking adipose tissue, inflammation and immunity | |||||||||||||||||||
| There has been much effort recently to define the role of adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, inflammation and immunity. The adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases. | ||||||||||||||||||||
| December 1, 2006 | Lymphatic vessels in cancer metastasis: bridging the gaps | |||||||||||||||||||
| Distant organ metastasis is the most important factor in determining patient survival in cancer. This is thought to occur via the body’s own systems for transporting fluid and cells, the blood vascular and lymphatic systems. Cancer cells may exploit these vascular systems by expressing growth factors, which alter the normal pattern of angiogenesis and lymphatic vessel growth (lymphangiogenesis), thus creating conduits for tumour metastasis. With respect to lymphatic metastasis, techniques which allow the mapping of a tumour’s lymphatic drainage and sampling of the ‘sentinel node’ from the regional lymph node group provide crucial prognostic information, determine further treatment and offer a window into tumour–host immune interactions. |
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