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| April 30,2005 | The use of whole genome amplification in the study of human disease | |||||||||
| The availability of large amounts of genomic DNA is of critical importance for many of the molecular biology assays used in the analysis of human disease. However, since the amount of patient tissue available is often limited and as particular foci of interest may consist of only a fewhundr ed cells, the yield of DNA is often insufficient for extensive analysis. To address this problem, several whole genome amplification (WGA) methodologies have been developed. Initial WGA approaches were based on the polymerase chain reaction (PCR). However, recent reports have described the use of non-PCR-based linear amplification protocols for WGA. | ||||||||||
| April 29,2005 | Multi-Tasking RGS Proteins in the Heart | |||||||||
| Regulator of G-protein–signaling (RGS) proteins play a key role in the regulation of G-protein– coupled receptor (GPCR) signaling. The characteristic hallmark of RGS proteins is a conserved ≈120-aa RGS region that confers on these proteins the ability to serve as GTPase-activating proteins (GAPs) for Gα proteins. Most RGS proteins can serve as GAPs for multiple isoforms of Gα and therefore have the potential to influence many cellular signaling pathways. However, RGS proteins can be highly regulated and can demonstrate extreme specificity for a particular signaling pathway. RGS proteins can be regulated by altering their GAP activity or subcellular localization; such regulation is achieved by phosphorylation, palmitoylation, and interaction with protein and lipid-binding partners. | ||||||||||
| April 28,2005 | Gene Expression Profiling of Breast Cancer: A New Tumor Marker | |||||||||
| In ideal clinical oncology practice, one would like to have a single platform assay that can provide both prognostic (estimates of risk for failure after surgery alone) and predictive (estimate of bene.t from speci.c therapy) information. Despite years of research, only estrogen receptors (ER), progesterone receptors, and HER-2 have been widely accepted for routine use in breast cancer, serving as predictive factors for endocrine and trastuzumab therapy, respectively 1. Until recently, new markers have been tested one, or at most two, at a time, a process that results in inef.cient tissue usage, long delays in analysis, and, if positive, implementation. | ||||||||||
| April 27,2005 | Immune modulation for prevention of type 1 diabetes mellitus | |||||||||
| Prevention of type 1 diabetes mellitus requires early intervention in the autoimmune process directed against β cells of the pancreatic islets of Langerhans. This autoimmune inflammatory process is thought to be caused by the effect of Th1 cells and their secreted cytokines (e.g. interferon) and to be suppressed by Th2-secreted anti-inflammatory cytokines (e.g. IL-4, IL-10). Various methods aimed specifically at halting or modulating this response have been attempted. An alternative method is the re-induction of tolerance towards the putative self antigen that causes the disease. | ||||||||||
| April 26,2005 | The role of nitric oxide in cardiovascular diseases | |||||||||
| Nitric oxide (NO) is a gaseous lipophilic free radical cellular messenger generated by three distinct isoforms of nitric oxide synthases (NOS), neuronal (nNOS), inducible (iNOS) and endothelial NOS (eNOS). NO plays an important role in the protection against the onset and progression of cardiovascular disease. Cardiovascular disease is associated with a number of different disorders including hypercholesterolaemia, hypertension and diabetes. The underlying pathology for most cardiovascular diseases is atherosclerosis, which is in turn associated with endothelial dysfunctional. | ||||||||||
| April 25,2005 | PROGRESS TOWARD AN HIV VACCINE | |||||||||
| The development of an HIV vaccine is proving to be an unprecedented challenge. The difficulty in creating this vaccine arises from the enormous genetic variation of the virus and the unusual importance of cytotoxic T lymphocytes (CTL) in controlling its spread. Whereas traditional vaccine strategies are unlikely to confer safe and effective HIV protection, novel strategies for eliciting CTL have provided substantial clinical benefits in nonhuman primate model systems. These vaccine strategies, including plasmid DNA and live recombinant vectors, are currently being evaluated in human clinical trials. | ||||||||||
| April 24,2005 | Epigenetic control of B cell differentiation | |||||||||
| Gene expression, differentiation and the specialized function of various cell types are controlled epigenetically by post-translational histone modifications. These modifications establish a “histone code” that is recognized by various regulatory proteins, thereby creating a stable pattern of gene expression. The focus of this review is to discuss how the chromatin modifications regulate immunoglobulin gene rearrangement and B cell differentiation. | ||||||||||
| April 23,2005 | The Year in Heart Failure | |||||||||
| Heart failure (HF) remains a dynamic field. Treatment continues to be refined and improved and, at last, there is evidence that the increased survival demonstrated in randomized clinical trial cohorts has been translated to the unselected general population. Beyond angiotensinconverting enzyme (ACE) inhibitors and beta-blockers, two more classes of drug, the angiotensin receptor blockers and aldosterone antagonists, were unequivocally demonstrated to have a survival benefit during 2003. This year also establishes a new era in device therapies, which also improve outcomes in patients with HF. | ||||||||||
| April 22,2005 | THE GENETICS OF HUMAN OBESITY | |||||||||
| Obesity is an important cause of morbidity and mortality in developed countries, and is also becoming increasingly prevalent in the developing world. Although environmental factors are important, there is considerable evidence that genes also have a significant role in its pathogenesis. The identification of genes that are involved in monogenic, syndromic and polygenic obesity has greatly increased our knowledge of the mechanisms that underlie this condition. In the future, dissection of the complex genetic architecture of obesity will provide new avenues for treatment and prevention, and will increase our understanding of the regulation of energy balance in humans. | ||||||||||
| April 21,2005 | Regulation of innate immunity by Rho GTPases | |||||||||
| Leukocytes are key cellular components of innate immunity. These phagocytic cells respond to bacteria at sites of infection through chemotactic sensing and directed motility regulated by Rho GTPases. The development of sensitive probes of Rho GTPase dynamics has provided insights into the temporal and spatial aspects of GTPase regulation during chemotaxis and subsequent microbial phagocytosis. The resulting destruction of ingested bacteria by means of reactive oxygen species (ROS) depends on a Rac-regulated ‘molecular switch’ that is modulated by antagonistic crosstalk involving Cdc42. Recent studies of leukocytes derived from Rac1- and Rac2-knockout mice have shown that these highly homologous GTPases have unique biological roles. | ||||||||||
| April 20,2005 | HDL AS A TARGET IN THE TREATMENT OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE | |||||||||
| Lipid abnormalities are among the key risk factors for cardiovascular disease. Indeed, lipid-modifying drugs — in particular, the statins, which primarily lower plasma levels of lowdensity lipoprotein (LDL) cholesterol — considerably reduce the risk of cardiovascular events, leading to their widespread use. Nevertheless, it seems that there might be limits to the degree of benefit that can be achieved by lowering LDL-cholesterol levels alone, which has led to increased interest in targeting other lipid-related risk factors for cardiovascular disease, such as low levels of high-density lipoprotein (HDL) cholesterol. | ||||||||||
| April 19,2005 | DNA REPAIR DEFECTS IN STEM CELL FUNCTION AND AGING | |||||||||
| Cellular DNA is under constant challenge by exogenous and endogenous genotoxic stress, which results in both transient and accumulated DNA damage and genomic instability. All cells are equipped with DNA damage response pathways that trigger DNA repair, cell cycle arrest, and, if need be, apoptosis, to eliminate DNA damage or damaged cells. The consequences of these processes for stem cells can be profound: diminution in stem cell pools, or, because of altered gene expression, an increased chance for stem cell differentiation or malignant transformation. Furthermore, a number of DNA repair abnormalities are linked to premature aging syndromes, and these are associated with defects in the stem cell population. | ||||||||||
| April 18,2005 | Short interfering RNAs as a tool for cancer gene therapy | |||||||||
| There are mainly two types of short RNAs that target complementary messengers in animals: small interfering RNAs and micro- RNAs. Both are produced by the cleavage of double-stranded RNA precursors by Dicer, a member of the Rnase III family of doublestranded specific endonucleases, and both guide the RNA-induced silencing complex to cleave specifically RNAs sharing sequence identity with them. In designing a particular RNA interference (RNAi), it is important to identify the sense/antisense combination that provides the most potent suppression of the target mRNA, and several rules have been established to give >90% gene expression inhibition. RNAi technology can be directed against cancer using a variety of strategies. | ||||||||||
| April 17,2005 | From genes to machines: DNA nanomechanical devices | |||||||||
| The structural properties that enable DNA to serve so effectively as genetic material can also be used for other purposes. The complementarity that leads to the pairing of the strands of the DNA double helix can be exploited to assemble more complex motifs, based on branched structures. These structures have been used as the basis of larger 2D and 3D constructions. In addition, they have been used to make nanomechanical devices. These devices range from DNA-based shape-shifting structures to gears and walkers, a DNA-stress gauge and even a translation device. The devices are activated by mechanisms as diverse as small molecules, proteins and, most intriguingly, other molecules of DNA. | ||||||||||
| April 16,2005 | MANAGEMENT OF PERIPHERAL VASCULAR DISEASE | |||||||||
| The management of patients with peripheral arterial occlusive disease (PAD) has to be planned in the context of natural history, epidemiology, and apparent risk factors that predict deterioration. The ankle-brachial index to date has proved to be the most effective, accurate, and practical method of PAD detection. Given that PAD is a powerful indicator of systemic atherosclerosis and (independent of symptoms) is associated with an increased risk of myocardial infarction and stroke, as well as a six times greater likelihood of death, the prevalence and demographic distribution of measurable PAD becomes particularly relevant. | ||||||||||
| April 15,2005 | THE ROLE OF BH3-ONLY PROTEINS IN THE IMMUNE SYSTEM | |||||||||
| Programmed cell death — also known as apoptosis — has a crucial role in the immune system of mammals and other animals. It removes useless cells and potentially dangerous cells, including lymphocytes, and is involved in killing pathogen-infected or damaged cells. Defects in this process have been found to cause or contribute to diseases of the immune system, including immunodeficiency, autoimmunity, lymphoma and leukaemia. This review describes BH3-only proteins, a pro-apoptotic subgroup of the BCL-2 family, and their role in the development and function of the immune system. | ||||||||||
| April 14,2005 | Physical methods for gene transfer: Improving the kinetics of gene delivery into cells | |||||||||
| One factor critical to successful gene therapy is the development of efficient delivery systems. Although advances in gene transfer technology, including viral and non-viral vectors, have been made, an ideal vector system has not yet been constructed. This review describes the basic principles behind various physical methods for gene transfer and assesses the advantages and performance of such approaches, compared to other transfection systems. In particular, the kinetics and efficiency of gene delivery, the toxicity, in vivo feasibility, and targeting ability of different physical methodologies are discussed and evaluated. | ||||||||||
| April 13,2005 | The DNA sequence of the human X chromosome | |||||||||
| The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. | ||||||||||
| April 12,2005 | Genetic causes of human heart failure | |||||||||
| Factors that render patients with cardiovascular disease at high risk for heart failure remain incompletely defined. Recent insights into molecular genetic causes of myocardial diseases have highlighted the importance of single-gene defects in the pathogenesis of heart failure. Through analyses of the mechanisms by which a mutation selectively perturbs one component of cardiac physiology and triggers cell and molecular responses, studies of human gene mutations provide a window into the complex processes of cardiac remodeling and heart failure. Knowledge gleaned from these studies shows promise for defining novel therapeutic targets for genetic and acquired causes of heart failure. | ||||||||||
| April 11,2005 | INTEGRIN-LINKED KINASE: A CANCER THERAPEUTIC TARGET UNIQUE AMONG ITS ILK | |||||||||
| Cancer development requires the acquisition of several capabilities that include increased replicative potential, anchorage and growth-factor independence, evasion of apoptosis, angiogenesis, invasion of surrounding tissues and metastasis. One protein that has emerged as promoting many of these phenotypes when dysregulated is integrin-linked kinase (ILK), a unique intracellular adaptor and kinase that links the cell-adhesion receptors, integrins and growth factors to the actin cytoskeleton and to a range of signalling pathways. The recent findings of increased levels of ILK in various cancers, and that inhibition of ILK expression and activity is antitumorigenic, makes ILK an attractive target for cancer therapeutics. | ||||||||||
| April 10,2005 | FAT CELLS: Afferent and Efferent Messages Define New Approaches to Treat Obesity | |||||||||
| For a long time neural and endocrine messages were studied for their impact on adipocyte metabolism and control of storage/release of fatty acids. In fact, bidirectional communication exists between adipocytes and other tissues. Several molecules secreted from adipocytes are involved in fat cell signaling to other tissues. Adipocyte products could initiate antagonistic effects on target tissues. Fat cells produce peptides that can elicit insulin resistance, such as tumor necrosis factor-α and resistin, as well as hormones that can improve insulin resistance, such as leptin and adiponectin. | ||||||||||
| April 9,2005 | NETWORK BIOLOGY: UNDERSTANDING THE CELL’S FUNCTIONAL ORGANIZATION | |||||||||
| A key aim of postgenomic biomedical research is to systematically catalogue all molecules and their interactions within a living cell. There is a clear need to understand how these molecules and the interactions between them determine the function of this enormously complex machinery, both in isolation and when surrounded by other cells. Rapid advances in network biology indicate that cellular networks are governed by universal laws and offer a new conceptual framework that could potentially revolutionize our view of biology and disease pathologies in the twenty-first century. | ||||||||||
| April 8,2005 | Antigen presentation and recognition in bacterial infections | |||||||||
| Antigen processing and recognition is a key feature of antibacterial immune responses to intracellular bacteria. In contrast to viruses, which are primarily controlled by conventional MHC II- and MHC I-restricted CD4+ or CD8+ T cells, respectively, unconventional T cells participate additionally in antibacterial protection. These unconventional T cells include glycolipid-specific CD1-restricted T cells and phospholigand-specific γδ T cells. We are just beginning to understand the broad spectrum of antigen recognition and stimulation of distinct T-cell populations by bacterial pathogens. From the host perspective, a broad spectrum of different T-cell populations that recognize proteins, lipids and carbohydrates strengthens protective immunity. | ||||||||||
| April 7,2005 | MODULATION OF NEURODEGENERATION BY MOLECULAR CHAPERONES | |||||||||
| Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease and polyglutamine diseases. | ||||||||||
| April 6,2005 | MANAGEMENT OF PERIPHERAL VASCULAR DISEASE | |||||||||
| The management of patients with peripheral arterial occlusive disease (PAD) has to be planned in the context of natural history, epidemiology, and apparent risk factors that predict deterioration. The ankle-brachial index to date has proved to be the most effective, accurate, and practical method of PAD detection. Given that PAD is a powerful indicator of systemic atherosclerosis and (independent of symptoms) is associated with an increased risk of myocardial infarction and stroke, as well as a six times greater likelihood of death, the prevalence and demographic distribution of measurable PAD becomes particularly relevant. Reliable information on interventions to confer symptom relief is much weaker and reflects discrepancies between published reports from centers of excellence and the experience of patients routinely treated in communities around the world. | ||||||||||
| April 5,2005 | THE PHENOGENETIC LOGIC OF LIFE | |||||||||
| For nearly a century we have understood that life works through genes, and so have had an elegant theory for general evolution. But this did not explain the kinds of traits that characterize organisms, nor how genes produce them. Advances in recent decades have opened the way for an understanding of the phenogenetic logic or relational principles of life, by which a few basic characteristics of genomes produce biological phenotypes through some basic developmental processes. This logic provides a general explanation of the nature and source of organismal design, and a powerful programme for research. | ||||||||||
| April 4,2005 | p53: TRAFFIC COP AT THE CROSSROADS OF DNA REPAIR AND RECOMBINATION | |||||||||
| p53 mutants that lack DNA-binding activities, and therefore, transcriptional activities, are among the most common mutations in human cancer. Recently, a new role for p53 has come to light, as the tumour suppressor also functions in DNA repair and recombination. In cooperation with its function in transcription, the transcription-independent roles of p53 contribute to the control and efficiency of DNA repair and recombination. | ||||||||||
| April 3,2005 | Adhesion remodeling underlying tissue morphogenesis | |||||||||
| Cell-adhesion molecules localized at adherens junctions (AJs) maintain the polarized architecture of epithelial cells but limit their movements. The morphogenesis of a developing epithelium is associated with the control of both cell shape and cell contacts. Epithelial cells remodel their contacts, and intercellular adhesion controlled by cadherin molecules is spatially and temporally regulated. Cell shape depends, in part, on the regulation of cell adhesion between different groups of cells. Patterned epithelial cell movements such as those that occur during cell intercalation – a universal process whereby cells exchange neighbors – rely on the polarized remodeling of AJs. Recent studies show that the understanding of adhesion will benefit from studies of developing organisms in which adhesion is regulated. | ||||||||||
| April 2,2005 | Pharmacotherapy for Chronic Heart Failure | |||||||||
| Heart failure is an important cause of morbidity and mortality. Clinical trials over the past 2 decades have revolutionized the care of patients with systolic heart failure, and substantial data support the use of angiotensin-converting enzyme inhibitors, β-blockers, angiotensin-receptor blockers, and aldosterone blockers in the management of this serious condition. This article reviews the evidence on the pharmacologic treatment of heart failure, with a focus on recent clinical trials. | ||||||||||
| April 1,2005 | NK cells in innate immunity | |||||||||
| NK cells have an important role in innate immune responses, particularly in anti-viral immunity. Recent studies have revealed a molecular basis for NK cell recognition of virus-infected cells, implicating the activating KIR and Ly49 receptors and NKG2D in this process. Additionally, mutual cooperation between NK cells and dendritic cells suggests that these innate cells can shape the nature of an adaptive immune response. These findings, as well as advances in understanding NK cell development and homeostasis, indicate that NK cell biology is more sophisticated than previously appreciated. |
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