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October 31, 2006 Vasoinhibins: endogenous regulators of angiogenesis and vascular function
  Vasoinhibins are a family of peptides derived from prolactin, growth hormone and placental lactogen that act on endothelial cells to suppress vasodilation and angiogenesis and to promote apoptosis-mediated vascular regression. Some of the pathways by which vasoinhibins act have now been defined, and recent developments indicate that endogenous vasoinhibins exert tonic and essential actions on blood vessel growth, dilation and regression in vivo. By studying the pathways that can generate vasoinhibins, and the nature of their receptors and key biological mediators, it should be possible to clarify the role of vasoinhibins in controlling vascular function in health and disease.
October 30, 2006 Mechanisms of chromosome instability in cancers
  Most tumours arise through clonal selection and waves of expansion of a somatic cell that has acquired genetic alterations in essential genes either controlling cell death or cell proliferation. Furthermore, stability of the genome in cancer cells becomes precarious and compromised because several cancer-predisposing mutations affect genes that are responsible for maintaining the integrity and number of chromosomes during cell division. Consequently, the archetypical transformation in tumour cells results in aneuploidy. Indeed, almost all tumour cells display a host of karyotype alterations, showing translocations, gains or losses of entire or large parts of chromosomes.
October 29, 2006 Toll-like receptors as molecular switches
  Members of the Toll family of single-pass transmembrane receptors are key mediators of innate immunity in both vertebrates and invertebrates. They respond to various pathogen-associated stimuli and transduce the complex signalling responses that are required for inflammation and for the subsequent development of adaptive immunity. Here, we propose a molecular mechanism for signalling by the Toll and Toll-like receptors that involves a series of protein conformational changes initiated by dimerization of their extracellular domains. The initial dimerization event, which is triggered by the interaction of the receptor with its ligand, might disrupt a pre-formed but non-functional dimer.
October 28, 2006 Genetic determinants of the metabolic syndrome
  The metabolic syndrome is a commonly encountered clinical phenotype presenting as concurrent metabolic abnormalities, including central obesity, dysglycemia, dyslipidemia, and hypertension. Several definitions exist, and it is debated whether or not the clustered risk factors impart a higher cardiovascular risk than the simple sum of the individual components. Nevertheless, the concept of a metabolic syndrome has proven helpful in emphasizing the importance of obesity, insulin resistance and related traits in relation to cardiovascular disease risk. Furthermore, the metabolic syndrome as defined by the National Cholesterol Education Program appears to have a component of heritability, which suggests a genetic basis. Indeed, patients with certain rare single-gene disorders express clusters of abnormalities commonly seen in the metabolic syndrome.
October 27, 2006 The nuclear membrane proteome: extending the envelope
  The marriage of proteomics with cell biology has produced extensive inventories of the proteins that inhabit several subcellular organelles. Recent proteomic analysis has identified many new putative transmembrane proteins in the nuclear envelope, and transcriptome profiling suggests that the nuclear-membrane proteome exhibits some significant variations among different tissues. Cell-type-specific differences in the composition of protein sub-complexes of the nuclear envelope, particularly those containing the disease-associated protein lamin A, could yield distinctive functions and, thus, explain the tissue specificity of a diverse group of nuclear-envelope-linked disorders in humans. Considered together, these recent results suggest an unexpected functional complexity at the nuclear envelope.
October 26, 2006 The role of heparan sulphate in inflammation
  The polysaccharide heparan sulphate is ubiquitously expressed as a proteoglycan in extracellular matrices and on cell surfaces. Heparan sulphate has marked sequence diversity that allows it to specifically interact with many proteins. This Review focuses on the multiple roles of heparan sulphate in inflammatory responses and, in particular, on its participation in almost every stage of leukocyte transmigration through the blood-vessel wall. Heparan sulphate is involved in the initial adhesion of leukocytes to the inflamed endothelium, the subsequent chemokine-mediated transmigration through the vessel wall and the establishment of both acute and chronic inflammatory reactions.
October 25, 2006 Nuclear receptors versus inflammation: mechanisms of transrepression
  Inflammation is a beneficial host response to external challenge or cellular injury that leads to the activation of a complex array of inflammatory mediators, finalizing the restoration of tissue structure and function. Although a beneficial response, prolonged inflammation can be detrimental to the host, contributing to the pathogenesis of many disease states. Considerable attention has been focused on the ability of several members of the nuclear receptor superfamily to inhibit transcriptional activation by signal-dependent transcription factors that include nuclear factor kB and activator protein 1, thereby, attenuating inflammatory responses to both acute and chronic challenge.
October 24, 2006 Chemogenomics: structuring the drug discovery process to gene families
  In the post-genomic era, if all proteins in a gene family can putatively be identified, how can drug discovery effectively tackle so many novel targets that might lack structural and small-molecule inhibitory data? In response, chemogenomics, a new approach that guides drug discovery based on gene families, has been developed. By integrating all information available within a protein family (sequence, SAR data, protein structure), chemogenomics can efficiently enable cross-SAR exploitation, directed compound selection and early identification of optimum selectivity panel members. This review examines recent developments in chemogenomics technologies and illustrates their predictive capabilities with successful examples from two of the major protein families: protein kinases and G-protein-coupled receptors.
October 23, 2006 Nuclear receptors as drug targets in metabolic diseases
  Nuclear receptors represent novel targets for the development of therapeutic agents for the treatment of numerous diseases, including type 2 diabetes, obesity dyslipidemia, atherosclerosis and the metabolic syndrome. There have been many recent advances in the development of new therapeutic agents for a subset of these receptors, including the peroxisome proliferator- activated receptors, the liver X receptors and the farnesoid X receptor. To date, the synthesis of selective modulators that regulate the activity of these receptors has been empirical. However, a detailed understanding of the molecular basis for selective modulation, as well as new insights into the biology of these receptors, might open the door to the rational design of a new generation of therapeutic agents with improved safety and efficacy.
October 22, 2006 Vascular smooth muscle cell senescence in atherosclerosis
  Markers of cell senescence have been identified in both the blood and vessel wall of patients with atherosclerosis. In particular, vascular smooth muscle cells (VSMCs) derived from human plaques show numerous features of senescence both in culture and in vivo. This review summarises the evidence for VSMC senescence in atherosclerosis, and outlines the mechanisms and triggers leading to their senescence.
October 21, 2006 Ontology-based integration of genomic and clinical databases
  ONTOFUSION is an ontology-based system designed for biomedical database integration. It is based on two processes: mapping and unification. Mapping is a semi-automated process that uses ontologies to link a database schema with a conceptual framework—named virtual schema. There are three methodologies for creating virtual schemas, according to the origin of the domain ontology used: (1) top-down—e.g. using an existing ontology, such as the UMLS or Gene Ontology—, (2) bottom-up—building a new domain ontology— and (3) a hybrid combination. Unification is an automated process for integrating ontologies and hence the database to which they are linked.
October 20, 2006 Novel approaches using natural killer cells in cancer therapy
  Strategies are emerging to apply natural killer (NK) cells as therapeutic agents against a broad range of malignancies. Novel clinical approaches aim to overcome limitations of original therapies, which have utilized lymphokine activated killer cells or systemic cytokine treatments. Remarkable results, including survival improvements and amelioration of graft versus host disease, were obtained with alloreactive NK cells in some cases. Other approaches in clinical evaluation include targeting heat-shock protein (Hsp) 70 expressing tumors with pre-stimulated autologous NK cells or the application of an NK cell line, NK-92, with enhanced cytolytic activity. Further mechanistic insights into NK cell cytotoxicity are a prelude to improved clinical cancer therapies.
October 19, 2006 PPARs and other nuclear receptors in inflammation
  Inflammation is a central component of several chronic human diseases, including atherosclerosis and type 2 diabetes. Several nuclear receptors repress inflammatory responses, but their molecular mechanisms remain poorly understood. The nuclear receptor superfamily is composed of transcription factors that have emerged as key regulators of inflammation and lipid homeostasis. These include the glucocorticoid receptor, which inhibits inflammatory programs of gene expression in response to natural corticosteroids and synthetic anti-inflammatory ligands such as dexamethasone. In addition, peroxisome proliferator-activated receptors and liver X receptors, in response to endogenous eicosanoids and oxysterols, respectively, modulate transcriptional pathways involved in inflammatory responses and lipid homeostasis.
October 18, 2006 Evolution of primate gene expression
  It has been suggested that evolutionary changes in gene expression account for most phenotypic differences between species, in particular between humans and apes. What general rules can be described governing expression evolution? We find that a neutral model where negative selection and divergence time are the major factors is a useful null hypothesis for both transcriptome and genome evolution. Two tissues that stand out with regard to gene expression are the testes, where positive selection has exerted a substantial influence in both humans and chimpanzees, and the brain, where gene expression has changed less than in other organs but acceleration might have occurred in human ancestors.
October 17, 2006 Imagining the brain cell: the neuron in visual culture
  Images of the exquisitely formed apparatus of the nervous system have great potential to capture the imagination. However, the fascinating complexity and diversity of neuronal form has only rarely been celebrated in broader visual culture. We discuss how scientific and cultural practices at the time of the neuron’s discovery generated a legacy of schematic and simplified popular neuronal imagery, which is only now being revised in the light of technological advances and a changing artistic climate.
October 16, 2006 Notch signalling: a simple pathway becomes complex
  A small number of signalling pathways are used iteratively to regulate cell fates, cell proliferation and cell death in development. Notch is the receptor in one such pathway, and is unusual in that most of its ligands are also transmembrane proteins; therefore signalling is restricted to neighbouring cells. Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.
October 15, 2006 Genetic and epigenetic biomarkers in cancer diagnosis and identifying high risk populations
  Biomarkers present the normal and/or disease state in humans. Genetic and epigenetic biomarkers assessed in easily accessible biological materials are useful in diagnosis, early onset or risk of developing cancer or to predict the treatment efficacy or clinical outcome of different human malignancies. Moreover, some of these markers are expressed during early stages of the tumor development and hence provide an opportunity to develop intervention and treatment strategies. Attempts are being made to validate cancer biomarkers in non-invasively collected samples. Multiplexing of clinically validated markers is still a challenge. Once validated, these markers can be utilized in clinical settings and to identify high risk populations. In this review, the current status of the clinical genetic and epigenetic biomarkers and their implication in cancer diagnosis and risk assessment are discussed.
October 14, 2006 Case-control studies in the genomic era: a clinician’s guide
  The goal of case-control association studies is to fi nd genetic variants in the human genome that infl uence common traits. The Human Genome and HapMap projects have added fresh impetus to this goal by cataloguing the raw genetic data behind human DNA variation. Studies that associate these genetic variants with phenotype improve both molecular diagnostics and drug discovery and off er clinicians important opportunities to improve care of patients. In this review I focus on case-control studies, which are the most widely used design and expected to be the most powerful. I also address the problem of case-control non-replication, which is widespread despite enormous eff ort and use of resources. Important causes of non-replication include inadequate statistical power to detect small and moderate eff ects, phenotype heterogeneity, population stratifi cation, publication bias, and multiple comparison testing.
October 13, 2006 BAFF, APRIL and their receptors: Structure, function and signaling
  BAFF, APRIL and their receptors play important immunological roles, especially in the B cell arm of the immune system. A number of splice isoforms have been described for both ligands and receptors in this subfamily, some of which are conserved between mouse and human, while others are species-specific. Structural and mutational analyses have revealed key determinants of receptor–ligand specificity. BAFF-R has a strong selectivity for BAFF; BCMA has a higher affinity for APRIL than for BAFF, while TACI binds both ligands equally well. The molecular signaling events downstream of BAFF-R, BCMA and TACI are still incompletely characterized. Survival appears to be mediated by upregulation of Bcl-2 family members through NF-B activation, degradation of the pro-apototic Bim protein, and control of subcellular localization of PCK. Very little is known about other signaling events associated with receptor engagement by BAFF and APRIL that lead for example to B cell activation or to CD40L-independent Ig switch.
October 12, 2006 Comparing antibody and small-molecule therapies for cancer
  The ‘magic bullet’ concept of specifically targeting cancer cells at the same time as sparing normal tissues is now proven, as several monoclonal antibodies and targeted small-molecule compounds have been approved for cancer treatment. Both antibodies and small-molecule compounds are therefore promising tools for target-protein-based cancer therapy. We discuss and compare the distinctive properties of these two therapeutic strategies so as to provide a better view for the development of new drugs and the future direction of cancer therapy.
October 11, 2006 High-throughput fluorescence microscopy for systems biology
  In this post-genomic era, we need to define gene function on a genomewide scale for model organisms and humans. The fundamental unit of biological processes is the cell. Among the most powerful tools to assay such processes in the physiological context of intact living cells are fluorescence microscopy and related imaging techniques. To enable these techniques to be applied to functional genomics experiments, fluorescence microscopy is making the transition to a quantitative and high-throughput technology.
October 10, 2006 Tetraploidy/Aneuploidy and Stem Cells in Cancer Promotion: The Role of Chromosome Passenger Proteins
  While polyploidy, a state of having fully duplicated sets of chromosomes per cell, has been described in normally developing bone marrow megakaryocytes or as an adaptive response in other cell types, aneuploidy is never detected in normal cells. Tetraploidy or aneuploidy can be induced by several signals and it is highly prevalent in different forms of cancers, suggesting a role for this cell cycle state in promoting cellular transformation. Investigations suggested that loss of heterozygosity of cancer-related genes in stem cells might contribute to genetic instability in progeny cells and to subsequent cancer development. Deregulated expression of chromosome passenger proteins, such as Aurora kinases or Survivin, is a hallmark of various cancers, and experimentally induced changes in these regulators can promote tetraploidy or aneuploidy and loss of heterozygosity. Our studies described an induction of tetraploidy/aneuploidy by a stable form of Aurora-B, leading to acquisition of transformation properties. It is intriguing to speculate that in some cancers, tetraploidy/aneuploidy induced by deregulated expression of a mitotic regulator represents a primary event that leads to unbalanced expression of a cluster of crucial genes and to cellular transformation.
October 9, 2006 Cardioprotection by Adiponectin
  Obesity-related disorders are closely associated with the pathogenesis of cardiovascular disease. Adiponectin is a circulating adipose tissuederived hormone that is down-regulated in obese individuals. Hypoadiponectinemia has been identified as an independent risk factor for type 2 diabetes, coronary artery disease, and hypertension, and experimental studies show that adiponectin plays a protective role in the development of insulin resistance, atherosclerosis, and inflammation. More recent findings have shown that adiponectin directly affects signaling in myocardial cells and exerts beneficial actions on the heart after pressure overload and ischemia–reperfusion injury. This review focuses on the role of adiponectin in the regulation of myocardial remodeling and acute cardiac injury.
October 8, 2006 The Cbl Family Proteins: Ring Leaders in Regulation of Cell Signaling
  The proto-oncogenic protein c-Cbl was discovered as the cellular form of v-Cbl, a retroviral transforming protein. This was followed over the years by important discoveries, which identified c-Cbl and other Cbl-family proteins as key players in several signaling pathways. c-Cbl has donned the role of a multivalent adaptor protein, capable of interacting with a plethora of proteins, and has been shown to positively influence certain biological processes. The identity of c-Cbl as an E3 ubiquitin ligase unveiled the existence of an important negative regulatory pathway involved in maintaining homeostasis in protein tyrosine kinase (PTK) signaling. Recent years have also seen the emergence of novel regulators of Cbl, which have provided further insights into the complexity of Cbl-influenced pathways. This review will endeavor to provide a summary of current studies focused on the effects of Cbl proteins on various biological processes and the mechanism of these effects. The major sections of the review are as follows: Structure and genomic organization of Cbl proteins; Phosphorylation of Cbl; Interactions of Cbl; Localization of Cbl; Mechanism of effects of Cbl: (a) Ubiquitylation-dependent events: This section elucidates the mechanism of Cbl-mediated downregulation of EGFR and details the PTK and non-PTKs targeted by Cbl. In addition, it addresses the functional requirements for E3 Ubiquitin ligase activity of Cbl and negative regulation of Cbl-mediated downregulation of PTKs, (b) Adaptor functions: This section discusses the mechanisms of adaptor functions of Cbl in mitogen-activated protein kinase (MAPK) activation, insulin signaling, regulation of Rasrelated protein 1 (Rap1), PI-30 kinase signaling, and regulation of Rho-family GTPases and cytoskeleton; Biological functions: This section gives an account of the diverse biological functions of Cbl and includes the role of Cbl in transformation, T-cell signaling and thymus development, B-cell signaling, mast-cell degranulation, macrophage functions, bone development, neurite growth, platelet activation, muscle degeneration, and bacterial invasion; Conclusions and perspectives.
October 7, 2006 Hepatic fibrosis and cirrhosis: The (myo)fibroblastic cell subpopulations involved
  Fibrosis, defined as the excessive deposition of extracellular matrix in an organ, is the main complication of chronic liver damage. Its endpoint is cirrhosis, which is responsible for significant morbidity and mortality. The accumulation of extracellular matrix observed in fibrosis and cirrhosis is due to the activation of fibroblasts, which acquire a myofibroblastic phenotype. Myofibroblasts are absent from normal liver. They are produced by the activation of precursor cells, such as hepatic stellate cells and portal fibroblasts. These fibrogenic cells are distributed differently in the hepatic lobule: the hepatic stellate cells resemble pericytes and are located along the sinusoids, in the Disse space between the endothelium and the hepatocytes, whereas the portal fibroblasts are embedded in the portal tract connective tissue around portal structures (vessels and biliary structures). Differences have been reported between these two fibrogenic cell populations, in the mechanisms leading to myofibroblastic differentiation, activation and “deactivation”, but confirmation is required. Second-layer cells surrounding centrolobular veins, fibroblasts present in the Glisson capsule surrounding the liver, and vascular smooth muscle cells may also express a myofibroblastic phenotype and may be involved in fibrogenesis. It is now widely accepted that the various types of lesion (e.g., lesions caused by alcohol abuse and viral hepatitis) leading to liver fibrosis involve specific fibrogenic cell subpopulations. The biological and biochemical characterisation of these cells is thus essential if we are to understand the mechanisms underlying the progressive development of excessive scarring in the liver. These cells also differ in proliferative and apoptotic capacity, at least in vitro. All this information is required for the development of treatments specifically and efficiently targeting the cells responsible for the development of fibrosis/cirrhosis.
October 6, 2006 Regulatory T cells in cancer
  Increasing evidence supports the existence of elevated numbers of regulatory T cells (Treg cells) in solid tumors and hematologic malignancies. Whereas the biology of CD4+CD25+FOXP3+ Treg cells in murine models seems to be rather straightforward, studies in human diseases are more difficult to interpret due to expression of CD25 on activated effector T cells as well as Treg cells.More importantly, early studies in human tumors were mainly focused onCD4+CD25+ Treg cells lacking interrogation of more specific markers such as FOXP3 expression. Although the increase of Treg cells seems to be a characteristic feature in most tumors, little is known about the molecular and cellular mechanisms responsible for the increase and maintenance of elevated levels of Treg cells in cancer. We will discuss earlier data in the context of recent findings in Treg-cell biology with a particular emphasis on CD4+CD25highFOXP3+ Treg cells in human malignancies.
October 5, 2006 Tracking STAT nuclear traffic
  Accurate cellular localization is crucial for the effective function of most signalling molecules and nuclear translocation is central to the function of transcription factors. The passage of large molecules between the cytoplasm and nucleus is restricted, and this restriction affords a mechanism to regulate transcription by controlling the access of transcription factors to the nucleus. In this Review, we focus on the signal transducer and activator of transcription (STAT) family of transcription factors. The regulation of the nuclear trafficking of STAT-family members is diverse. Some STAT proteins constitutively shuttle between the nucleus and cytoplasm, whereas others require tyrosine phosphorylation for nuclear localization. In either case, the regulation of nuclear trafficking can provide a target for therapeutic intervention.
October 4, 2006 Biomarkers in Acute Cardiac Disease
  The use of biomarkers to aid diagnosis and treatment is increasing rapidly as genomics and proteomics help us expand the number of markers we can use and as an improved understanding of the pathophysiology of cardiac disease guides their use. However, as with all rapidly expanding fields, there is the risk of excessive enthusiasm unless we are circumspect about the data that guide the clinical use of these new tools. This review focuses first on how to use troponin, which at present is the best validated of the new markers, and will hopefully provide insight into how to use this biomarker more productively by distinguishing subsets of patients and by providing an understanding of the meaning of elevations in various clinical situations. The review then discusses the use as well as the knowledge gaps associated with emerging biomarkers such as B-type natriuretic peptide and C-reactive protein, which are increasingly moving toward more productive clinical use. Finally, it reflects on some of the large number of markers that are still in development.
October 3, 2006 The endocytic pathway mediates cell entry of dsRNA to induce RNAi silencing
  Many metazoan cells can take up exogenous double-stranded (ds) RNA and use it to initiate an RNA silencing response, however, the mechanism for this uptake is ill-defined. Here, we identify the pathway for dsRNA uptake in Drosophila melanogaster S2 cells. Biochemical and cell biological analyses, and a genome-wide screen for components of the dsRNA-uptake machinery, indicated that dsRNA is taken up by an active process involving receptor-mediated endocytosis. Pharmacological inhibition of endocytic pathways disrupted exogenous dsRNA entry and the induction of gene silencing. This dsRNA uptake mechanism seems to be evolutionarily conserved, as knockdown of orthologues in Caenorhabditis elegans inactivated the RNA interference response in worms. Thus, this entry pathway is required for systemic RNA silencing in whole organisms. In Drosophila cells, pharmacological evidence suggests that dsRNA entry is mediated by pattern-recognition receptors. The possible role of these receptors in dsRNA entry may link RNA interference (RNAi) silencing to other innate immune responses.
October 2, 2006 Regulation of angiogenesis by hypoxia-inducible factor 1
  Hypoxia is an imbalance between oxygen supply and demand that occurs in cancer and in ischemic cardiovascular disease. Hypoxiainducible factor 1 (HIF-1) was originally identified as the transcription factor that mediates hypoxia-induced erythropoietin expression. More recently, the delineation of molecular mechanisms of angiogenesis has revealed a critical role for HIF-1 in the regulation of angiogenic growth factors. In this review, we discuss the role of HIF-1 in developmental, adaptive and pathological angiogenesis. In addition, potential therapeutic interventions involving modulation of HIF-1 activity in ischemic cardiovascular disease and cancer will be discussed.
October 1, 2006 Mitochondrial disease
  Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. This review updates the topic of mitochondrial diseases by reviewing the most important recent advances in this area. The factors infl uencing inheritance, maintenance and replication of mtDNA are reviewed and the genotype-phenotype of mtDNA disorders has been expanded, with new insights into epidemiology, pathogenesis and its role in ageing. Recently identifi ed nuclear gene mutations of mitochondrial proteins include mutations of frataxin causing Friedreich’s ataxia, PINK1, DJ1 causing Parkinson’s disease and POLG causing infantile mtDNA depletion syndrome, ophthalmoplegia, parkinsonism, male subfertility and, in a transgenic mouse model, premature senescence. Mitochondrial defects in neurodegenerative diseases include Parkinson’s, Alzheimer’s and Huntington’s disease. Improved understanding of mtDNA inheritance and mutation penetrance patterns, and novel techniques for mtDNA modifi cation off er signifi cant prospects for more accurate genetic counselling and eff ective future therapies.

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