bluuebunny/crossref_metadata_2025 huggingface dataset:
Epstein–Barr virus infection: basis of malignancy and potential for therapy
Authors: Murray Paul G. , Young Lawrence S.
Published: October 2003

The Epstein–Barr virus (EBV) is a human herpesvirus that is usually carried lifelong as an asymptomatic infection. EBV is the causative agent of infectious mononucleosis and has been linked to the development of several malignant tumours, including B-cell neoplasms such as Burkitt's lymphoma and Hodgkin's disease, certain forms of T-cell lymphoma, and some epithelial tumours, such as undifferentiated nasopharyngeal carcinoma and a proportion of gastric cancers. All these tumours are characterised by the presence of multiple extrachromosomal copies of the circular viral genome in the tumour cells and the expression of EBV-encoded latent genes, which appear to contribute to the malignant phenotype. An increasing understanding of the function of EBV latent genes and of the nature of the immune response to the virus is providing exciting new possibilities for the treatment of EBV-associated malignancies. For example, adoptive transfer of virus-specific cytotoxic T lymphocytes has already been of value in the treatment of EBV-positive B-cell lymphomas arising in post-transplant patients, and this approach is currently being investigated in other EBV-associated tumours. In addition, gene therapy offers the opportunity to deliver agents that might directly interfere with the function of specific EBV genes. This review summarises the role of EBV in malignancy. In particular, it focuses on the latent proteins as a basis for understanding how EBV might contribute to the process of transformation. Strategies to target EBV in tumours, potentially providing alternative therapeutic approaches, are also discussed.
Molecular organisation of cell–matrix contacts: essential multiprotein assemblies in cell and tissue function
Authors: Adams Josephine Clare
Published: October 2003

The adhesion of cells to their surrounding extracellular matrix has vital roles in embryonic development, inflammatory responses, wound healing and adult tissue homeostasis. Cells attach to extracellular matrix by specific cell-surface receptors, of which the integrins and transmembrane proteoglycans are major representatives. The engagement of adhesion receptors triggers assembly of functional matrix contacts, in which bound matrix components, adhesion receptors and associated intracellular cytoskeletal and signalling molecules form large, localised multiprotein complexes. This review discusses the functional categories of matrix contacts, examples of the biological roles of matrix contacts in normal physiology, and examples of the ways in which abnormalities of matrix contacts are associated with major human diseases.
Chagas disease: role of parasite genetic variation in pathogenesis
Authors: Macedo Andréa M. , Oliveira Riva P. , Pena Sérgio D.J.
Published: October 2003

Chagas disease, caused by the parasite protozoan Trypanosoma cruzi, is characterised by a variable clinical course, from symptomless cases to severe chronic disease with cardiac and/or gastrointestinal involvement. This variability has been attributed both to differences in the host response and to genomic heterogeneity of the parasite. This article reviews the evidence in favour of an important role of the genetic constitution of T. cruzi in determining the clinical characteristics of Chagas disease and discusses the basis of the ‘Clonal-Histotropic Model’ for the pathogenesis of this disease.
The liver: a model of organ-specific lymphocyte recruitment
Authors: Lalor Trish , Adams David
Published: October 2003

The liver is constantly exposed to gut-derived antigens that enter via the portal vein, and it must modulate immune responses so that harmful pathogens are cleared but necessary food antigens are ignored. The liver contains a large resident and migratory population of lymphocytes and macrophages that provide immune surveillance against foreign antigen. This population of cells can be rapidly expanded in response to infection or injury by recruiting leukocytes from the circulation, a process that is dependent on the ability of lymphocytes to recognise, bind to and migrate across the endothelial cells that line the vasculature. Lymphocytes can enter the liver at several sites: the vascular endothelium in the portal tracts (comprising the hepatic artery, portal vein and bile ductule), the sinusoids (through which the blood percolates past the hepatocytes) or the central hepatic veins (through which the blood exits). The requirements and physical conditions at each site vary and there is evidence that different combinations of adhesion proteins are involved at these different sites. This article discusses the expression and function of adhesion molecules within the liver and demonstrates how specific populations of effector lymphocytes can be selectively recruited to the liver.
Aberrant DNA methylation in cancer: potential clinical interventions
Authors: Strathdee G. , Brown R.
Published: October 2003

DNA methylation, the addition of a methyl group to the carbon-5 position of cytosine residues, is the only common covalent modification of human DNA and occurs almost exclusively at cytosines that are followed immediately by a guanine (so-called CpG dinucleotides). The bulk of the genome displays a clear depletion of CpG dinucleotides, and those that are present are nearly always methylated. By contrast, small stretches of DNA, known as CpG islands, are comparatively rich in CpG nucleotides and are nearly always free of methylation. These CpG islands are frequently located within the promoter regions of human genes, and methylation within the islands has been shown to be associated with transcriptional inactivation of the corresponding gene. Alterations in DNA methylation might be pivotal in the development of most cancers. In recent years, it has become apparent that the pattern of DNA methylation observed in cancer generally shows a dramatic shift compared with that of normal tissue. Although cancers often exhibit clear reductions throughout their genomes in the levels of DNA methylation, this goes hand-in-hand with increased methylation at the CpG islands. Such changes in methylation have a central role in tumourigenesis; in particular, methylation of CpG islands has been shown to be important in transcriptional repression of numerous genes that function to prevent tumour growth or development. Studies of DNA methylation in cancer have thus opened up new opportunities for diagnosis, prognosis and ultimately treatment of human tumours.
Manipulation of dendritic cells as an approach to improved outcomes in transplantation
Authors: Coates P. Toby H. , Colvin Bridget L. , Hackstein Holger , Thomson Angus W.
Published: October 2003

At the time of organ transplantation, a variety of non-parenchymal cells are transplanted simultaneously with the allograft. Recognition of the importance of these cells as potential immunostimulatory cells lead to the concept of ‘passenger leukocytes’ as the principal instigators of rejection. Passenger leukocytes include interstitial dendritic cells (DCs) and blood-derived monocytes/macrophages. As investigators have discovered the significance of DCs in influencing graft outcome, so have they begun to determine the best ways to influence DCs themselves. This review discusses the role of DCs in transplantation and then focuses on three different approaches for manipulating DCs to improve allograft survival: (1) targeting of chemokines involved in DC migration, (2) pharmacological arrest of DC maturation, and (3) genetic engineering of DCs.
Recent advances in understanding endogenous fibrinolysis: implications for molecular-based treatment of vascular disorders
Authors: Bodary Peter F. , Wickenheiser Kevin J. , Eitzman Daniel T.
Published: October 2003

The fate of a forming thrombus is determined through the delicate balance between the coagulation cascade, favouring clot formation, and the fibrinolytic system, favouring clot lysis. These processes occur simultaneously, and enhancement of fibrinolysis has been shown to reduce occlusive thrombus formation in animal models. This review examines the roles of the major fibrinolytic factors involved in clot lysis. The regulation of plasmin activity by plasminogen activators, α-2-antiplasmin, plasminogen activator inhibitor 1, and thrombin-activatable fibrinolysis inhibitor, and their effects on thrombus formation in vivo are discussed. Since alterations in fibrinolytic capacity appear to affect thrombus formation in animal models, there is considerable interest in the pharmacological manipulation of fibrinolysis.
The role of Raf kinases in malignant transformation
Authors: Kolch Walter , Kotwaliwale Ashwin , Vass Keith , Janosch Petra
Published: October 2003

The Raf kinases are proto-oncogenes that work at the entry point of the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway, a signalling module that connects cell-surface receptors and Ras proteins to nuclear transcription factors. The pathway impinges on all the functional hallmarks of cancer cells: immortalisation, growth-factor-independent proliferation, insensitivity to growth-inhibitory signals, ability to invade and metastasise, ability to attract blood vessels, and evasion of apoptosis. Indeed, the pathway is hyperactivated in 30% of all human tumours including prevalent cancers of the colon and lung. The molecular mechanisms underlying the role of Raf kinase in tumourigenesis and the opportunities for therapeutic intervention are reviewed in this article.
Mitochondria as targets for detection and treatment of cancer
Authors: Modica-Napolitano Josephine S. , Singh Keshav
Published: October 2003

Mitochondria are dynamic intracellular organelles that play a central role in oxidative metabolism and apoptosis. The recent resurgence of interest in the study of mitochondria has been fuelled in large part by the recognition that genetic and/or metabolic alterations in this organelle are causative or contributing factors in a variety of human diseases including cancer. Several distinct differences between the mitochondria of normal cells and cancer cells have already been observed at the genetic, molecular and biochemical levels. As reviewed in this article, certain of these alterations in mitochondrial structure and function might prove clinically useful either as markers for the early detection of cancer or as unique molecular sites against which novel and selective chemotherapeutic agents might be targeted.
Telomerase-directed molecular therapeutics
Authors: Keith W. Nicol , Bilsland Alan , Evans T.R. Jeffry , Glasspool Rosalind M.
Published: October 2003

The management of malignant disease remains one of the most challenging areas of modern medicine. The lifetime risk of developing cancer in the western world is estimated to be as high as 1 in 3. Traditionally, surgery, chemotherapy and radiotherapy have been the primary choice of treatment for patients with malignant tumours. Despite advances in the use and development of conventional cytotoxic agents, the cure rate remains disappointing in most patients with advanced disease of the common solid tumours. Consequently, the development of novel anti-cancer therapies is a high priority in cancer medicine. In recent years, a new generation of cancer therapies has emerged, based on a growing understanding of the molecular events that contribute to malignant transformation. A major difference between normal and cancer cells is the ability of cancer cells to multiply in an unrestricted and ungoverned fashion. In this context, there is considerable interest in elucidating the mechanisms that allow this unrestricted proliferation and that ultimately result in immortal cancer cells. It is now clear that the enzyme telomerase confers immortality on cells in most types of cancer. With the cancer cell reliant on telomerase for its survival, telomerase represents an extremely attractive mechanism-based target for the development of new cancer therapeutics.
Hereditary transthyretin amyloidosis: molecular basis and therapeutical strategies
Authors: Saraiva Maria João Mascarenhas
Published: October 2003

Transthyretin (TTR) is a transport protein for thyroid hormones and vitamin A and might have an important role in the nervous system. However, TTR can undergo a conformational change and form amyloid fibrils, in both acquired and hereditary forms of systemic amyloidosis. More than 80 TTR mutations have been associated with autosomal dominant amyloidosis, usually presenting with peripheral and autonomic neuropathy and/or cardiomyopathy. Major areas of research in TTR amyloidosis include: molecular mechanisms leading to fibril formation; mechanisms of fibril-induced cell death; modulators of phenotypic expression of the disease; and therapeutic strategies.
The molecular genetics of schizophrenia: an emerging consensus
Authors: Faraone Stephen V. , Taylor Levi , Tsuang Ming
Published: October 2003

Schizophrenia is perhaps the most debilitating mental disease and determining the underlying cause has become a challenging area of psychiatric research. It is relatively well established that genes play a role in the aetiology of schizophrenia. In this article, a review of important findings related to schizophrenia as a genetic trait will be provided, including a discussion of family, twin and adoption studies. Molecular genetic studies of specific candidate genes are then reviewed. Some controversies within the literature are examined and possible directions for future research are discussed.
Advances in the diagnosis and treatment of leprosy
Authors: Katoch Vishwa M.
Published: October 2003

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that mainly affects the skin and peripheral nerves. Over recent years, many important advances have been made in developing molecular diagnostics, in identifying highly effective drugs and designing multidrug regimens for treatment, and in unravelling the genomic structure and functions of the leprosy bacillus. Using the new information about specific sequences of M. leprae, several gene probes and gene amplification systems for confirming diagnosis and monitoring treatment have been developed. Among these, polymerase chain reaction (PCR)-based methods have been useful in confirming the diagnosis in paucibacillary leprosy (where few bacilli are present). RNA-targeting systems for monitoring the progress of treatment, in situ hybridisation techniques for analysing specimens with nonspecific histological features, and molecular methods for direct detection of rifampicin/dapsone resistance are other major technological advances with immense applied value. Several effective regimens for the treatment of leprosy have been developed, which include rifampicin, clofazimine and dapsone as core drugs. Although these regimens are generally satisfactory, limitations in terms of persisting activity and late reactions/relapses in paucibacillary leprosy, and persistence of dead and/or live organisms in multibacillary forms of the disease, have been observed.
Muscular dystrophies, dilated cardiomyopathy, lipodystrophy and neuropathy: the nuclear connection
Authors: Maidment Stephen L. , Ellis Juliet A.
Published: October 2003

An understanding of muscle structure and function is central to improving our knowledge of the group of muscle diseases referred to as muscular dystrophies. These diseases involve a progressive weakening and wasting of skeletal muscle, which can be associated with life-threatening cardiac arrhythmias. The vast majority of these diseases arise from defects in either cytoskeletal or structural proteins, resulting in a breakdown of muscle cell integrity. However, mutations in two nuclear proteins – emerin and lamin A/C – have also been demonstrated to give rise to a muscular dystrophy phenotype. In addition, mutations in lamin A/C can give rise to a dilated cardiomyopathy, a lipodystrophy or a neuropathy. It is far from clear how mutations in nuclear proteins can result in a dystrophy, or cause more than one clinically distinct disease. Understanding the functional role of nuclear proteins in causing these diseases will therefore provide novel insights into muscle function, and should hopefully provide new directions for treatment.
Presenilin-interacting proteins
Authors: Chen Qi , Schubert David
Published: October 2003

Familial Alzheimer's disease (FAD) accounts for 5–10% of deaths from Alzheimer's disease (AD), and approximately 50% of these cases have been definitely linked to missense mutations in three genes, encoding the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). Of these, the vast majority of FAD-linked mutations are within PS1. There has been an extensive effort to identify proteins that functionally interact with PS1 and PS2 because of their clear roles in FAD. The goal of this review is to describe these proteins and to discuss in more detail the probable biological functions of a subset of the better-studied interacting proteins. In particular, the review examines APP, Notch, nicastrin, modifier of cellular adhesion (MOCA), β-catenin, and the group of proteins involved in cell death, calcium metabolism and cell adhesion. We argue that, although a few of the interacting proteins are unambiguously involved in well-studied cellular pathways, their exact roles within these pathways have not been clearly defined, and indeed might vary between cell types. We also question the physiological relevance of some of the work linking PS to cell death pathways. Finally, we point out the value of using flies and worms to sort out the often contradictory work in the PS field, and we mention how knowledge of PS-interacting pathways will contribute to the development of new therapeutic strategies in AD.
Androgenetic alopecia: pathogenesis and potential for therapy
Authors: Ellis Justine A. , Sinclair Rodney , Harrap Stephen B.
Published: October 2003

Androgenetic alopecia occurs in men and women, and is characterised by the loss of hair from the scalp in a defined pattern. Determining factors appear to be genetic predisposition coupled with the presence of sufficient circulating androgens. The prevalence of this condition is high (up to 50% of white males are affected by 50 years of age) and, although there are no serious direct health consequences, the loss of scalp hair can be distressing. Knowledge of the pathogenesis of androgenetic alopecia has increased markedly in recent years. Pre-programmed follicles on the scalp undergo a transformation from long growth (anagen) and short rest (telogen) cycles, to long rest and short growth cycles. This process is coupled with progressive miniaturisation of the follicle. These changes are androgen dependent, and require the inheritance of several genes. To date, only one of these genes, which encodes the androgen receptor (AR), has been identified. Of the many treatments available for androgenetic alopecia, only two (finasteride and minoxidil) have been scientifically shown to be useful in the treatment of hair loss. However, these therapies are variable in their effectiveness. Discovery of the involvement of the AR gene, and the identification of other genes contributing to the condition, might lead to the development of new and more effective therapies that target the condition at a more fundamental level.
Pre- and early postnatal nongenetic determinants of type 2 diabetes
Authors: Ozanne Susan E. , Hales C. Nick
Published: October 2003

Epidemiological studies have revealed strong and internationally reproducible links between early growth restriction and subsequent risk of developing type 2 diabetes and the metabolic syndrome (glucose intolerance, hypertension and hypertriglyceridaemia). This effect can exist independently of genetic factors. There is also direct evidence that poor maternal nutrition and maternal smoking cause both a reduction in birthweight and subsequent loss of glucose tolerance. High rates of growth in childhood may add to these effects. The ‘thrifty phenotype’ hypothesis attempts to explain these associations in terms of an altered programming of growth and metabolism that aids survival both pre- and postnatally. Type 2 diabetes is envisaged as a consequence of a clash of this programming with adult obesity. Tests of this hypothesis in animal models have shown that both the metabolic syndrome and type 2 diabetes can result from early growth restriction in rats consequent upon rat dams being fed a reduced protein, isocaloric diet (in which the protein is replaced by an equal quantity of nonprotein energy). A variety of other models of early growth restriction in rats lead to a similar phenotype. Several structural and gene expression changes have been shown in many tissues, including pancreas, liver, kidney, muscle and adipose tissue. Changes in gene expression include those concerned with hormone receptors, signalling and glycolytic enzymes. Many important questions remain for future research.
Molecular and cellular bases of syndromic craniosynostoses
Authors: Bonaventure Jacky , El Ghouzzi Vincent
Published: October 2003

Premature fusion of cranial sutures underlies the clinical condition of ‘craniosynostosis’, a common human disorder that occurs in both nonsyndromic and syndromic forms. The subgroup of syndromic craniosynostoses usually associates limb abnormalities and facial dysmorphism to skull distortion. Over the past decade, some of the genes causing these phenotypes have been identified. Among these, the gene encoding FGFR2, one of four members of the fibroblast growth factor receptor (FGFR) family, has been shown to account for several severe conditions including Apert, Pfeiffer, Crouzon, Beare–Stevenson and Jackson–Weiss syndromes. Two other FGFRs, FGFR1 and FGFR3, also account for craniosynostoses of variable severity [Pfeiffer, Crouzon with acanthosis nigricans (a pre-malignant skin disorder), and Muenke syndromes]. By contrast, Saethre–Chotzen syndrome and craniosynostosis (Boston-type) arise from mutations in the Twist and muscle segment homeobox 2 (MSX2) transcription factors, respectively. Whereas most FGFR mutations are likely to cause ligand-independent activation of the receptor, leading to an upregulation of signaling pathways, mutations in the basic helix–loop–helix (bHLH) transcription factor Twist appear to induce loss of protein function. This review will summarise and discuss some of the cellular and molecular mechanisms involved in normal and abnormal craniofacial development, focusing on the possible interactions between the different factors controlling membranous ossification.
Skin repair and scar formation: the central role of TGF-β
Authors: Beanes Steven R. , Dang Catherine , Soo Chia , Ting Kang
Published: October 2003

Wound healing is a complex process that we have only recently begun to understand. Central to wound repair is transforming growth factor β (TGF-β), a cytokine secreted by several different cell types involved in healing. TGF-β has diverse effects, depending upon the tissue studied. This review focuses on healing in skin, particularly the phases of cutaneous wound repair and the role of TGF-β in normal and impaired wound-healing models. It also explores TGF-β activity in scarless foetal wound healing. Knowledge of TGF-β function in scarless repair is critical to improving healing in clinical scenarios, such as diabetic wounds and hypertrophic scars.
Anti-p53-directed immunotherapy of malignant disease
Authors: Theobald Matthias , Offringa Rienk
Published: October 2003

Mutation and aberrant expression of the p53 tumour suppressor protein are the most frequent molecular alterations in human malignancy. Peptides derived from the p53 protein and presented by major histocompatibility complex molecules for T-cell recognition could serve as universal tumour-associated antigens for cancer immunotherapy. Because p53 normally functions as a ubiquitously expressed self-protein, controlling cell-cycle progression and apoptosis, it also represents a paradigm target molecule for tumour-reactive yet self-antigen-specific T cells. Tailoring p53-based cancer immunotherapy thus requires both interference with p53-specific self-tolerance and induction of the entire repertoire of p53-reactive T cells. Transferring selected T-cell receptor genes into human T cells offers a novel and appealing strategy to meet these requirements.
Grb7-based molecular therapeutics in cancer
Authors: Pero Stephanie C. , Daly Roger J. , Krag David N.
Published: October 2003

Traditional anti-cancer drugs preferentially kill rapidly growing tumour cells rather than normal cells. However, most of these drugs have no preferential selection towards cancer cells and are taken up by the whole body, resulting in significant adverse side effects. Therapeutic molecules that could specifically inhibit undesirable phenotypes are an attractive way of eliminating cancer cells. There is a widespread effort to develop inhibitors against signal transduction molecules that play a key role in the proliferative, migratory and invasive properties of a cancer cell. Grb7 is an adaptor-type signalling protein that is recruited via its Src-homology 2 (SH2) domain to a variety of tyrosine kinases. Grb7 is overexpressed in breast, oesophageal and gastric cancers, and may contribute to the invasive potential of cancer cells. Molecular interactions involving Grb7 therefore provide attractive targets for therapeutic intervention.
Innate immunity and brain inflammation: the key role of complement
Authors: Francis Karen , van Beek Johan , Canova Cecile , Neal Jim W. , Gasque Philippe
Published: October 2003

The complement inflammatory cascade is an essential component of the phylogenetically ancient innate immune response and is crucial to our natural ability to ward off infection. Complement is involved in host defence by triggering the generation of a membranolytic complex (the C5b-9 complex) at the surface of the pathogen. Complement fragments (opsonins; C1q, C3b and iC3b) interact with complement cell-surface receptors (C1qRp, CR1, CR3 and CR4) to promote phagocytosis and a local pro-inflammatory response that, ultimately, contributes to the protection and healing of the host. Complement is of special importance in the brain, where entrance of elements of the adaptive immune system is restricted by a blood–brain barrier. There is now compelling evidence that complement is produced locally in response to an infectious challenge. Moreover, complement biosynthesis and activation also occurs in neurodegenerative disorders such as Alzheimer's, Huntington's and Pick's diseases, and the cytolytic/cytotoxic activities of complement are thought to contribute to neuronal loss and brain tissue damage. However, recent data suggest that at least some of the complement components have the ability to contribute to neuroprotective pathways. The emerging paradigm is that complement is involved in the clearance of toxic cell debris (e.g. amyloid fibrils) and apoptotic cells, as well as in promoting tissue repair through the anti-inflammatory activities of C3a. Knowledge of the unique molecular and cellular innate immunological interactions that occur in the development and resolution of pathology in the brain should facilitate the design of effective therapeutic strategies.
Gene therapy for cancer and metastatic disease
Authors: Kesmodel Susan B. , Spitz Francis R.
Published: October 2003

Gene therapy has been applied to the treatment of cancer and metastatic disease for over ten years. Research in this area has utilised multiple gene therapy approaches including targeting tumour suppressor genes and oncogenes, stimulating the immune system, targeted chemotherapy, antiangiogenic strategies, and direct viral oncolysis. In recent years, gene delivery vectors have been developed that selectively target tumour cells through tumour-specific receptors, deletion of certain viral gene sequences, or incorporation of tumour-specific promoter sequences that drive gene expression. Preclinical models have produced promising results, demonstrating significant tumour regression and reduction of metastatic disease. Unfortunately, only limited responses have been observed in clinical trials. The main limitations in treating metastatic disease include poor vector transduction efficiencies and difficulties in targeting remote tumour cells with systemic vector delivery. Currently, various groups are investigating means to improve gene delivery and clinical responses by continuing to modify gene delivery vectors and by concentrating on combination gene therapy and multimodality therapy.
Cobalamin transport proteins and their cell-surface receptors
Authors: Seetharam Bellur , Yammani Raghunatha R.
Published: October 2003

The primary function of cobalamin (Cbl; vitamin B12) is the formation of red blood cells and the maintenance of a healthy nervous system. Before cells can utilise dietary Cbl, the vitamin must undergo cellular transport using two distinct receptor-mediated events. First, dietary Cbl bound to gastric intrinsic factor (IF) is taken up from the apical pole of ileal epithelial cells via a 460 kDa receptor, cubilin, and is transported across the cell bound to another Cbl-binding protein, transcobalamin II (TC II). Second, plasma TC II–Cbl is taken up by cells that need Cbl via the TC II receptor (TC II-R), a 62 kDa protein that is expressed as a functional dimer in cellular plasma membranes. Human Cbl deficiency can develop as a result of acquired or inherited dysfunction in either of these two transmembrane transport events. This review focuses on the biochemical, cellular and molecular aspects of IF and TC II and their cell-surface receptors.
Toll-like receptors and intestinal defence: molecular basis and therapeutic implications
Authors: Cario Elke
Published: October 2003

Toll-like receptors (TLRs) play a principle role in distinct pathogen recognition and in the initiation of innate immune responses of the intestinal mucosa. Activated innate immunity interconnects downstream with adaptive immunity in complex feedback regulatory loops. Intestinal disease might result from inappropriate activation of the mucosal immune system driven by TLRs in response to normal luminal flora.
Huntington's disease: molecular basis of neurodegeneration
Authors: Rubinsztein David C. , Carmichael Jenny
Published: October 2003

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product (‘huntingtin’). Studies in humans and mouse models suggest that the mutation is associated with a deleterious gain-of-function. Several studies have suggested that the large huntingtin protein is cleaved to produce a shorter N-terminal fragment containing the polyglutamine expansion, and that the polyglutamine expansion causes the protein fragment to misfold and form aggregates (inclusions) in the nuclei and processes of neurons. It is likely that neurotoxicity is caused by the misfolded protein in its soluble form, and/or in aggregates, and/or in the process of aggregation. A wide range of potential mechanisms for neurotoxicity have been proposed, including caspase activation, dysregulation of transcriptional pathways, increased production of reactive oxygen species, and inhibition of proteasome activity. In this review we consider the current status of research in the field and possible mechanisms whereby the HD mutation might result in neurodegeneration.
Nonviral gene delivery: techniques and implications for molecular medicine
Authors: Parker Alan L. , Newman Christopher , Briggs Simon , Seymour Leonard , Sheridan Paul J.
Published: October 2003

Medical research continues to illuminate the origins of many human diseases. Gene therapy has been widely proposed as a novel strategy by which this knowledge can be used to deliver new and improved therapies. Viral gene transfer is relatively efficient but there are concerns relating to the use of viral vectors in humans. Conversely, nonviral vectors appear safe but inefficient. Therefore, the development of an efficient nonviral vector remains a highly desirable goal. This review focuses on the numerous challenges preventing efficient nonviral gene transfer in vivo and discusses the many technologies that have been adopted to overcome these problems.
Repeat expansion and autosomal dominant neurodegenerative disorders: consensus and controversy
Authors: Rudnicki Dobrila D. , Margolis Russell L.
Published: October 2003

Repeat-expansion mutations cause 13 autosomal dominant neurodegenerative disorders falling into three groups. Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs) types 1, 2, 3, 7 and 17 are each caused by a CAG repeat expansion that encodes polyglutamine. Convergent lines of evidence demonstrate that neurodegeneration in these diseases is a consequence of the neurotoxic effects of abnormally long stretches of glutamines. How polyglutamine induces neurodegeneration, and why neurodegeneration occurs in only select neuronal populations, remains a matter of intense investigation. SCA6 is caused by a CAG repeat expansion in CACNA1A, a gene that encodes a subunit of the P/Q-type calcium channel. The threshold length at which the repeat causes disease is much shorter than in the other polyglutamine diseases, and neurodegeneration may arise from expansion-induced change of function in the calcium channel. Huntington's disease-like 2 (HDL2) and SCAs 8, 10 and 12 are rare disorders in which the repeats (CAG, CTG or ATTCT) are not in protein-coding regions. Investigation into these diseases is still at an early stage, but it is now reasonable to hypothesise that the net effect of each expansion is to alter gene expression. The different pathogenic mechanisms in these three groups of diseases have important implications for the development of rational therapeutics.
Molecular mechanisms by which dietary isoflavones potentially prevent atherosclerosis
Authors: Cassidy Aedin , de Pascual Teresa Sonia , Rimbach Gerald
Published: October 2003

Dietary isoflavones are currently receiving much attention because of their potential role in preventing coronary artery disease and other chronic diseases. Accumulating evidence from cell culture and laboratory animal experiments indicates that isoflavones have the potential to prevent or delay atherogenesis. Suggested mechanisms of action include: a reduction in low-density lipoprotein (LDL) cholesterol and a potential reduction in the susceptibility of the LDL particle to oxidation; (2) an improvement in vascular reactivity; (3) an inhibition of pro-inflammatory cytokines, cell adhesion proteins and nitric oxide (NO) production; and (4) an inhibition of platelet aggregation. These mechanisms are consistent with the epidemiological evidence that a high consumption of isoflavone-rich soy products is associated with a reduced incidence of coronary artery disease. Biological effects of isoflavones are dependent on many factors, including dose consumed, duration of use, protein-binding affinity, and an individual's metabolism or intrinsic oestrogenic state. Further clinical studies are necessary to determine the potential health effects of isoflavones in specific population groups as we currently know little about age-related differences in exposure to these compounds and there are few guidelines on optimal dose for cardiovascular health benefits.
Human
herpesvirus 6
Authors: Dewhurst Stephen , Skrincosky David , van
Loon Nanette
Published: October 2003

Human herpesvirus 6 (HHV-6) is a T-lymphotropic herpesvirus, which infects
almost all children by the age of two years and persists lifelong. Two distinct
variants of HHV-6, HHV-6A and HHV-6B, have been described, and the latter has
been shown to be a common cause of acute febrile illnesses in young children,
including exanthem subitum (roseola). HHV-6 has also been associated with a
number of neurological disorders, including encephalitis and seizures, and the
virus has been postulated to play a role in acquired immunodeficiency syndrome
(AIDS), multiple sclerosis (MS) and chronic fatigue immunodeficiency syndrome
(CFIDS). This review provides a critical summary of research conducted on HHV-6.
Human
herpesvirus 7
Authors: Dewhurst Stephen , Skrincosky David , van Loon Nanette
Published: October 2003

Human herpesvirus 7 (HHV-7) is a recently described T-lymphotropic herpesvirus,
which infects almost all children by the age of three years and persists lifelong,
with the shedding of infectious virus in saliva. HHV-7 is similar to human herpesvirus
6 (HHV-6) in its genetic content and in many of its biological properties, which
include the ability to cause at least some cases of exanthem subitum (roseola).
Despite these similarities, important differences between HHV-7 and HHV-6 exist,
including the fact that HHV-7 binds to the cellular CD4 molecule and uses this
protein as a necessary component of its receptor, while HHV-6 binds to a different
(and unknown) receptor. Furthermore, the pathogenesis and sequelae of HHV-7
infection remain very poorly understood. This review provides a critical summary
of research on HHV-7.
Clinical
disease, immunity and protection against Plasmodium falciparum malaria
in populations living in endemic areas
Authors: Hviid Lars
Published: October 2003

Malaria remains one of the biggest health problems in large parts of the world.
In sub-Saharan Africa alone, it is currently estimated that there are more than
150 million clinical cases annually, and that about 2 million people die from
the disease every year. The bulk of malaria-related morbidity and mortality
in an endemic setting (malaria is regularly found) is concentrated in children
below the age of five years, and the increasing resistance to infection and
disease with age is conventionally thought to reflect a slow and gradual acquisition
of protective immunity. Many recent and comprehensive reviews of malarial immunity
exist; rather than attempting to add another, this review summarises some of
the recent evidence on how protective immunity is acquired in humans and what
precipitates clinical disease, specifically as it relates to populations living
in areas where the disease is endemic. It is becoming increasingly clear that
naturally acquired protective immunity depends largely on responses directed
against highly variable parasite antigens. This implies that a successful blood-stage
vaccine against this disease must be able to either induce protective responses
against many of these variants, or artificially initiate protective immune responses
that do not normally occur following natural exposure to the parasites. Such
protective immune responses might either rely on a different immunological mechanism,
or be directed against other antigens, other than those seen in naturally acquired
protective immunity. It remains to be seen whether it will be possible to induce
protective responses such as these by ‘artificially’ immunising humans.
Human cellular immune responses against human papillomaviruses in cervical neoplasia
Authors: Man Stephen
Published: October 2003

Human papillomaviruses (HPVs) are ubiquitous DNA viruses that infect cutaneous and mucosal epithelia. A subset of HPVs infects the female genital tract, to induce cervical lesions that can progress to malignancy in some women. DNA from HPVs can be found in >94% of cervical carcinomas (CaCx) worldwide; this strong association suggests that it might be possible to develop either prophylaxis or therapies for cervical neoplasia, based on the manipulation of human immune responses against HPVs. This review examines the current research into human immune responses against HPVs in CaCx and the potential impact of this research on human health.
Measuring
human T-lymphocyte function
Authors: Hickling Julian K.
Published: October 2003

T lymphocytes (T cells) play critical roles in the regulation of immune responses,
and are responsible for mediating many of the effector mechanisms of the immune
system. For this reason, there has always been a need for assays to measure
accurately the activity of populations of T cells, both in model (animal) systems
and in humans. The expansion of the biotechnology industry has led to a dramatic
increase in the number of novel immunotherapeutics that are being developed
for the treatment of cancer, autoimmune disorders and infectious diseases. This
increase in activity in the field of immunotherapy, coupled with the expense
of clinical trials, has led to renewed interest in methods that accurately assess
T-cell function, as researchers seek to maximise the amount of information that
can be obtained from each clinical study. Assessing the quantitative and qualitative
nature of a T-cell response, for example following vaccination or immunosuppressive
therapy, can provide valuable information about the efficacy of a treatment,
in place of a clinical endpoint. This article reviews some of the established
methods that are used to monitor human T-cell activity, and describes some new
approaches that are in development to increase the speed, sensitivity and relevance
of such methods.
Structure–function
analysis and the molecular origins of anti-DNA antibodies in systemic lupus erythematosus
Authors: Kalsi Jatinderpal , Ravirajan Chelliah T. , Rahman Anisur , Isenberg David A.
Published: October 2003

Patients with the autoimmune rheumatic disease systemic lupus erythematosus
(SLE or ‘lupus’) develop a wide variety of clinical and serological manifestations
including the presence of antibodies to double-stranded DNA (dsDNA), which are
often diagnostic and potentially pathogenic. In this review, we have examined
the links between the structure and function of anti-dsDNA antibodies, emphasising
their clinical associations. We have also reviewed studies involving animal
models, the analysis of human antibody sequences and studies of, and using,
computer modelling and crystal structure.
Molecular
genetics and the assessment of human cancers
Authors: Caldas Carlos , Pharoah Paul D.P.
Published: October 2003

The past 20 years have seen rapid advances in the understanding of the biology
of human cancers, and a large body of evidence now supports the idea that accumulated
genetic changes underlie the development of neoplasia. In this article, we have
reviewed the current research into the genetic bases of cancer and discussed
the potential clinical applications of recent advances, with particular reference
to the possibility of using molecular genetic tests for pre-symptomatic screening,
clinical diagnosis and clinical staging. The possibility that the genetic profile
of a tumour, its ‘molecular fingerprint’, will improve the ability
of oncologists to predict tumour behaviour and thus help to determine optimum
treatment has also been considered. Although the potential for the application
of molecular genetic technologies is enormous, these technologies have yet to
be subjected to rigorous evaluation in a clinical setting, and much work needs
to be done before they are adopted for use in routine clinical care.
Molecular-based
diagnosis of Entamoeba histolytica infection
Authors: Huston Christopher
D. , Haque Rashidul , Petri William A.
Published: October 2003

Infection with Entamoeba histolytica, the protozoan parasite that causes amoebic
colitis and liver abscess, results in 34 million to 50 million symptomatic cases
of amoebiasis (all illnesses caused by E. histolytica, including amoebic dysentery)
worldwide each year, causing 40 thousand to 100 thousand deaths annually. As
a result of accruing biochemical, genetic and immunological data, E. histolytica
was re-defined in 1993 to recognise the existence of two morphologically identical
but genetically distinct human parasites: E. histolytica, the aetiological agent
of invasive intestinal and extraintestinal amoebiasis, and Entamoeba dispar,
a non-pathogenic intestinal parasite. Because microscopy is unable to distinguish
between these two organisms, it should no longer be relied upon to diagnose
amoebiasis. Sensitive and specific molecular techniques that are able to distinguish
E. histolytica from E. dispar have been developed recently; they include (1)
the detection of an E. histolytica antigen using an enzyme-linked immunosorbent
assay (ELISA), (2) the use of the polymerase chain reaction (PCR) to amplify
amoebic DNA, and (3) the culture of stool samples followed by isoenzyme analysis.
Of these three test methods, only antigen detection using ELISA can be performed
rapidly and easily, making it the diagnostic test method of choice for clinical
use in the developing world, where the morbidity and mortality caused by E.
histolytica are greatest. However, the PCR method is a powerful tool for the
genetic typing of different amoebic strains. Together these two methods should
result in both improved clinical diagnosis and treatment of amoebiasis, and
a greater understanding of the epidemiology of E. histolytica. Such knowledge
will not only assist public health efforts to control amoebiasis, but also facilitate
the careful testing of the anti-amoebic vaccines that are currently being developed.
Cell motility and cell morphology: How some viruses take control
Authors: Smith Geoffrey L. , Sanderson Christopher M.
Published: October 2003

Viruses replicate inside host cells, where they use host biochemical and structural components to facilitate the production of new virus particles. As a consequence of co-evolution with their hosts, viruses have acquired host genes and genetic mutations that confer dominance over normal cell function. Research on virus–cell interactions has focused on the identification of mechanisms of virus dominance in order to develop therapeutic strategies for preventing productive infection. Although such research remains an essential part of molecular virology, viruses are also important genetic tools that can be used to analyse cell function. Because virus genomes contain genetic information, some of which was derived from host cells, it is possible that the analyses of virus–host interactions might lead to the identification of functionally dominant virus genes and novel eukaryotic counterparts. In this article, we have described how transforming and non-transforming viruses can control cell motility (cell migration or membrane projection), and explained how the analysis of virus cytopathic effects (CPEs) led to the identification of a novel family of cellular genes that regulate diverse aspects of cell motility.