 |
 |
 |
||||||
每日一文 |
||||||||
|
||||||||
|
|
||||||||
| March 31,2004 | Recipes for adult stem cell plasticity | |||||||
| A large body of evidence supports the idea that certain adult stem cells, particularly those of bone marrow origin, can engraft at alternative locations, particularly when the recipient organ is damaged. Under strong and positive selection pressure these cells will clonally expand/ differentiate, making an important contribution to tissue replacement. Similarly, bone marrow derived cells can be amplified in vitro and differentiated into many types of tissue. Despite seemingly irrefutable evidence for stem cell plasticity, a veritable chorus of detractors has emerged, some doubting its very existence, motivated perhaps by more than a little self interest. The issues that have led to this situation include the inability to reproduce certain quite startling observations, and extrapolation from the behaviour of embryonic stem cells to suggest that adult bone marrow cells simply fuse with other cells and adopt their phenotype. | ||||||||
| March 30,2004 | IMPLICATIONS OF THE PRECAUTIONARY PRINCIPLE FOR PRIMARY PREVENTION AND RESEARCH | |||||||
| The precautionary principle (PP) is an extension of the public health presage that prevention is better than cure. The PP has recently achieved new relevance in regard to serious but uncertain threats to human health and the environment, and has now entered national and international legislation. However, frameworks for its unambiguous application in practice are yet to be designed. They will depend on legal and cultural circumstances and are likely to involve pluralities of perspectives and stakeholder participation. The rules for causal reasoning and dose dependence need to be addressed and may be conveniently expressed in accordance with probability theory. Although the PP will allow action before convincing evidence is secured, it is not science averse. | ||||||||
| March 29,2004 | Epoetin Alfa | |||||||
| Recombinant human erythropoietin (epoetin alfa) has been used in clinical settings for more than a decade. Its indications have expanded considerably from its original use as hormone therapy in the treatment of anemia in adults with chronic kidney disease. Since the introduction of epoetin alfa, a greater understanding of anemia pathophysiology and the interactions of erythropoietin, iron, and erythropoiesis has been elucidated. Anemia is now independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia in various patient populations are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia with epoetin alfa. Moreover, this agent’s therapeutic use may extend beyond currently accepted roles. Epoetin alfa is undergoing evaluation with promising results in a variety of new clinical settings, including anemia associated with congestive heart failure, ribavirin–interferon alfa treatment of hepatitis C virus infection, and critical illness. | ||||||||
| March 28,2004 | A comparison of oligonucleotide and cDNA-based microarray systems | |||||||
| Large-scale public data mining will become more common as public release of microarray data sets becomes a corequisite for publication. Therefore, there is an urgent need to clarify whether data from different microarray platforms are comparable. To assess the compatibility of microarray data, results were compared from the two main types of high-throughput microarray expression technologies, namely, an oligonucleotide-based and a cDNA-based platform, using RNA obtained from complex tissue (human colonic mucosa) of five individuals. From 715 sequence-verified genes represented on both platforms, 64% of the genes matched in "present" or "absent" calls made by both platforms. Calls were influenced by spurious signals caused by Alu repeats in cDNA clones, clone annotation errors, or matched probes that were designed to different regions of the gene; however, these factors could not completely account for the level of call discordance observed. | ||||||||
| March 27,2004 | Gender, sex hormones, and vascular tone | |||||||
| The greater incidence of hypertension and coronary artery disease in men and postmenopausal women compared with premenopausal women has been related, in part, to gender differences in vascular tone and possible vascular protective effects of the female sex hormones estrogen and progesterone. However, vascular effects of the male sex hormone testosterone have also been suggested. Estrogen, progesterone, and testosterone receptors have been identified in blood vessels of human and other mammals and have been localized in the plasmalemma, cytosol, and nuclear compartments of various vascular cells, including the endothelium and the smooth muscle. The interaction of sex hormones with cytosolic/nuclear receptors triggers long-term genomic effects that could stimulate endothelial cell growth while inhibiting smooth muscle proliferation. | ||||||||
| March 26,2004 | In the Search for Stroke Genes | |||||||
| In spite of a significant improvement in control of numerous predisposing risk factors, stroke remains a major health problem and a common cause of death and disability in our societies. Genetic predisposition to stroke development exists and has been documented in both animal models and in humans. However, a precise definition of genetic factors responsible for common forms of stroke is still lacking, mainly due to its complex nature, the confounding presence of other predisposing risk factors, and the genetic heterogeneity of human populations. In contrast, important breakthroughs have been reached for monogenic forms of stroke, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. | ||||||||
| March 25,2004 | Stress-induced apoptosis | |||||||
| Apoptosis is a form of programmed cell death executed by caspases activated along signalling pathways initiated by ligation of cell-surface death receptors (extrinsic pathway) or by perturbation of the mithocondrial membrane promoted by physical or chemical stress agents (intrinsic pathway). In metazoans, this evolutionary conserved, genetically controlled process has a role in a variety of physiological settings, as development, homeostasis of tissues and maintenance of the organism integrity. When deranged by impaired regulation or inappropriate activation apoptosis contributes to the pathogenesis of diseases as autoimmunity, cancer, restenosis, ischaemia, heart failure and neurodegenerative disorders. In this review we will present a survey of the stressinduced intrinsic, mithochondrial, pathway and, based on recent experimental data, we will propose a view compatible with an emergent conceptual symmetry between the two apoptogenic extrinsic and intrinsic pathways. | ||||||||
| March 24,2004 | Cell-cycle targeted therapies | |||||||
| Eukaryotic organisms depend on an intricate and evolutionary conserved cell cycle to control cell division. The cell cycle is regulated by a number of important protein families which are common targets for mutational inactivation or overexpression in human tumours. The cyclin D and E families and their cyclin-dependent kinase partners initiate the phosphorylation of the retinoblastoma tumour suppressor protein and subsequent transition through the cell cycle. Cyclin/cdk activity and therefore control of cell division is restrained by two families of cyclin dependent kinase inhibitors. A greater understanding of the cell cycle has led to the development of a number of compounds with the potential to restore control of cell division in human cancers. This review will introduce the protein families that regulate the cell cycle, their aberrations in malignant progression and pharmacological strategies targeting this important process. | ||||||||
| March 23,2004 | Hemostatic Regulators of Tumor Angiogenesis | |||||||
| The maintenance of vascular integrity and control of blood loss are regulated by a sophisticated system of circulating and cell-associated hemostatic factors. These factors control local platelet aggregation, the conversion of soluble fibrinogen to an insoluble fibrin polymer, and the dissolution of fibrin. However, hemostatic factors are also involved in a number of physiologic processes, including development, tissue remodeling, wound repair, reproduction, inflammation, and angiogenesis. In this review, we outline ways in which angiogenesis is coordinated with and regulated by hemostasis. We focus on inhibitors of angiogenesis contained within platelets or harbored as cryptic fragments of hemostatic proteins and assess the experimental and preclinical evidence for their ability to inhibit tumor angiogenesis and, thus, their potential to be anticancer agents. Finally, we review the results of recent clinical trials involving angiogenesis inhibitors and the evidence that antiangiogenic therapy may be associated with hemostatic complications. | ||||||||
| March 22,2004 | TISSUE ENGINEERING APPLICATIONS OF THERAPEUTIC CLONING | |||||||
| Fewtreatment options are available for patients suffering from diseased and injured organs because of a severe shortage of donor organs available for transplantation. Therapeutic cloning, where the nucleus from a donor cell is transferred into an enucleated oocyte in order to extract pluripotent embryonic stem cells, offers a potentially limitless source of cells for replacement therapy. Scientists in the field of tissue engineering apply the principles of cell transplantation, material science, and engineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. The present chapter reviews recent advances that have occurred in therapeutic cloning and tissue engineering and describes applications of these new technologies that may offer novel therapies for patients with end-stage organ failure. | ||||||||
| March 21,2004 | MOLECULAR MECHANISMS OF MAMMALIAN DNA REPAIR AND THE DNA DAMAGE CHECKPOINTS | |||||||
| DNA damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death. Damage to DNA induces several cellular responses that enable the cell either to eliminate or cope with the damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations. These DNA damage response reactions include: (a) removal of DNA damage and restoration of the continuity of the DNA duplex; (b) activation of a DNA damage checkpoint, which arrests cell cycle progression so as to allow for repair and prevention of the transmission of damaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes in the transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavily damaged or seriously deregulated cells. | ||||||||
| March 20,2004 | NEW APPROACHES TO HEMODIALYSIS | |||||||
| Treatment of end-stage renal disease with dialysis is characterized by high mortality rate, low quality of life, and high cost. Recent randomized controlled studies showed that increasing the dialysis dose above the currently recommended levels in thrice-weekly hemodialysis does not decrease the patient mortality rate. Short daily hemodialysis or daily home nocturnal hemodialysis are promising alternatives. Both improve quality of life and control blood pressure and anemia; nocturnal hemodialysis additionally controls serum phosphates without phosphate binders, allows a free diet, and corrects sleep apnea. Although the direct cost of daily hemodialysis is higher than that of conventional hemodialysis, the cost of total care, especially when delivered at home, seems to be lower. | ||||||||
| March 19,2004 | THE INTEGRATION OF PHARMACOKINETICS AND PHARMACODYNAMICS | |||||||
| Pharmacokinetic (PK) and pharmacodynamic (PD) studies have proven to be powerful and instructive tools, particularly in elucidating important aspects of human pharmacology. Nevertheless, they remain imperfect tools in that they only allow researchers to indirectly extrapolate, through computational modeling, the dynamic processes of drug action. Furthermore, neither tool alone provides a complete nor necessarily relevant picture of drug action. This reviewexplores the utility and applications of PK and PD in the study of drugs, provides examples of lessons learned from their application to studies of human pharmacology, points out some of their limitations, and advances the thesis that these tools ideally should be employed together in an integrated approach. | ||||||||
| March 18,2004 | Achieving antigen-specific immune regulation | |||||||
| A study in this issue of the JCI shows that in response to autoantigens consisting of peptides from normal proteins, patients with diabetes mount a T cell response characterized by production of IFN-g (see the related article beginning on page 451). However, in response to these same antigens, T cells from normal control subjects produce IL-10. The antigen-specific response characterized by release of a regulatory cytokine suggests a mechanism for the control of autoimmunity that is initiated at the time of antigen presentation. | ||||||||
| March 17,2004 | GENES AND SPECIATION | |||||||
| It is only in the past five years that studies of speciation have truly entered the molecular era. Recent molecular analyses of a handful of genes that are involved in maintaining reproductive isolation between species (speciation genes) have provided some striking insights. In particular, it seems that despite being strongly influenced by positive selection, speciation genes are often non-essential, having functions that are only loosely coupled to reproductive isolation. Molecular studies might also resolve the long-running debate on the relative importance of allopatric and parapatric modes of speciation. | ||||||||
| March 16,2004 | Jak family of kinases in cancer | |||||||
| The family of Jak kinases is composed from at least four different tyrosine kinases (Tyk2, Jak1, Jak2, Jak3) that share signi?cant structural homology with each other. The members of this family of kinases associate constitutively with a variety of cytokine and hormone receptors. Upon binding of the speci?c ligands to their receptors, Jak kinases are rapidly activated and their kinase activities induced, to regulate tyrosine phosphorylation of various effectors and initiate activation of downstream signaling pathways. The discovery of this family of tyrosine kinases dates back in the early 1990s with the cloning of the Tyk-2 tyrosine kinase as a critical element of the Type I interferon signaling pathway. Extensive work over the last few years has provided evidence that Jakk inases play important roles in the generation of responses for interferons, which are cytokines that exhibit important antitumor activities. | ||||||||
| March 15,2004 | A FUNCTION-BASED FRAMEWORK FOR UNDERSTANDING BIOLOGICAL SYSTEMS | |||||||
| Systems biology research is currently dominated by integrative, multidisciplinary approaches. Although important, these strategies lack an overarching systems perspective such as those used in engineering. We describe here the Axiomatic Design approach to system analysis and illustrate its utility in the study of biological systems. Axiomatic Design relates functions at all levels to the behavior of biological molecules and uses a Design Matrix to understand these relationships. Such an analysis reveals that robustness in many biological systems is achieved through the maintenance of functional independence of numerous subsystems. When the interlinking (coupling) of systems is required, biological systems impose a functional period in order to maximize successful operation of the system. | ||||||||
| March 14,2004 | ADULT STEM CELL PLASTICITY | |||||||
| There has been unprecedented recent interest in stem cells, mainly because of the hope they offer for cell therapy. Adult stem cells are an attractive source of cells for therapy, especially in view of the recent claims that they are remarkably plastic in their developmental potential when exposed to new environments. Some of these claims have been either difficult to reproduce or shown to be misinterpretations, leaving the phenomenon of adult stem cell plasticity under a cloud. There are, however, other examples of plasticity where differentiated cells or their precursors can be reprogrammed by extracellular cues to alter their character in ways that could have important implications for cell therapy and other forms of regenerative treatment. | ||||||||
| March 13,2004 | Nutritional genomics | |||||||
| The integration of genomics into nutritional sciences has illuminated the complexity of genome responses to nutritional exposures while offering opportunities to increase the effectiveness of nutritional interventions, both clinical and population based. Nutrients elicit multiple physiological responses that affect genome stability, imprinting, expression, and viability. These effects confer both health benefits and risks, some of which may not become apparent until later in life. Nutritional genomics challenges us to understand the reciprocal and complex interactions among the human genome and dietary components in normal physiology and pathophysiology. | ||||||||
| March 12,2004 | TOWARD ALZHEIMER THERAPIES BASED ON GENETIC KNOWLEDGE | |||||||
| Genetic analysis has allowed the dissection of the pathogenic pathway that leads to Alzheimer’s disease. It has also been integral to the development of earlier and more accurate diagnostic practices. This analysis has identified many potential therapeutic targets, and clinical trials aimed at these targets are now under way. If these approaches are successful, it will be a spectacular validation of genetic-knowledge– based treatment strategies; if they are not, researchers will need to re-evaluate this approach toward understanding and developing strategies for treating complex diseases. | ||||||||
| March 11,2004 | Islet Transplantation as a Treatment for Diabetes — A Work in Progress | |||||||
| In 1993 the diabetes control and complications trial (dcct) es- tablished the modern standard of care for the medical management of type 1 diabetes mellitus.1The DCCT randomly assigned 1441 patients to conventional or intensive treatment. The latter included multiple daily determinations of blood glucose levels at home by finger stick; combinations of daily injections of long-, intermediate-, and short-acting insulin; and dietary and psychological support. The clinical outcomes in terms of secondary complication rates were much better in the intensively treated group than in the conventionally treated group; thereafter, intensive treatment became the norm. More recent improvements in home glucose and glycosylated hemoglobin monitoring and insulin preparations have further enabled patients with diabetes to attain near-normal glycemic control without frequent episodes of hypoglycemia. | ||||||||
| March 10,2004 | The Class II cytokine receptor (CRF2) family: overview and patterns of receptor–ligand interactions | |||||||
| Expanded genomic information has driven the discovery of new members of the human Class II family of cytokine receptors (CRF2), which now includes 12 proteins. The corresponding cytokines have been identified, paired with their receptors and initially characterized for function. These cytokines include: a new human Type I IFN, IFN-; molecules related to IL-10 (IL-19, IL-20, IL-22, IL-24, IL-26); and IFN-s (IL-28/29), which have antiviral and cell stimulatory activities reminiscent of Type I IFNs, but act through a distinct receptor. In response to ligand binding, the CRF2 proteins form heterodimers, leading to cytokine-specific cellular responses; these diverse physiological functions are just beginning to be explored. Progress in structural and mutational analysis of ligand–receptor interactions now presents a more reliable framework for understanding receptor–ligand interactions, and for predicting key regions in less well studied members of the CRF2 family. The relationships between the CRF2 proteins will be summarized, as will the progress in identifying patterns of receptor interactions with ligands. | ||||||||
| March 9,2004 | A Dangerous Detour–Cell Signaling Pathways Involved in Cancer Progression | |||||||
| The intensive effort poured into cancer research over the last 30 years has led to a tremendous increase in our understanding of cancer biology and of the cellular processes whose dysregulation has been implicated in cancer pathogenesis and progression. In many cases, the road to cancer pathogenesis and progression represents a detour from the normal pathways involved in cell signaling. This Focus Issue of Science’s STKE highlights cell signaling pathways implicated in various aspects of cancer progression. | ||||||||
| March 8,2004 | Back to the Future with Ubiquitin | |||||||
| Two papers published in 1984 by the Varshavsky labo- ratory revealed that the ubiquitin/proteasome pathway is the principal system for degradation of short-lived proteins in mammalian cells, setting the stage for fu- ture demonstrations of this pathway's many regulatory roles. This perspective discusses the impact of those papers and highlights some of the subsequent insights that have led to our current appreciation of the breadth of ubiquitin-mediated signaling. | ||||||||
| March 7,2004 | A New Method of Predicting US and State-Level Cancer Mortality Counts for the Current Calendar Year | |||||||
| Every January for more than 40 years, the American Cancer Society (ACS) has estimated the total number of cancer deaths that are expected to occur in the United States and individual states in the upcoming year. In a collaborative effort to improve the accuracy of the predictions, investigators from the National Cancer Institute and the ACS have developed and tested a new prediction method. The new method was used to create the mortality predictions for the first time in Cancer Statistics, 2004 and Cancer Facts & Figures 2004. The authors present a conceptual overview of the previousACSmethod and the new state-space method (SSM), and they review the results of rigorous testing to determine which method provides more accurate predictions of the observed number of cancer deaths from the years 1997 to 1999. | ||||||||
| March 6,2004 | The pharmacogenomics of Alzheimer’s disease | |||||||
| Alzheimer’s disease (AD) is a neurodegenerative disorder mostly affecting geriatric patients worldwide. The high emotional and economic impact of AD on patients, families, and the society has made AD one of the paramount geriatric syndromes. Efforts to find disease-modifying therapy have not yet been rewarding. Despite our increasing appreciation of the role of genetics in AD pathogenesis, pharmacogenomic approaches to uncover drug targets have not been extensively explored. The current knowledge of the genetics of both familial and non-familial (sporadic) AD, and the emerging data on the effect of Apolipoprotein E (ApoE) alleles on the response to AD therapeutic agents, is evidence that the potential utility of pharmacogenomics may not be limited to the familial AD (FAD) but provide answers for AD as a whole. | ||||||||
| March 5,2004 | Nature－China voices | |||||||
| 中国正在快速发展成为亚太地区以及整个世界的一个主要经济力量，是因为中国人天生具有宏图大志，也是由于他们对新技术一如既往地追求，同时中国从未放弃成为世界级科学大国的努力。尽管有不断的发展，尽管中国政府对科学研究的投入巨大，但中国尚未充分发挥其科学潜力，原因在本期（Nature专为中国的研究人员撰写的采用中文形式发表的增刊）的系列文章进行了讨论： |
||||||||
| March 4,2004 | DRUG-ELUTING STENTS | |||||||
| Advances in catheter and stent design have made stent implantation the standard coronary angioplasty procedure. Unfortunately, in-stent restenosis continues to plague this procedure, with the optimum binary restenosis rates reaching ~10% to 20%. In the past few years, it has become clear that in-stent restenosis is largely due to the migration and proliferation of vascular smooth muscle cells to form a neointima. To address this issue, stents coated with drug-delivery vehicles have been developed to deliver antiproliferative therapeutics. Two drugs, rapamycin and taxol, have been the lead compounds for testing the idea of a drug-eluting stent. These drugs have been successful largely because of the solid mechanistic understanding of their effects and extensive preclinical examination. | ||||||||
| March 3,2004 | Control of renin synthesis | |||||||
| Studies published recently have considerably enhanced our understanding of the mechanisms controlling renin production. With regard to the control of renin transcription, two enhancer regions have been identified that markedly augment renin synthesis in cell lines. In the absence of this enhancer activity, the basic promoter of the renin gene increases transcription only twoto threefold. The location of one transcription enhancer in the mouse gene is at about -2.7 kb and in humans at roughly -11 kb. A second important region has been identified in a chorionic cell line to be located ~5 kb upstream of the transcription start site in humans. Another potentially important regulatory region may lie within ~3.9 kb upstream of the -11 kb enhancer, as suggested by several conserved sequences among species in this region. In addition to the control of renin transcription, it seems that renin translation and the stability of renin mRNA are also effectively regulated. | ||||||||
| March 2,2004 | CYTOSTATIC AND APOPTOTIC ACTIONS OF TGF-β IN HOMEOSTASIS AND CANCER | |||||||
| The cytostatic and apoptotic functions of transforming growth factor-β (TGF-β) help restrain the growth of mammalian tissues; loss of these effects leads to hyperproliferative disorders and is common in cancer. However, tumour cells that are relieved from TGF-β growth constraints might then overproduce this cytokine to create a local immunosuppressive environment that fosters tumour growth and exacerbates the invasive and metastatic behaviour of the tumour cells themselves. For these reasons, there is a growing interest in understanding and therapeutically targeting TGF-β-mediated processes in cancer progression. | ||||||||
| March 1,2004 | ROLE OF SIGNAL REGULATION BY G-PROTEINS | |||||||
| The primary and most effective treatment for severe pain is the administration of narcotic analgesics, such as morphine and other opiates; yet, these drugs are renowned for their ability to rapidly induce tolerance and dependence following repeated administration. In opioid tolerance, the intensity of opioid-induced effects decreases upon repeated administration and the dose of the opioid must be increased to manifest the same extent of effects. Physical dependence appears after discontinuation of opioid uptake and results in withdrawal symptoms, such as hyperanalgesia, gastrointestinal cramp and joint and muscle aches. The symptoms are suppressed by continuous administration of opioids and this repeated cycle rapidly leads to opioid addiction. |
|
|||||||