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| October 31,2005 | Role of endogenous antisense RNA in cardiac gene regulation | |||||||||||||||
| Endogenous antisense RNA has been detected for a range of eukaryotic genes and now appears to be a common phenomenon in mammalian cells. Its abundance compared to levels of its complementary sense mRNA indicates that antisense RNA may be involved in posttrancriptional regulation of a gene. In general a downregulating effect on gene expression has been demonstrated or suggested. Due to the heterogeneity in origin and character of different antisense transcripts alternative functions such as stabilizing the corresponding sense transcript and being part of gene recombination must be considered. Regulation by endogenous antisense RNA has been shown for a plethora of genes, including cardiac genes, such as myosin heavy chainMHC, atrial light chain, and troponin I. | ||||||||||||||||
| October 30,2005 | Tumour invasion and metastasis: challenges facing drug discovery | |||||||||||||||
| Initial attempts at directly targeting metastatic spread using inhibitors of matrix metalloproteases failed to deliver the promise of anti-invasive therapy. A new generation of targeted agents with the potential to act as anti-invasives has recently entered the clinic but there is, as yet, no clear route to demonstrate an effect upon tumour metastasis. Because advances with monoclonal antibodies are likely to increase the number of potential anti-invasive agents, more clinically predictive drug discovery cascades are required to reduce the perceived risks associated with their generation. Once they reach the clinic, new approaches will be essential to help early indicators of clinical response meet ethical standards and avoid unnecessary clinical failures. | ||||||||||||||||
| October 29,2005 | PHARMACOGENOMICS AND INDIVIDUALIZED DRUG THERAPY | |||||||||||||||
| Pharmacogenetics deals with inherited differences in the response to drugs. The best-recognized examples are genetic polymorphisms of drug-metabolizing enzymes, which affect about 30% of all drugs. Loss of function of thiopurine Smethyltransferase (TPMT) results in severe and life-threatening hematopoietic toxicity if patients receive standard doses of mercaptopurine and azathioprine. Gene duplication of cytochrome P4502D6 (CYP2D6), which metabolizes many antidepressants, has been identified as a mechanism of poor response in the treatment of depression. There is also a growing list of genetic polymorphisms in drug targets that have been shown to influence drug response. | ||||||||||||||||
| October 28,2005 | Role of Angiogenesis in Cardiovascular Disease | |||||||||||||||
| The role of angiogenesis in atherosclerosis and other cardiovascular diseases has emerged as a major unresolved issue. Angiogenesis has attracted interest from opposite perspectives. Angiogenic cytokine therapy has been widely regarded as an attractive approach both for treating ischemic heart disease and for enhancing arterioprotective functions of the endothelium; conversely, a variety of studies suggest that neovascularization contributes to the growth of atherosclerotic lesions and is a key factor in plaque destabilization leading to rupture. Here, we critically review the evidence supporting a role for angiogenesis and angiogenic factors in atherosclerosis and neointima formation, emphasizing the problems raised by some of the landmark studies and the suitability of animal models of atherosclerosis and neointimal thickening for investigating the role of angiogenesis. | ||||||||||||||||
| October 27,2005 | Somatic evolution of cancer cells | |||||||||||||||
| Cancers develop through a process called genomic instability, which generates diversity, from which clonal evolution may occur. In colorectal cancers, this process has been extensively studied, and there are three identifiable processes involved in generating diversity at the genetic or epigenetic level. Colorectal cancers may have chromosomal instability (CIN), microsatellite instability (MSI), or the CpG island methylator phenotype (CIMP). Each of these processes is associated with a unique mutational or epigenetic “signature” identifiable in the tumor cells, and there are important conceptual and clinical implications of each. | ||||||||||||||||
| October 26,2005 | DISEASE GENE DISCOVERY THROUGH INTEGRATIVE GENOMICS | |||||||||||||||
| The availability of complete genome sequences and the wealth of largescale biological data sets now provide an unprecedented opportunity to elucidate the genetic basis of rare and common human diseases. Here we review some of the emerging genomics technologies and data resources that can be used to infer gene function to prioritize candidate genes.We then describe some computational strategies for integrating these large-scale data sets to provide more faithful descriptions of gene function, and how such approaches have recently been applied to discover genes underlying Mendelian disorders. | ||||||||||||||||
| October 25,2005 | Mechanisms of sudden cardiac death | |||||||||||||||
| Despite recent advances in preventing sudden cardiac death (SCD) due to cardiac arrhythmia, its incidence in the population at large has remained unacceptably high. Better understanding of the interaction among various functional, structural, and genetic factors underlying the susceptibility to, and initiation of, fatal arrhythmias is a major goal and will provide new tools for the prediction, prevention, and therapy of SCD. Here, we review the role of aberrant intracellular Ca2+ handling, ionic imbalances associated with acute myocardial ischemia, neurohumoral changes, and genetic predisposition in the pathogenesis of SCD due to cardiac arrhythmia. Therapeutic measures to prevent SCD are also discussed. | ||||||||||||||||
| October 24,2005 | Hematopoietic stem cell trafficking in liver injury | |||||||||||||||
| Bone marrow (BM) hematopoietic stem cells (HSCs) have been shown to facilitate regeneration in multiple nonhematopoietic tissues by either generating epithelial cells or altering the inflammatory response. Depending on injury type, the predominant mechanism of epithelial lineage regeneration occurs by spontaneous cell fusion or transdifferentiation. Irrespective of the mechanism, mobilization from the BM is a prerequisite. Mechanisms by which HSCs mobilize into damaged organs are currently under scrutiny. Murine and human studies have shown that the chemokine SDF-1 and its receptor CXCR4 participate in the mobilization of HSCs from BM and in the migration of HSCs to injured liver. SDF-1 is a potent HSC chemoattractant and is produced by the liver. | ||||||||||||||||
| October 23,2005 | Molecular Machinery and Mechanism of Cell Secretion | |||||||||||||||
| Secretion occurs in all living cells and involves the delivery of intracellular products to the cell exterior. Secretory products are packaged and stored in membranous sacs or vesicles within the cell. When the cell needs to secrete these products, the secretory vesicles containing them dock and fuse at plasma membrane-associated supramolecular structures, called porosomes, to release their contents. Specialized cells for neurotransmission, enzyme secretion, or hormone release use a highly regulated secretory process. Similar to other fundamental cellular processes, cell secretion is precisely regulated. During secretion, swelling of secretory vesicles results in a build-up of intravesicular pressure, allowing expulsion of vesicular contents. The extent of vesicle swelling dictates the amount of vesicular contents expelled. | ||||||||||||||||
| October 22,2005 | Biochemistry and cell biology of mammalian scavenger receptors | |||||||||||||||
| Scavenger receptors are integral membrane proteins that bind a wide variety of ligands including modified or oxidised low-density lipoproteins, apoptotic cells and pathogens. Modified low-density lipoprotein accumulation is thought to be an early event in vascular disease and thus scavenger receptor function is critical in this context. The scavenger receptor family has at least eight different subclasses (A–H) which bear little sequence homology to each other but recognize common ligands. Here we review our current understanding of the scavenger receptor subclasses with emphasis on their genetics, protein structure, biochemical properties, membrane trafficking, intracellular signalling and links to disease states. We also highlight emerging areas where scavenger receptors play roles in cell and animal physiology. | ||||||||||||||||
| October 21,2005 | Treatment of hepatitis C | |||||||||||||||
| Hepatitis C virus is a leading cause of chronic liver disease, with over 170 million people infected worldwide. It is also the leading indication for liver transplantation. Complications from chronic hepatitis C infection include cirrhosis, hepatic decompensation, and hepatocellular carcinoma. As a result, treatment strategies to prevent such complications have been widely researched, although many questions remain unanswered. To date, the standard therapy for chronic hepatitis C infection is the combination of peginterferon and ribavirin. Treatment strategies differ based on factors such as genotype and liver biopsy results. Other strategies must be considered for special groups, such as patients with acute hepatitis C infection, hepatitis C/human immunodeficiency virus (HIV) coinfection, and prior nonresponse to interferon or relapse after its use. | ||||||||||||||||
| October 20,2005 | Phosphoinositide 3-kinases as drug targets in cancer | |||||||||||||||
| The past two years have seen phosphoinositide 3-kinases (PI3Ks) move from being seen as potential targets for chemotherapeutics, to one of them—PI3Kα—being generally accepted as validated. A huge amount of work indicated that there was an important role for PI3Ks in tumour progression and, particularly, in the control of proliferation, survival and regulation of the potential oncogene PKB. These links were further strengthened by studies showing that the tumour suppressor, PTEN, is an antagonist of PI3K signalling and that somatic mutations of p110α (PIK3CA) are present in a variety of cancers. | ||||||||||||||||
| October 19,2005 | Coronary artery stents: identification and evaluation | |||||||||||||||
| First introduced in the 1980s, the coronary stent has been used to reduce the rate of arterial restenosis. Coronary stent implantation is currently a common procedure performed by interventional cardiologists, and the market for development and design is constantly expanding and evolving. This article was designed to assist pathologists in the accurate identification of coronary stents that are currently available, in addition to some that are no longer being implanted. The stents reviewed here were chosen based on frequency of use and/or occurrence in the literature. Some of the newer models have yet to undergo extensive clinical testing. The summaries accompanying each stent include concise physical descriptions and documented complications, intended to serve as a guide for the investigating pathologist. | ||||||||||||||||
| October 18,2005 | Genetical genomics in humans and model organisms | |||||||||||||||
| Genetical genomics has been proposed to map loci controlling gene-expression differences (eQTLs) that might underlie functional trait variation. We briefly review the studies in model species and conclude that, although they successfully demonstrate the utility of genetical genomics, they are too limited to unlock the full potential of this approach and some results should be interpreted with caution. We subsequently elaborate on two recent studies that use this approach in humans. The many differences between these studies complicate meaningful comparisons between them. A joint analysis of the two experiments offers some scope for more powerful genetical genomics. | ||||||||||||||||
| October 17,2005 | DENDRITIC-CELL TRAFFICKING TO LYMPH NODES THROUGH LYMPHATIC VESSELS | |||||||||||||||
| Antigen-presenting dendritic cells often acquire foreign antigens in peripheral tissues such as the skin. Optimal encounter with naive T cells for the presentation of these antigens requires that the dendritic cells migrate to draining lymph nodes through lymphatic vessels. In this article, we review important aspects of what is known about dendritic-cell trafficking into and through lymphatic vessels to lymph nodes. We present these findings in the context of information about lymphatic-vessel biology. Gaining a better understanding of the crosstalk between dendritic cells and lymphatic vessels during the migration of dendritic cells to lymph nodes is essential for future advances in manipulating dendritic-cell migration as a means to fine-tune immune responses in clinical settings. | ||||||||||||||||
| October 16,2005 | Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases | |||||||||||||||
| Endothelial dysfunction and cell loss are prominent features in cardiovascular disease. Endothelial progenitor cells (EPCs) originating from the bone marrow play a significant role in neovascularization of ischemic tissues and in re-endothelialization of injured blood vessels. Several studies have shown the therapeutic potential of EPC transplantation in rescue of tissue ischemia and in repair of blood vessels and bioengineering of prosthetic grafts. Recent small-scale trials have provided preliminary evidence of feasibility, safety, and efficacy in patients with myocardial and critical limb ischemia. However, several studies have shown that age and cardiovascular disease risk factors reduce the availability of circulating EPCs (CEPCs) and impair their function to varying degrees. | ||||||||||||||||
| October 15,2005 | Tyrosine Kinases as Targets for Cancer Therapy | |||||||||||||||
| Protein tyrosine kinases (tks) are enzymes that catalyze the transfer of phosphate from ATP to tyrosine residues in polypeptides. The human genome contains about 90 TK and 43 TK-like genes, the products of which regulate cellular proliferation, survival, differentiation, function, and motility. More than 25 years ago, TKs were implicated as oncogenes in animal tumors induced by retroviruses. However, they were largely ignored in drug development because of a paucity of evidence for a causative role in human cancer and concerns about drug specificity and toxicity. The landscape was changed radically by the success of imatinib mesylate, an inhibitor of the BCR-ABL TK in chronic myeloid leukemia (CML) — a result heralded as a proof-of-principle and a triumph of targeted cancer therapy. | ||||||||||||||||
| October 14,2005 | Imaging Molecular Interactions in Living Cells | |||||||||||||||
| Hormones integrate the activities of their target cells through receptor-modulated cascades of protein interactions that ultimately lead to changes in cellular function. Understanding how the cell assembles these signaling protein complexes is critically important to unraveling disease processes, and to the design of therapeutic strategies. Recent advances in live-cell imaging technologies, combined with the use of genetically encoded fluorescent proteins, now allow the assembly of these signaling protein complexes to be tracked within the organized microenvironment of the living cell. Here, we review some of the recent developments in the application of imaging techniques to measure the dynamic behavior, colocalization, and spatial relationships between proteins in living cells. | ||||||||||||||||
| October 13,2005 | Soluble ICAM-1: A marker of vascular inflammation and lifestyle | |||||||||||||||
| The circulating form of a membrane-bound intercellular adhesion molecule-1 (ICAM-1), has been the source of recent debate as a candidate marker of vascular inflammation in atherosclerosis and myocardial infarction, although its increased levels were also observed in other diseases affecting the cardiovascular system, such as myocarditis, inflammatory cardiomyopathy and heart failure per se. Faulty dietary habits, a sedentary mode of life, smoking, and alcohol abuse, are factors which at least in part contribute to atherosclerosis. This paper describes the responses of sICAM-1 levels to nutrients, physical activity, smoke exposure and alcohol consumption. | ||||||||||||||||
| October 12,2005 | A review of HIV-1 Tat protein biological effects | |||||||||||||||
| The authors have reviewed some biological properties of HIV-1 Tat protein, and have also reported some personal data. This viral regulatory protein is endowed with multifunctional activities, acting as an endogenous factor in the infected cells and exogenously, on those uninfected. In particular, Tat-induced proliferation and differentiation of HIV target cells which promotes viral infection, is discussed in this review. However, exogenous Tat protein can sometimes also produce, directly or indirectly, damaging effects in different organs and host systems, such as myocardium, kidney, liver and central nervous system (CNS). | ||||||||||||||||
| October 11,2005 | Finding schizophrenia genes | |||||||||||||||
| Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identified a number of potential regions of linkage and 2 associated chromosomal abnormalities, and accumulating evidence favors several positional candidate genes. These findings are grounds for optimism that insight into genetic factors associated with schizophrenia will help further our understanding of this disease and contribute to the development of new ways to treat it. | ||||||||||||||||
| October 10,2005 | New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport | |||||||||||||||
| The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. | ||||||||||||||||
| October 9,2005 | Therapeutic targeting of the tumor microenvironment | |||||||||||||||
| Cancer is not a solo performance, but rather an ensemble production. Tumor cells play the leading villains, with a diverse supporting cast of normal cells that can be recruited to aid their malignant progression. The supporting players in the tumor microenvironment include stromal fibroblasts, infiltrating immune cells, the blood and lymphatic vascular networks, and the extracellular matrix (Figure 1). Normal cells can contribute both positive and negative signals to the tumor.They can be coopted or modified by the cancer cells to produce a variety of growth factors, chemokines, and matrix-degrading enzymes that enhance the proliferation and invasion of the tumor. | ||||||||||||||||
| October 8,2005 | The Medicine and Public Health Initiative | |||||||||||||||
| The Medicine and Public Health Initiative (MPHI) was created jointly 10 years ago by the American Medical Association and the American Public Health Association to bridge the nearly century-wide gulf between the respective disciplines. We review the history of MPHI and its growing significance in light of recent terrorism events. We report on current MPHI activities by examining three bellwether states—California, Florida, and Texas—as well as international sites. Upon its inception, MPHI was rapidly embraced and nationally disseminated. Sustainability 10 years later in the post-911 world requires renewed commitment by all collaborators. | ||||||||||||||||
| October 7,2005 | Structural and Genetic Bases of Arterial Stiffness | |||||||||||||||
| Arterial stiffness has independent predictive value for cardiovascular events. We review data concerning the heritability of arterial stiffness, and propose an integrated view of the structural and genetic determinants of arterial stiffness, based on a candidate gene approach and recent studies on gene expression profile. Arterial stiffness seems to have a genetic component, which is largely independent of the influence of blood pressure and other cardiovascular risk factors. In animal models of essential hypertension (SHR and SHR-SP), structural modifications of the arterial wall include an increase in the number of elastin/smooth muscle cell (SMC) connections, and smaller fenestrations of the internal elastic lamina, possibly leading to redistribution of the mechanical load toward elastic materials. | ||||||||||||||||
| October 6,2005 | Role of CDK/cyclin complexes in transcription and RNA splicing | |||||||||||||||
| The production of mRNAs in all living organisms is an extremely complex process that includes multiple catalytic activities such as transcription, capping, splicing, polyadenylation, cleavage and export. All of these processes are controlled by a large group of proteins which form very dynamic complexes interacting with DNA and pre-mRNAs to coordinate these activities. Phosphorylations play a central role in regulating formation, activation and inactivation of these complexes. A growing number of protein kinases have been identified that are capable of phosphorylating proteins involved in mRNA production. Among them, Cyclin-dependent Kinases (CDKs) represent a family of serine/threonine protein kinases that become active upon binding to a cyclin regulatory partner. | ||||||||||||||||
| October 5,2005 | 2005 诺贝尔医学生理学奖 | |||||||||||||||
| 10月3日，瑞典卡罗林斯卡医学院宣布，把2005年诺贝尔生理学或医学奖授予澳大利亚科学家巴里·马歇尔和罗宾·沃伦，以表彰他们发现了导致胃炎和胃溃疡的细菌-幽门螺杆菌。诺贝尔奖委员会在授奖词中说，由于巴里·马歇尔和罗宾·沃伦1982年的发现，使得原本慢性的、经常无药可救的胃溃疡变成了只需抗生素和一些其他药物短期就可治愈的疾病。 在1982年马歇尔和沃伦发现这种细菌之前，生活压力和生活方式被认为是胃溃疡的主要引发原因。1979年根据活组织切片检查结果，J. Robin Warren发现50%左右的病人的胃腔下半部分附生着许多微小的、弯曲状的细菌。Warren的发现引起了Barry J. Marshall的极大兴趣，他们决定联合对取自100个病人的活组织切片进行研究。经过反复试验，Marshall成功地培育出一种当时尚不为人知晓的细菌-后来被命名为幽门螺杆菌。基于上述试验结果，Marshall和Warren认为，幽门螺杆菌是导致这些病症的关键因素。通过培育这种细菌，使病理诊断变得及其简单。 CMBI特将两位获奖者背景、相关论文及网络链接资源等信息汇总于此，以供广大读者了解学习之用。 |
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| October 4,2005 | Kidney in Early Atherosclerosis | |||||||||||||||
| Atherosclerosis represents one of the major causes of premature death in the United States today, and it is frequently associated with, exacerbates, and is aggravated by chronic kidney disease (CKD). Atherosclerosis integrates the response to a number of insults, and consequently, the accelerated atherosclerosis found in CKD patients is associated with activation of a variety of humoral and tissue mechanisms. Hypertension, diabetes, dyslipidemia, obesity, metabolic syndrome, and additional nontraditional risk factors can damage the kidney directly and by promoting intrarenal atherogenesis, even in the absence of obstructive lesions in the renal artery. | ||||||||||||||||
| October 3,2005 | The Theoretical Basis of Transcriptional Therapy of Cancer | |||||||||||||||
| Aberrant gene silencing is a frequent event in cancer and plays a critical role in the molecular pathogenesis of malignant transformation. The two major mechanisms of silencing in cancer include transcriptional repression by mutated or aberrantly expressed transcription factors, and aberrant epigenetic silencing by hypermethylation of tumor suppressor or DNA repair– related genes. Both of these mechanisms require the activities of multiprotein chromatin remodeling and modifying machines, several of which may be mutated in cancer. The end result is genetic reprogramming of cells to express combinations of genes that confer the neoplastic phenotype. | ||||||||||||||||
| October 2,2005 | Apoptosis-based therapies for hematologic malignancies | |||||||||||||||
| Apoptosis is an intrinsic cell death program that plays critical roles in tissue homeostasis, especially in organs where high rates of daily cell production are offset by rapid cell turnover. The hematopoietic system provides numerous examples attesting to the importance of cell death mechanisms for achieving homeostatic control. Much has been learned about the mechanisms of apoptosis of lymphoid and hematopoietic cells since the seminal observation in 1980 that glucocorticoids induce DNA fragmentation and apoptosis of thymocytes and the demonstration in 1990 that depriving colony-stimulating factors from factordependent hematopoietic cells causes programmed cell death. From an understanding of the core components of the apoptosis machinery at the molecular and structural levels, many potential new therapies for leukemia and lymphoma are emerging. | ||||||||||||||||
| October 1,2005 | Mechanisms of Insulin Resistance in Humans and Possible Links With Inflammation | |||||||||||||||
| Insulin resistance is a major player in the pathogenesis of the metabolic syndrome and type 2 diabetes, and yet, the mechanisms responsible for it remain poorly understood. Magnetic resonance spectroscopy studies in humans suggest that a defect in insulin-stimulated glucose transport in skeletal muscle is the primary metabolic abnormality in insulin-resistant type 2 diabetics. Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1 associated phosphatidylinositol 3-kinase activity. |
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