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| Mar 31, 2008 | Discovery, biology and therapeutic potential of RNA interference, microRNA and antagomirs | ||||||||||||
| The discovery of small RNA molecules as regulators of posttranscriptional gene silencing has paved the way to specifically target any given protein via the RNA interference (RNAi) pathway. An endogenous class of these molecules, the microRNA (miRNA), is proposed to control expression of up to one third of all genes and may be utilized as diagnostic and prognostic marker for diseases. In addition the recent employment of antagomirs that specifically inhibit function of a given miRNA represents a powerful tool to determine the role of these molecules in disease pathogenesis. Here, we describe our current understanding of the structure, biogenesis and function of small RNA, as well as their potential and limitation as novel therapeutic approaches. | |||||||||||||
| Mar 30, 2008 | Profiling microRNA expression with microarrays | ||||||||||||
| The discovery of several types of small RNAs (sRNAs) has led to a steady increase in available RNA databases. Many of these sRNAs remain to be validated and functionally characterized. Recent advances in microRNA (miRNA)-expression profiling of different tissues, stages of development and physiological or pathological states are beginning to be explored using several technological approaches. In this review, these recent advances in miRNA microarray technology and their applications, particularly in basic research and clinical diagnosis, will be summarized and discussed. The methods for miRNA enrichment and probe design and labeling will also be discussed with an emphasis on evaluation of predicted miRNA sequences, analysis of miRNA expression and exploration of the potential roles of miRNA sequences in the regulation of stem cell differentiation and tissue- and time-specific profiling patterns of their target genes. | |||||||||||||
| Mar 29, 2008 | Genetically altered animals in the study of the metabolic functions of peptide hormone systems | ||||||||||||
| Here we present examples of how genetically altered animals contribute to a final postulation of the physiological roles of certain hormone systems, bringing new insights into the field. | |||||||||||||
| Mar 28, 2008 | New frontiers in microarray technology development | ||||||||||||
| Within the past decade, microarray-based assays have moved from being technology-driven to application-oriented high-output assay systems. The basic principles of microarray technology were already described in the early 1980s by Ekins’ Ambient Analyte Theory. The driving force behind this theory was the quest for increased sensitivity in the determination of low concentrations of diagnostically important substances, such as hormones. | |||||||||||||
| Mar 27, 2008 | Pathobiology of the sentinel node | ||||||||||||
| There is increasing evidence for the efficacy of lymphatic mapping and sentinel lymph node biopsy in predicting prognosis, reducing the morbidity traditionally associated with regional lymph node dissection and increasing survival in subgroups of patients with cutaneous melanoma. Further study is needed to determine the role of the immune system in the spread of nodal metastases and the role of immunomodulatory therapy to prevent or possibly even reverse nodal metastases. | |||||||||||||
| Mar 26, 2008 | Heme oxygenase and carbon monoxide initiate homeostatic signaling | ||||||||||||
| Carbon monoxide (CO), a gaseous second messenger, arises in biological systems during the oxidative catabolism of heme by the heme oxygenase (HO) enzymes. Many biological functions of HO, such as regulation of vessel tone, smooth muscle cell proliferation, neurotransmission, and platelet aggregation, and anti-inflammatory and antiapoptotic effects have been attributed to its enzymatic product, CO. How can such diverse actions be achieved by a simple diatomic gas; can its protective effects be explained via regulation of a common signaling pathway? A number of the known signaling effects of CO depend on stimulation of soluble guanylate cyclase and/or activation of mitogen-activated protein kinases... | |||||||||||||
| Mar 25, 2008 | The logic and regulation of cell cycle exit and reentry | ||||||||||||
| Tissue repair and regeneration are very complex biological events, whose successful attainment requires far more than mere cell division. However, almost unavoidably they entail cell proliferation as a fundamental premise. Full regeneration or repair cannot be achieved without replacing cells lost to disease or injury, replacement that can only take place via proliferation of surviving cells. This review endeavors to outline the molecular bases of exit from and reentry into the cell cycle. In recent years, the decision to proliferate or not has been seen as mostly the concern of cyclins and cyclin-dependent kinases. This account tries to show that cell cycle inhibitors are as important as the positive regulators in the making of this decision. Finally, the authors wish to suggest that the molecular knowledge of the cell cycle can be harnessed to the benefit of many aspects of regenerative medicine. | |||||||||||||
| Mar 24, 2008 | Lipid Management to Reduce Cardiovascular Risk: A New Strategy Is Required | ||||||||||||
| One of the foremost medical advances of the past 2 decades has been proof that elevated low-density lipoprotein (LDL) is a cause of atherosclerotic cardiovascular disease (ASCVD) and that lowering of LDL levels will reduce risk for ASCVD. The application of this knowledge in clinical and public health arenas offers the opportunity to greatly reduce morbidity and mortality from ASCVD. This article outlines the rationale underlying this opportunity. | |||||||||||||
| Mar 23, 2008 | Let Me Count the Ways: Mechanisms of Gene Regulation by miRNAs and siRNAs | ||||||||||||
| The downregulation of gene expression by miRNAs and siRNAs is a complex process involving both translational repression and accelerated mRNA turnover, each of which appears to occur by multiple mechanisms. Moreover, under certain conditions, miRNAs are also capable of activating translation. A variety of cellular proteins have been implicated in these regulatory mechanisms, yet their exact roles remain largely unresolved. | |||||||||||||
| Mar 22, 2008 | Cell and gene therapies in epilepsy – promising avenues or blind alleys? | ||||||||||||
| The past decades have brought several advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs (AEDs), more than one-third of patients are resistant to pharmacological treatment. Furthermore, current AEDs do not prevent the development and progression of epilepsy. Thus, there is an urgent need to develop new therapies for AED-resistant patients, for prevention of epilepsy in patients at risk and for disease modification. Cell replacement and gene therapies have been proposed to offer potential approaches for improvements in therapy, but are such approaches really more promising than new pharmacological strategies? Here we critically review and discuss data from epilepsy models and human tissue studies indicating that cell and gene therapies might provide alternative therapeutic approaches for AED-resistant focal epilepsies and might have antiepileptogenic or disease-modifying potential. However, several crucial issues remain to be resolved to develop cell and gene therapies into effective and safe therapies. | |||||||||||||
| Mar 21, 2008 | β-cell regeneration: Neogenesis, replication or both | ||||||||||||
| Both type I and type II diabetes are characterized by beta-cell loss and dysfunction. Therefore, a major goal of diabetes therapy is to promote the formation of new beta-cells, either in vitro for transplantation or in vivo, i.e., beta-cell regeneration. The question of whether beta-cell regeneration occurs by replication of preexisting beta-cells or by neogenesis from a precursor within the pancreas is a major focus of interest. Lineage-tracing studies have found evidence only for beta-cell replication, while earlier studies based upon the appearance of insulin-positive cells in areas outside of islets formed the basis for the belief that neogenesis from precursors can occur in adult animals. Recently, we found that nonendocrine pancreatic epithelial cells could be induced to undergo endocrine differentiation under the influence of inductive factors from the human fetal pancreas. One possibility is that, similar to models of hepatocyte regeneration, beta-cells can arise either by neogenesis or replication, depending on the particular stimulus. Clearly, understanding the nature and control of beta-cell regeneration is critical for success in efforts to treat diabetes by beta-cell replacement. | |||||||||||||
| Mar 20, 2008 | Evolution of complexity in miRNA-mediated gene regulation systems | ||||||||||||
| Using Arabidopsis microRNA (miRNA)-mediated gene regulation system as a model, we investigated how complex systems evolve with special attention to selection to maintain the systems. We found that the copy number of miRNA genes within each system is a key factor to determine the complexity of the system, indicating a crucial role of gene duplication to increase the complexity. Furthermore, we show that the mode of selection to maintain the systems depend on their complexity levels. | |||||||||||||
| Mar 19, 2008 | Cancer Proliferation Gene Discovery Through Functional Genomics | ||||||||||||
| Retroviral short hairpin RNA (shRNA)-mediated genetic screens in mammalian cells are powerful tools for discovering loss-of-function phenotypes. We describe a highly parallel multiplex methodology for screening large pools of shRNAs using half-hairpin barcodes for microarray deconvolution. We carried out dropout screens for shRNAs that affect cell proliferation and viability in cancer cells and normal cells. We identified many shRNAs to be antiproliferative that target core cellular processes, such as the cell cycle and protein translation, in all cells examined. Moreover, we identified genes that are selectively required for proliferation and survival in different cell lines. Our platform enables rapid and cost-effective genome-wide screens to identify cancer proliferation and survival genes for target discovery. Such efforts are complementary to the Cancer Genome Atlas and provide an alternative functional view of cancer cells. | |||||||||||||
| Mar 18, 2008 | Cell Adhesion Mechanisms in Platelets | ||||||||||||
| At sites of vascular injury, platelets come into contact with the subendothelial extracellular matrix which triggers their activation and the formation of a hemostatic plug. This process is crucial for normal hemostasis, but may also lead to pathological thrombus formation causing diseases such as myocardial infarction or stroke. The initial capture of flowing platelets is mediated by the interaction of the glycoprotein (GP) Ib-V-IX complex with von Willebrand factor (vWF) immobilized on exposed collagens. This interaction allows the binding of the collagen receptor GPVI to its ligand and to initiate cellular activation, a process that is reinforced by locally produced thrombin and soluble mediators released from platelets. These events lead to the shift of beta1 and beta3 integrins on the platelet surface from a low to a high affinity state, thereby enabling them to bind their ligands and to mediate firm adhesion, spreading, coagulant activity, and aggregation. This review summarizes the most important structural and functional properties of these adhesion receptors and briefly discusses their potential as targets for antithrombotic therapy. | |||||||||||||
| Mar 17, 2008 | Signaling networks in aging | ||||||||||||
| Aging – long considered to be solely the result of wear and tear – is in fact regulated by specific genetic pathways. Simple changes in the environment (e.g. dietary restriction) can drastically extend lifespan, suggesting that several of these genetic pathways control longevity in response to changes in the surroundings. Here we summarize the key signaling modules identified so far that regulate aging and longevity. | |||||||||||||
| Mar 16, 2008 | Urotensin II: a cardiovascular and renal update | ||||||||||||
| Urotensin II is a highly conserved undecapeptide which is well represented in the nervous system, heart and kidney. This review summarizes recent studies on cardiovascular and renal pathophysiology of urotensin II and clinical studies exploring the role of this peptide in cardiovascular and renal diseases. RECENT FINDINGS: Urotensin II was initially seen as a vasoconstrictor/cardiodepressant compound and implicated in myocardial and renal dysfunction. Emerging evidence in experimental models and in humans indicates that urotensin II may play a cardioprotective role in coronary heart disease and in chronic renal failure. SUMMARY: Administration of urotensin II produces a cardiodepressant effect in normal rats but exerts beneficial renal hemodynamic effects and preserves myocardial contractility in rats with chronic volume overload. Both urotensin II and urotensin-related peptide exhibit a myocardial protective property in an ischemia-reperfusion injury model in the isolated perfused rat heart. In patients with acute cardiac ischemia, circulating urotensin II is lower than normal and low plasma urotensin II signals a higher risk of adverse clinical events following myocardial infarction. Similarly, low urotensin II appears linked to death, cardiomyopathy and cardiovascular complications in patients with advanced renal insufficiency. | |||||||||||||
| Mar 15, 2008 | Experimental validation of miRNA targets | ||||||||||||
| MicroRNAs are natural, single-stranded, small RNA molecules that regulate gene expression by binding to target mRNAs and suppress its translation or initiate its degradation. In contrast to the identification and validation of many miRNA genes is the lack of experimental evidence identifying their corresponding mRNA targets. The most fundamental challenge in miRNA biology is to define the rules of miRNA target recognition. This is critical since the biological role of individual miRNAs will be dictated by the mRNAs that they regulate. Therefore, only as target mRNAs are validated will it be possible to establish commonalities that will enable more precise predictions of miRNA/mRNA interactions. Currently there is no clear agreement as to what experimental procedures should be followed to demonstrate that a given mRNA is a target of a specific miRNA. Therefore, this review outlines several methods by which to validate miRNA targets. Additionally, we propose that multiple criteria should be met before miRNA target validation should be considered "confirmed." | |||||||||||||
| Mar 14, 2008 | Mechanisms of Gene Regulation by miRNAs and siRNAs | ||||||||||||
| The downregulation of gene expression by miRNAs and siRNAs is a complex process involving both translational repression and accelerated mRNA turnover, each of which appears to occur by multiple mechanisms. Moreover, under certain conditions, miRNAs are also capable of activating translation. A variety of cellular proteins have been implicated in these regulatory mechanisms, yet their exact roles remain largely unresolved. | |||||||||||||
| Mar 13, 2008 | Human monoclonal antibodies by immortalization of memory B cells | ||||||||||||
| The administration of hyper immune sera to prevent or treat life-threatening infections is a remarkable milestone in medicine and biotechnology that has been achieved more than a century ago. Yet, the therapeutic use of monoclonal antibodies in this field has developed slowly over the last decades. Here we compare and contrast current methods to generate human monoclonal antibodies and highlight the advantages of exploiting the human antibody repertoire using a novel method that allows efficient immortalization and cloning of human memory B cells. This method, which has been successfully applied to isolate broadly neutralizing antibodies against SARS and H5N1 influenza viruses, is expected to accelerate the development of therapeutics in the field of infectious diseases not only by providing neutralizing antibodies for passive serotherapy, but also by generating relevant information for vaccine design. | |||||||||||||
| Mar 12, 2008 | Biomarkers in heart failure management | ||||||||||||
| Recent literature on the role of biomarkers in heart failure is reviewed, focusing on B-type natriuretic peptide. RECENT FINDINGS: Knowledge of the processes which increase ventricular stress, thus increasing B-type natriuretic peptide, is key to appropriate utilization and interpretation of B-type natriuretic peptide levels. B-type natriuretic peptide is a useful adjunct to confirm or rule out heart failure. B-type natriuretic peptide is a robust prognostic indicator in all stages of heart failure, with prognostic significance in patients undergoing cardiac and noncardiac surgery, and in those with acute coronary syndromes. Serial B-type natriuretic peptide testing predicts outcomes in hospitalized patients with heart failure. The role of B-type natriuretic peptide in screening high-risk populations is promising, but its use in unselected populations is unclear. There is increasing evidence that the use of B-type natriuretic peptide to guide heart failure management is associated with improved clinical outcomes and reduced health costs. SUMMARY: Biomarkers play an important role in heart failure, but there remain unanswered questions regarding optimization of their use. They should be used as an adjunct to, not replacement for, clinical assessment. Currently available B-type natriuretic peptide assays have limitations relating to clinical variability and assay specificity. Other neurohormonal, inflammatory and metabolic markers may add complementary information to that provided by currently available B-type natriuretic peptide assays. | |||||||||||||
| Mar 11, 2008 | New G-protein-coupled receptor crystal structures: insights and limitations | ||||||||||||
| G-protein-coupled receptors (GPCRs) constitute a large family of structurally similar proteins that respond to a chemically diverse array of physiological and environmental stimulants. Until recently, high-resolution structural information was limited to rhodopsin, a naturally abundant GPCR that is highly specialized for the detection of light. Non-rhodopsin GPCRs for diffusible hormones and neurotransmitters have proven more resistant to crystallography approaches, possibly because of their inherent structural flexibility and the need for recombinant expression. Recently, crystal structures of the human beta(2) adrenoceptor have been obtained using two different approaches to stabilize receptor protein and increase polar surface area. These structures, together with the existing structures of rhodopsin, represent an important first step in understanding how GPCRs work at a molecular level. Much more high-resolution information is needed for this important family of membrane proteins, however: for example, the structures of GPCRs from different families, structures bound to ligands having different efficacies, and structures of GPCRs in complex with G proteins and other signaling molecules. Methods to characterize the dynamic aspects of the GPCR architecture at high resolution will also be important. | |||||||||||||
| Mar 10, 2008 | Aldosterone and Vascular Inflammation | ||||||||||||
| Oxidative stress and inflammation contribute to increased cardiovascular morbidity and mortality associated with activation of the renin-angiotensin (Ang)-aldosterone system (RAAS). Studies in cultured cells in vitro and in rodent models in vivo demonstrate that aldosterone and/or mineralocorticoid receptor (MR) activation cause oxidative stress and vascular inflammation. | |||||||||||||
| Mar 9, 2008 | Recent advances in the prevention of mother-to-child transmission | ||||||||||||
| The reviews in this issue illustrate both the major scientific advances in the field of mother-to-child transmission of HIV and the equally huge gaps still experienced in translating scientific advances into practice for the majority of women in need. While mother-to-child transmission has been reduced to 1–2% in the low-prevalence, high-resource settings of North America and Europe, coverage of interventions for the prevention of mother-to-child transmission (PMTCT) remains low in many high-prevalence, low-resource settings in Africa and Asia, and transmission rates, especially through breastfeeding, remain unacceptably high | |||||||||||||
| Mar 8, 2008 | Modulators of neuronal cell death in epilepsy | ||||||||||||
| Experimental and human data have shown that certain seizures cause damage to brain. Such neuronal loss may result in cognitive impairments and perhaps contribute to the development or phenotype of emergent epilepsy. Recent work using genetically modified mice, Tat protein transduction, and viral vectors has shown functional effects of manipulating Bcl-2 and Bcl-w, heat shock proteins, caspases, and their regulators and endonucleases on neuronal death in models of status epilepticus. Ancillary effects on seizure induction and excitability thresholds have emerged for several genes suggesting additional properties of therapeutic potential. Differing hippocampal expression of certain Bcl-2 family genes, elevated endoplasmic reticulum stress chaperones, and death receptor pathway modulation in epilepsy patients support clinical relevance of this focus. These findings may yield potentially valuable adjunctive neuroprotective or anti-epileptogenic strategies. | |||||||||||||
| Mar 7, 2008 | Robotic mitral surgery: current and future roles | ||||||||||||
| PURPOSE OF REVIEW: Cardiac surgery, like other surgical fields, is evolving to a more minimally invasive approach. Robotic technology now allows complex mitral valve repairs to be carried out via small incisions with complete avoidance of a sternotomy. The purpose of this review is to assess the current role of robotics in the repair of the mitral valve, and to speculate as to what advances may be forthcoming. RECENT FINDINGS: Several groups have now confirmed that complex mitral valve repairs can be carried out robotically with early results comparable to open repair. SUMMARY: Endoscopic mitral repair has become a reality. With further technological advancements and continued clinical experience, this may become the standard approach for mitral valvuloplasty. | |||||||||||||
| Mar 6, 2008 | New molecular concepts and targets in acute myeloid leukemia | ||||||||||||
| Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres. The critical role of telomeres in cell proliferation and aging is illustrated in patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Here, the role of telomeres and telomerase in human biology is reviewed from a personal historical perspective. | |||||||||||||
| Mar 5, 2008 | New molecular concepts and targets in acute myeloid leukemia | ||||||||||||
| PURPOSE OF REVIEW: Most patients with acute myeloid leukemia treated with chemotherapy relapse. It is increasingly recognized that the cause of chemoresistance and relapse resides within the leukemia stem cell population. Successful eradication of leukemia stem cells would require a comprehensive profile of both the acquired molecular lesions and intrinsic features of leukemia stem cells. This review describes recent work identifying molecular markers that may lead to development of novel therapeutics, ultimately aiming to eradicate leukemia stem cells in acute myeloid leukemia. RECENT FINDINGS: In recent years, novel specific cell surface antigens have allowed identification of leukemia stem cells and permitted their distinction from normal hematopoietic stem cells. Novel concepts of leukemia stem cells and niche interaction have elucidated the mechanisms that control leukemia stem cell survival and chemoresistance. Recent detection of genetic aberrations affecting regulators of HOX gene expression and chromatin modifying enzymes, such as CDX2 and hDOT1L, respectively, elucidates new key players in stem cell self-renewal and leukemic transformation. SUMMARY: The discovery of novel markers and survival pathways for leukemia stem cells has increased our potential to specifically target and eliminate the leukemic stem cell compartment, which is likely to improve clinical outcomes in acute myeloid leukemia. | |||||||||||||
| Mar 4, 2008 | Regulatory CD4 T cells: sensing the environment | ||||||||||||
| The immunosuppressive properties of naturally occurring regulatory T cells (Tregs) have classically been linked to an intrinsic state of hyporesponsiveness, yet, paradoxically, Tregs are phenotypically in an activated state and have intact proliferative capacity. In consideration of several recent biochemical reports on the intracellular signaling pathways operating in activated CD4(+)CD25(+) Tregs, we argue that the responsiveness of Tregs depends greatly on the local microenvironment. In particular, what influences Tregs to remain anergic or to proliferate arises from their ability to probe the extracellular milieu to respond to external stimuli for the modulation of intracellular signaling events, leading to very different quantitative and qualitative functional outcomes. | |||||||||||||
| Mar 3, 2008 | Location, location: protein trafficking and lipolysis in adipocytes | ||||||||||||
| The storage and mobilization of lipid are central functions of fat cells. Recent proteomic studies suggest that intracellular triglyceride storage droplets are dynamic organelles, and that the signaling events underlying lipid mobilization alter protein trafficking to a specialized subset of these droplets. Here we review recent research that has identified new players in hormone-stimulated lipolysis, and the role of perilipin A, a lipid droplet scaffold protein, in organizing and directing lipolytic protein trafficking. | |||||||||||||
| Mar 2, 2008 | Pleiotropic effects of statin therapy: molecular mechanisms and clinical results | ||||||||||||
| Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. | |||||||||||||
| Mar 1, 2008 | IDBD: Infectious Disease Biomarker Database | ||||||||||||
| Biomarkers enable early diagnosis, guide molecularly targeted therapy and monitor the activity and therapeutic responses across a variety of diseases. Despite intensified interest and research, however, the overall rate of development of novel biomarkers has been falling. Moreover, no solution is yet available that efficiently retrieves and processes biomarker information pertaining to infectious diseases. Infectious Disease Biomarker Database (IDBD) is one of the first efforts to build an easily accessible and comprehensive literature-derived database covering known infectious disease biomarkers. IDBD is a community annotation database, utilizing collaborative Web 2.0 features, providing a convenient user interface to input and revise data online. It allows users to link infectious diseases or pathogens to protein, gene or carbohydrate biomarkers through the use of search tools. It supports various types of data searches and application tools to analyze sequence and structure features of potential and validated biomarkers. Currently, IDBD integrates 611 biomarkers for 66 infectious diseases and 70 pathogens. It is publicly accessible at http://biomarker.cdc.go.kr and http://biomarker.korea.ac.kr. |
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