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| November 30, 2006 | The centrosome and the DNA damage induced checkpoint | ||||||||||||||||||
| The centrosome, the microtubule-organizing center of the cell, acts as a localization point, where signaling molecules are able to interact. Many kinases and phosphatases critical for regulation of DNA damage signaling pathways localize to the centrosome. This review will discuss the possible involvement of the centrosome in mediating DNA damage checkpoint control, in particular the effect of DNA damage signaling pathways involved in initiation or maintenance of cell cycle arrest on the centrosome. The mechanisms that lead to centrosome abnormalities such as centrosome hyperamplification and multipolarity in response to DNA damage will also be addressed. | |||||||||||||||||||
| November 29, 2006 | Cytochrome P450 enzymes: Central players in cardiovascular health and disease | ||||||||||||||||||
| Cardiovascular disease (CVD) is a human health crisis that remains the leading cause of death worldwide. The cytochrome P450 (CYP) class of enzymes are key metabolizers of both xenobiotics and endobiotics. Many CYP enzyme families have been identified in the heart, endothelium and smooth muscle of blood vessels. Furthermore, mounting evidence points to the role of endogenous CYP metabolites, such as epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraenoic acids (HETEs), prostacyclin (PGI2), aldosterone, and sex hormones, in the maintenance of cardiovascular health. Emerging science and the development of genetic screening have provided us with information on the differences in CYP expression among populations and groups of individuals. | |||||||||||||||||||
| November 28, 2006 | Understanding hematopoietic stem-cell microenvironments | ||||||||||||||||||
| The hematopoietic system is the paradigm for adult mammalian stem-cell research. Recent advances have improved our understanding of the cellular and molecular components of the microenvironment – or niche – that regulates hematopoietic stem cells (HSCs). Here, we summarize the molecular and cellular properties of two types of niche, namely the osteoblastic and the vascular niche, in homeostatic regulation of HSC behavior, including its maintenance, proliferation, differentiation, mobilization and homing. We highlight the most recent findings and point to an important trend to the study of niche activity in cancers. Knowledge of the basic features of the HSC niches, including physical location, cell type and various signaling pathways, should provide insights into other stem-cell systems and benefit clinical applications. | |||||||||||||||||||
| November 27, 2006 | Current perspectives on medical education in China | ||||||||||||||||||
| A number of factors in recent years have greatly increased the expectations of the people of China of their health care system. Dramatic economic growth during the last few decades has brought about an increase in general living standards for a sizeable proportion of China’s population, and with it a greater demand for quality health services. At the same time, the opening up of China’s interactions with the outside world, particularly through international trade and communications, has generated increased awareness of the possibilities of modern systems of medical care as provided elsewhere in the developed world. | |||||||||||||||||||
| November 26, 2006 | Transcriptional Pathways Direct Cardiac Development and Regeneration | ||||||||||||||||||
| Elegant studies using gene disruption strategies have defined a set of genes that are essential for normal cardiac development. Although these studies have provided a framework for the molecular regulation of cardiac morphogenesis, the genetic program of the cardiac progenitors has been incompletely defined. We used a transgenic strategy to specifically target the cardiac progenitors early during cardiac morphogenesis. With the use of flow cytometry and transcriptome analysis, we comprehensively defined the molecular program of the cardiac progenitors at distinct developmental stages. | |||||||||||||||||||
| November 25, 2006 | Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases | ||||||||||||||||||
| Cardiovascular disease affects approximately 60% of the adult population over the age of 65 and represents the number one cause of death in the United States. Coronary atherosclerosis is responsible for the vast majority of the cardiovascular events, and a number of cardiovascular risk factors have been identified. In recent years, it has become clear that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis. Much evidence supports the presence of insulin resistance as the fundamental pathophysiologic disturbance responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the metabolic syndrome. | |||||||||||||||||||
| November 24, 2006 | Signaling by the Angiotensin-Converting Enzyme | ||||||||||||||||||
| Inhibition of the angiotensin-converting enzyme (ACE) protects against the progression of several cardiovascular diseases. Because of its dual role in regulating angiotensin II and bradykinin levels, the positive clinical effects of ACE inhibitors were thought to be the consequence of concomitant reductions in the production of angiotensin II and the degradation of bradykinin. Recent evidence suggests that some of the beneficial effects of ACE inhibitors on cardiovascular function and homeostasis can be attributed to novel mechanisms. | |||||||||||||||||||
| November 23, 2006 | The surprising complexity of signal sequences | ||||||||||||||||||
| Most secreted and many membrane proteins contain cleavable N-terminal signal sequences that mediate their targeting to and translocation across the endoplasmic reticulum or bacterial cytoplasmic membrane. Recent studies have identified many exceptions to the widely held view that signal sequences are simple, degenerate and interchangeable. Growing evidence indicates that signal sequences contain information that specifies the choice of targeting pathway, the efficiency of translocation, the timing of cleavage and even postcleavage functions. As a consequence, signal sequences can have important roles in modulating protein biogenesis. Based on a synthesis of studies in numerous experimental systems, we propose that substrate-specific sequence elements embedded in a conserved domain structure impart unique and physiologically important functionality to signal sequences. | |||||||||||||||||||
| November 22, 2006 | Manufacturing and Quality Control of Cell-based Tumor Vaccines | ||||||||||||||||||
| Tumor vaccines play an increasingly important role in the therapy of various malignant diseases. The efficacy of these new products is currently being explored in many clinical trials all over the world. Cell-based tumor vaccines can be classified as somatic cell therapy, or, depending on whether genetic modifications have been applied, as gene-transfer medicinal products. Few specific guidance documents are available to standardize the development and production of cell-based tumor vaccines. Here, we review the different types of cell-based cancer vaccines that are currently being used in clinical trials. Furthermore, we discuss regulatory guidance documents available in the European Union and describe methods that have been applied so far to ensure that the cell-based vaccines meet acceptable standards, including potency assays. | |||||||||||||||||||
| November 21, 2006 | Genetic susceptibility to myocardial infarction and coronary artery disease | ||||||||||||||||||
| Atherosclerotic involvement in the coronary arteries, which can result in heart attack and sudden death, is a common disease and prototypic of a complex human trait. To understand its genomic basis, eight linkage studies of sibling pairs have been performed. Although there was limited inter-study concordance of important loci, two gene variants in the leukotriene pathway (ALOX5AP and LTA4) have emerged as susceptibility factors for myocardial infarction (MI). Genome-wide association studies have also been undertaken, and the pro-inflammatory cytokine lymphotoxin-α (LTA), and its key ligand galectin-2 (LGALS2) have been identified as genes implicated in predisposition for heart attack. | |||||||||||||||||||
| November 20, 2006 | Progress and prospects: gene transfer into embryonic stem cells | ||||||||||||||||||
| With the isolation of human embryonic stem cells (hESCs) in 1998 came the realization of a long-sought aspiration for an unlimited source of human tissue. The difficulty of differentiating ESCs to pure, clinically exploitable cell populations to treat genetic and degenerative diseases is being solved in part with the help of genetically modified cell lines. With progress in genome editing and somatic cell nuclear transfer, it is theoretically possible to obtain genetically repaired isogenic cells. Moreover, the prospect of being able to select, isolate and expand a single cell to a vast population of cells could achieve a unique level of quality control, until now unattainable in the field of gene therapy. | |||||||||||||||||||
| November 19, 2006 | Transmission of hepatitis C virus by blood transfusions and other medical procedures | ||||||||||||||||||
| Hepatitis C virus (HCV) is a leading cause of chronic blood-borne infection and chronic liver disease. The global epidemic of HCV infection emerged in the second half of the 20th century, and several lines of evidence indicate that it was primarily triggered and fed iatrogenically by the increasing use of parenteral therapies and blood transfusion. In developed countries, the rapid improvement of healthcare conditions and the introduction of anti-HCV screening for blood donors have led to a sharp decrease in the incidence of iatrogenic hepatitis C, but the epidemic continues to spread in developing countries, where the virus is still transmitted through unscreened blood transfusions and non-sterile injections. | |||||||||||||||||||
| November 18, 2006 | Circulating Endothelial Cells in Cardiovascular Disease | ||||||||||||||||||
| Quantification of circulating endothelial cells (CECs) in peripheral blood is developing as a novel and reproducible method of assessing endothelial damage/dysfunction. The CECs are thought to be mature cells that have detached from the intimal monolayer in response to endothelial injury and are a different cell population to endothelial progenitor cells (EPCs). The EPCs are nonleukocytes derived from the bone marrow that are believed to have proliferative potential and may be important in vascular regeneration. Currently accepted methods of CEC quantification include the use of immunomagnetic bead separation (with cell counting under fluorescence microscopy) and flow cytometry. | |||||||||||||||||||
| November 17, 2006 | Functions of Human Replication Protein A (RPA): From DNA Replication to DNA Damage and Stress Responses | ||||||||||||||||||
| Human replication protein A (RPA), a heterotrimeric protein complex, was originally defined as a eukaryotic single-stranded DNA binding (SSB) protein essential for the in vitro replication of simian virus 40 (SV40) DNA. Since then RPA has been found to be an indispensable player in almost all DNA metabolic pathways such as, but not limited to, DNA replication, DNA repair, recombination, cell cycle, and DNA damage checkpoints. Defects in these cellular reactions may lead to genome instability and, thus, the diseases with a high potential to evolve into cancer. This extensive involvement of RPA in various cellular activities implies a potential modulatory role for RPA in cellular responses to genotoxic insults. | |||||||||||||||||||
| November 16, 2006 | Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia | ||||||||||||||||||
| For long, T-cell acute lymphoblastic leukemia (T-ALL) remained in the shadow of precursor B-ALL because it was more seldom, and showed a normal karyotype in more than 50% of cases. The last decennia, intense research has been carried out on different fronts. On one side, development of normal thymocyte and its regulation mechanisms have been studied in multiple mouse models and subsequently validated. On the other side, molecular cytogenetics (fluorescence in situ hybridization) and mutation analysis revealed cytogenetically cryptic aberrations in almost all cases of T-ALL. Also, expression microarray analysis disclosed gene expression signatures that recapitulate specific stages of thymocyte development. | |||||||||||||||||||
| November 15, 2006 | Plasma markers of activated hemostasis in the early diagnosis of acute coronary syndromes | ||||||||||||||||||
| Because acute coronary syndromes (ACS) are caused by intracoronary thrombosis, plasma markers of coagulation have relevance for early diagnosis. To provide a critical review of these studies and specific attempts to close the diagnostic time gap left by traditional plasma markers of heart injury. Studies of ACS patients, with at least one control group, were included when blood samples were taken within 24 h after first symptoms prior to medication or intervention. Special attention was paid to studies reporting diagnostic performance, or combination of several markers into a single diagnostic index. Markers with short plasma half-life (FPA, TAT, etc.) reflect ongoing thrombosis and may identify patients at increased risk. Markers with longer half-life (F1+2, D-Dimer, etc.) may be more useful to indicate a single acute thrombotic event. However, results are highly variable and depend on sampling time, clot property, degree of coronary obstruction and physiological condition. Early diagnostic performance of hemostatic markers was poor even when combined with heart injury markers. Early measurement of hemostatic plasma markers in ACS patients provides pathophysiological information and may be helpful in risk stratification or to monitor anticoagulant therapy, but does not seem useful in routine clinical diagnosis of ACS. | |||||||||||||||||||
| November 14, 2006 | Cytogenetic and molecular aspects of lung cancer | ||||||||||||||||||
| Lung cancer is one of the most common cancers worldwide and its pathogenesis is closely associated with tobacco smoking. Continuous exposure of smoking carcinogens results in the accumulation of several alterations of tumorigenesis related genes leading to neoplastic bronchial lesions. Lung cancer is divided in two main histological groups, non-small cell lung carcinomas (NSCLCs) and small cell lung carcinomas (SCLCs). It seems that lung tumorigenesis is a multistep process in which a number of genetic events including alterations of oncogenes and tumor suppressor genes have been occurred. Cytogenetic abnormalities in lung cancer are very complex. However, a number of recurrent cytogenetic abnormalities have been identified. | |||||||||||||||||||
| November 13, 2006 | The mechanisms, diagnosis, and management of severe asthma in adults | ||||||||||||||||||
| There has been a recent increase in the prevalence of asthma worldwide; however, the 5–10% of patients with severe disease account for a substantial proportion of the health costs. Although most asthma cases can be satisfactorily managed with a combination of anti-infl ammatory drugs and bronchodilators, patients who remain symptomatic despite maximum combination treatment represent a heterogeneous group consisting of those who are under-treated or non-adherent with their prescribed medication. After excluding under-treatment and poor compliance, corticosteroid refractory asthma can be identifi ed as a subphenotype characterised by a heightened neutrophilic airway infl ammatory response in the presence or absence of eosinophils, with evidence of increased tissue injury and remodelling. | |||||||||||||||||||
| November 12, 2006 | Adhesions that mediate invasion | ||||||||||||||||||
| Infiltration of new tissue areas requires that a mammalian cell overcomes the physical and biochemical barrier of the surrounding extracellular matrix. Cell migration during embryonic development, and growth, invasion and dispersal of metastatic tumor cells depend to a large extent on the controlled degradation of extracellular matrix components. Localized degradation of the surrounding matrix is seen at defined adhesive (podosomes) and/or protrusive (invadopodia) locations in a variety of normal cells and aggressive carcinoma cells, suggesting that these membrane-associated cellular devices have a central role in mediating polarized migration in cells that cross-tissue boundaries. | |||||||||||||||||||
| November 11, 2006 | Insulators: exploiting transcriptional and epigenetic mechanisms | ||||||||||||||||||
| Insulators are DNA sequence elements that prevent inappropriate interactions between adjacent chromatin domains. One type of insulator establishes domains that separate enhancers and promoters to block their interaction, whereas a second type creates a barrier against the spread of heterochromatin. Recent studies have provided important advances in our understanding of the modes of action of both types of insulator. These new insights also suggest that the mechanisms of action of both enhancer blockers and barriers might not be unique to these types of element, but instead are adaptations of other gene-regulatory mechanisms. | |||||||||||||||||||
| November 10, 2006 | mTOR and cancer: insights into a complex relationship | ||||||||||||||||||
| mTOR (mammalian target of rapamycin) has come a long way since its humble beginnings as a kinase of unknown function. As part of the mTORC1 and mTORC2 complexes mTOR has key roles in several pathways that are involved in human cancer, stimulating interest in mTOR inhibitors and placing it on the radar of the pharmaceutical industry. Here, I discuss the rationale for the use of drugs that target mTOR, the unexpectedly complex mechanism of action of existing mTOR inhibitors and the potential benefits of developing drugs that function through different mechanisms. The purpose is not to cover all aspects of mTOR history and signalling, but rather to foster discussion by presenting some occasionally provocative ideas. | |||||||||||||||||||
| November 9, 2006 | Role of the Renin-Angiotensin-Aldosterone System and Proinflammatory Mediators in Cardiovascular Disease | ||||||||||||||||||
| Inflammation is a key mechanism in the initiation, progression, and clinical sequelae of cardiovascular diseases (CVDs), including atherosclerosis, nephropathy, and cardiomyopathy. Angiotensin II, the major effector peptide of the renin-angiotensin-aldosterone system (RAAS), plays a significant role in the advent and perpetuation of these inflammatory diseases, most notably in atherogenesis. Consequently, suppression of the influence of angiotensin II by angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce or potentially reverse atherosclerosis and other inflammation-associated CVDs. | |||||||||||||||||||
| November 8, 2006 | Neurological aspects of spinal-cord repair: promises and challenges | ||||||||||||||||||
| During the past few years, several approaches to spinal-cord repair have been successfully established in animal models. For their use in trials of spinal-cord injury (SCI) in human beings, specifi c diffi culties that aff ect the success of clinical trials have to be recognised. First, transection of the spinal cord is commonly applied in animal models, whereas contusion, which generally leads to injury in two to three segments, represents the typical injury mechanism in human beings. Second, the quadrupedal organisation of locomotion in animals and the more complex autonomic functions in human beings, challenge translation of animal behaviour into recovery from SCI in people. Third, the extensive damage of motor neurons and roots associated with spinal-cord contusion is not addressed in current translational studies. | |||||||||||||||||||
| November 7, 2006 | 老年痴呆研究百年 | ||||||||||||||||||
| This week marks a century since the first description of Alzheimer's disease (AD). Despite approval of several drugs for AD, the disease continues to rob millions of their memories and their lives. Fortunately, many new therapies directly targeting the mechanisms underlying AD are now in the pipeline. Among the investigative AD therapies in clinical trials are several strategies to block pathogenic amyloid-β peptides and to rescue vulnerable neurons from degeneration. Complementary but less mature strategies aim to prevent the copathogenic effects of apolipoprotein E and the microtubule-associated protein tau. New insights into selective neuronal vulnerability and the link between aging and AD may provide additional entry points for therapeutic interventions. | |||||||||||||||||||
| November 6, 2006 | Pathogen-derived immunomodulatory molecules | ||||||||||||||||||
| The identification of molecules from various pathogens that modulate innate and/or adaptive immunity is a dynamic and rapidly developing area of research. These immunomodulatory molecules (IM) have been optimized during pathogen–host co-evolution, and have a potential application as novel immunotherapeutics. In this review, we illustrate the use of pathogen IM that have been produced as recombinant proteins, with different modes of modulatory activity, and discuss their potential to modulate undesirable immune responses in human diseases. | |||||||||||||||||||
| November 5, 2006 | Acute myocardial infarction and heart failure | ||||||||||||||||||
| Apoptosis is a key pathologic feature in acute myocardial infarction and heart failure. Experimental animal studies have shown beneficial effects of inhibiting apoptosis. Understanding the mechanisms involved in the apoptotic cascade may be useful in better understanding of heart failure and its management. Not only in vivo detection of apoptosis may prove clinically useful in the diagnosis and risk stratification of patients with ischemic heart disease, but anti-apoptotic treatments (specific and non-specific) may be effective in the prevention and treatment of post-infarction remodelling and heart failure. | |||||||||||||||||||
| November 4, 2006 | SNAREs — engines for membrane fusion | ||||||||||||||||||
| Since the discovery of SNARE proteins in the late 1980s, SNAREs have been recognized as key components of protein complexes that drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging. | |||||||||||||||||||
| November 3, 2006 | Molecular imaging of cell-mediated cancer immunotherapy | ||||||||||||||||||
| New strategies based on the activation of a patient’s immune response are being sought to complement present conventional exogenous cancer therapies. Elucidating the trafficking pathways of immune cells in vivo, together with their migratory properties in relation to their differentiation and activation status, is useful for understanding how the immune system interacts with cancer. Methods based on tissue sampling to monitor immune responses are inadequate for repeatedly characterizing the responses of the immune system in different organs. A solution to this problem might come from molecular and cellular imaging – a branch of biomedical sciences that combines biotechnology and imaging methods to characterize, in vivo, the molecular and cellular processes involved in normal and pathologic states. | |||||||||||||||||||
| November 2, 2006 | Imaging of acute stroke | ||||||||||||||||||
| Thrombolytic therapy has led to a higher proportion of patients presenting to hospital early, and this, with parallel developments in imaging technology, has greatly improved the understanding of acute stroke pathophysiology. Additionally, MRI, including diff usion-weighted imaging (DWI) and gradient echo, or T2*, imaging is important in understanding basic structural information—such as distinguishing acute ischaemia from haemorrhage. It has also greatly increased sensitivity in the diagnosis of acute cerebral ischaemia. The pathophysiology of the ischaemic penumbra can now be assessed with CT or MRI-based perfusion imaging techniques, which are widely available and clinically applicable. | |||||||||||||||||||
| November 1, 2006 | Adeno-associated Virus Serotypes: Vector Toolkit for Human Gene Therapy | ||||||||||||||||||
| Recombinant adeno-associated viral (AAV) vectors have rapidly advanced to the forefront of gene therapy in the past decade. The exponential progress of AAV-based vectors has been made possible by the isolation of several naturally occurring AAV serotypes and over 100 AAV variants from different animal species. These isolates are ideally suited to development into human gene therapy vectors due to their diverse tissue tropisms and potential to evade preexisting neutralizing antibodies against the common human AAV serotype 2. Despite their prolific application in several animal models of disease, the mechanisms underlying selective tropisms of AAV serotypes remain largely unknown. |
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