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| May 31,2004 | Obesity and hypertension | |||||||||
| The association between obesity and hypertension is well documented, although the exact nature of this relation remains unclear. Sympathetic nervous and renin-angiotensin-aldosterone system activation appear to play an important role in the sodium and water retention, rightward shift in the pressure-natriuresis, and blood pressure elevation observed in obese individuals. Visceral obesity and the ectopic deposition of adipose tissue may be important in the activation of these systems and in the target organ damage that ensues. Weight loss is critical in the effective management of obesity hypertension and the accompanying target organ damage, although recidivism rates are high. | ||||||||||
| May 30,2004 | p53: 25 years after its discovery | |||||||||
| Since its discovery 25 years ago, the p53 protein has emerged as a key tumor suppressor protein at the crossroads of cellular stress response pathways. Through these pathways, which can lead to cell-cycle arrest, DNA repair, cellular senescence, differentiation and apoptosis, p53 facilitates the repair and survival of damaged cells or eliminates severely damaged cells from the replicative pool to protect the organism. Because of these dynamic and multiple functions of p53, which are largely lost following mutations in the gene encoding p53, this molecule continues to be studied intensively in biomedical research, including the fields of toxicology and pharmacology. In this article, we briefly review the first 25 years of research on p53. | ||||||||||
| May 29,2004 | SNPs in cancer research and treatment | |||||||||
| Genetic variation in the human genome is an emerging resource for studying cancer, a complex set of diseases characterised by both environmental and genetic contributions. The number of common germ-line variants is great, on the order of 10–15 million per person, and represents a remarkable opportunity to investigate the aetiology, interindividual differences in treatment response and outcomes of specific cancers. The study of genetic variation can elucidate critical determinants in environmental exposure and cancer, which could have future implications for preventive and early intervention strategies. However, we are in the initial stages of characterising the tools to rigorously analyse the genetic contributions to complex diseases, such as cancer. | ||||||||||
| May 28,2004 | The Molecular Biology Database Collection | |||||||||
| The Molecular Biology Database Collection is a public resource listing key databases of value to the biologist, including those featured in this issue of Nucleic Acids Research, and other high-quality databases. All databases included in this Collection are freely available to the public. This listing aims to serve as a convenient starting point for searching the web for reliable information on various aspects of molecular biology, biochemistry and genetics. This year's update includes 548 databases, 162 more than the previous one. | ||||||||||
| May 27,2004 | Human genome research in China | |||||||||
| Significant progress in human genome research has been made in China since 1994. This review aims to give a brief and incomplete introduction to the major research institutions and their achievements in human genome sequencing and functional genomics in medicine, with emphasis on the "1% Sequencing Project", the generation of single nucleotide polymorphism and haplotype maps of the human genome, disease gene identification, and the molecular characterization of leukemia and other diseases. Chinese efforts towards the sequencing of pathogenic microbial genomes and of the rice (Oryza sativa ssp. Indica) genome are also described. | ||||||||||
| May 26,2004 | Genetic Testing for Cardiovascular Disease Susceptibility | |||||||||
| Genetic susceptibility tests are already advertised on the Internet to identify individuals at above average risk for cardiovascular disease (CVD), such as deep vein thrombosis, hyperlipidemia, or atherosclerosis, whereas other tests claim to predict response to a particular drug treatment. Some kits are available to the public directly, bypassing a doctor. Their value, however, must be considered carefully, because although a genotype may be strongly and consistently associated with an intermediate trait, and because the intermediate trait is a strong predictor of CVD risk, there may be little or no association of genotype with risk over and above that of the measured trait. | ||||||||||
| May 25,2004 | Metastases to the heart | |||||||||
| Primary tumors of the heart are rare, occurring at a frequency of ~0.02% in pooled autopsy series [1]. Histologically, three-quarters of primary heart tumors turn out to be benign, almost half of them being myxomas [2]. Whether benign or malignant, the majority of primary cardiac tumors are intracavitary and preferentially develop in the left atrium, thereby leading to left ventricular inflow obstruction. Embolism is also common. Secondary or metastatic heart tumors occur comparatively more frequently, with an at least 100 times higher incidence than primary tumors of the heart [3]. Intracavitary growth of secondary heart tumors, however, is unusual. Therefore, despite their frequency, metastatic heart tumors only rarely gain clinical attention. | ||||||||||
| May 24,2004 | DNA Replication Fidelity | |||||||||
| When describing the structure of the DNA double helix, Watson and Crick (1) wrote, "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material." Fifty years later, interest in the fidelity of DNA copying mechanisms remains high because the balance between correct and incorrect DNA synthesis is relevant to a great deal of biology. High fidelity DNA synthesis is beneficial for maintaining genetic information over many generations and for avoiding mutations that can initiate and promote human diseases such as cancer and neurodegenerative diseases. | ||||||||||
| May 23,2004 | Dendritic guidance | |||||||||
| Like axons, dendrites need guidance for proper orientation and positioning within the brain. Guidance determines synaptic connectivity as well as the strength of transmission. Recent in vivo studies have demonstrated that several cell-surface receptors, previously known as axon guidance molecules, are also responsible for the directed outgrowth of dendrites. Collectively, these studies reveal that the function of guidance molecules in individual neurons and individual processes is diverse and likely to be specifically regulated. Here, these studies are reviewed and emerging issues and implications are discussed. | ||||||||||
| May 22,2004 | An overview on its current perspectives and treatment options | |||||||||
| Obesity is a multi-factorial disorder, which is often associated with many other significant diseases such as diabetes, hypertension and other cardiovascular diseases, osteoarthritis and certain cancers. The management of obesity will therefore require a comprehensive range of strategies focussing on those with existing weight problems and also on those at high risk of developing obesity. Hence, prevention of obesity during childhood should be considered a priority, as there is a risk of persistence to adulthood. This article highlights various preventive aspects and treatment procedures of obesity with special emphasis on the latest research manifolds. | ||||||||||
| May 21,2004 | New insights into haematopoietic stem cell transplantation for patients with haemoglobinopathies | |||||||||
| Although improvements in conservative treatment have considerably ameliorated the prognosis of haemoglobinopathies, haematopoietic stem cell transplantation (HSCT) still remains the only curative treatment for patients with thalassemia and sickle cell disease (SCD). The majority of patients with thalassaemia given HSCT from a human leucocyte antigen (HLA)-identical sibling can be cured of their disease. Regarding patients with SCD, HSCT is reserved almost exclusively for children who have significant sickle-related morbidity. HSCT from an unrelated volunteer, carefully selected by high-resolution HLA-typing, can be an alternative for patients lacking a compatible family donor, as the results obtained using such donors are comparable with those obtained employing an HLA-identical sibling. | ||||||||||
| May 20,2004 | Advances in Molecular Carcinogenesis | |||||||||
| Survival of patients with advanced solid tumors has not significantly improved over the past 30 years. Although molecularly targeted anticancer drugs offer promise, few drugs make it through the end of the Food and Drug Administration approval process. Animal models that more closely resemble human carcinogenesis may bridge the gap between preclinical success and benefits for patients. We discuss pros and cons of several mouse models, including genetically engineered mice that each represent different aspects of human cancer, and the screening of targeted drugs in these models. | ||||||||||
| May 19,2004 | Carbon monoxide in biology and medicine | |||||||||
| Carbon monoxide (CO), a product of organic oxidation processes, arises in vivo during cellular metabolism, most notably heme degradation. CO binds to the heme iron of most hemoproteins. Tissue hypoxia following hemoglobin saturation represents a principle cause of CO-induced mortality in higher organisms, though cellular targets cannot be excluded. Despite extreme toxicity at high concentrations, low concentrations of CO can confer cytoprotection during ischemia/reperfusion or inflammation-induced tissue injury. Likewise, heme oxygenase, an enzyme that produces CO, biliverdin and iron, as well as a secondary increase in ferritin synthesis, from the oxidation of heme, can confer protection in vivo and in vitro. | ||||||||||
| May 18,2004 | Cytokines as therapeutics and targets of therapeutics | |||||||||
| Cytokine research has spawned the introduction of new therapies that have revolutionized the treatment of many important diseases. These therapeutic advances have resulted from two very different strategies. The first therapeutic strategy embodies the administration of purified, recombinant cytokines. The second relies on the administration of therapeutics that inhibit the harmful effects of upregulated, endogenous cytokines. Examples of successful cytokine therapeutics include hematopoietic growth factors (colony stimulating factors) and interferons. Prime examples of cytokine antagonists that have profoundly altered the treatment of some inflammatory disorders are agents that inhibit the effects of tumor necrosis factor (TNF). | ||||||||||
| May 17,2004 | Current developments of immunotherapy in the clinic | |||||||||
| The clinical application of immunotherapy for cancer is rapidly moving forward in multiple areas, including the adoptive transfer of anti-tumor-reactive T cells and the use of 'therapeutic'vaccines. Recently, both clinical and immunological endpoints have shown improvement. Novel strategies designed in the laboratory and proven in preclinical animal tumor models are now entering the clinic, with the intent of enhancing current therapeutic efficacy. These novel strategies involve breaking tolerance to tumor self-antigens by inhibiting regulatory cells, boosting T-cell co-stimulation and using combinations of recombinant cytokines and other defined molecules with 'immuno-enhancing'activities. | ||||||||||
| May 16,2004 | Tolerance and Cancer | |||||||||
| The development of malignant disease might be seen as a failure of immune surveillance. However, not all tumors are naturally immunogenic, and even among those that are immunogenic, the uncontrolled rapid growth of a tumor may sometimes out-run a robust immune response. Nevertheless, recent evidence suggests that mechanisms of tolerance that normally exist to prevent autoimmune disease may also preclude the development of an adequate antitumor response and that tumors themselves have the ability to thwart the development of effective immune responses against their antigens. A major challenge has been to develop approaches to breaking this tolerance in tumor-bearing hosts, and recent advances in our understanding of antigen presentation and tolerance have led to some promising strategies. | ||||||||||
| May 15,2004 | Bioinformatic analysis of the nucleolus | |||||||||
| The nucleolus is a plurifunctional, nuclear organelle, which is responsible for ribosome biogenesis and many other functions in eukaryotes, including RNA processing, viral replication and tumour suppression. Our knowledge of the human nucleolar proteome has been expanded dramatically by the two recent MS studies on isolated nucleoli from HeLa cells [Andersen, Lyon, Fox, Leung, Lam, Steen, Mann and Lamond (2002) Curr. Biol. 12, 1-11; Scherl, Coute, Deon, Calle,Kindbeiter, Sanchez, Greco, Hochstrasser and Diaz (2002) Mol. Biol. Cell 13, 4100-4109]. Nearly 400 proteins were identified within the nucleolar proteome so far in humans. | ||||||||||
| May 14,2004 | Bcl-2 family members and disease | |||||||||
| Apoptosis plays an important role during development and in the maintenance of multicellular organisms. Bcl-2 family members affect cell death in either a positive or negative fashion. Although some redundancy exists between family members, expression of certain family members is important during development in an organ-specific manner. The founding family member bcl-2 tends to be highly expressed in the embryo and declines postnatally following differentiation and maturation. Altered expression of bcl-2, as well as other family members, has been observed in disease states potentially affecting treatment modalities. | ||||||||||
| May 13,2004 | A Novel Proteomic Screen for Peptide-Protein Interactions | |||||||||
| Regulated interactions between short, unstructured amino acid sequences and modular protein domains are central to cell signaling. Here we use synthetic peptides in "active" (e.g. phosphorylated) and "control"(e.g. nonphosphorylated) forms as baits in affinity pull-down experiments to determine such interactions by quantitative proteomics. Stable isotope labeling by amino acids in cell culture distinguishes specific binders directly by the isotope ratios determined by mass spectrometry (Blagoev, B., Kratchmarova, I., Ong, S.-E., Nielsen, M., Foster, L. J., and Mann, M. (2003) Nat. Biotechnol. 21, 315-318). A tyrosine-phosphorylated peptide of the epidermal growth factor receptor specifically retrieved the Src homology domain (SH) 2- and SH3 domain-containing adapter protein Grb2. | ||||||||||
| May 12,2004 | Chips with everything | |||||||||
| Two developments are set to revolutionise research in and clinical management of infectious diseases. First, the completion of the human genome project together with the sequencing of many pathogen genomes, and second, the development of microarray technology. This review explains the principles underlying DNA microarrays and highlights the uses to which they are being put to investigate the molecular basis of infectious diseases. Pathogen studies enable identification of both known and novel organisms, understanding of genetic evolution, and investigation of determinants of pathogenicity. Host studies show the complexities of development and activation of both innate and adaptive immunity. Host-pathogen studies allow global analysis of gene expression during pathogenesis. | ||||||||||
| May 11,2004 | MAXIMIZING THE POTENTIAL OF FUNCTIONAL GENOMICS | |||||||||
| Geneticists have made tremendous progress in understanding the genetic basis of phenotypes, and genomics promises to bring further insights at a rapid pace. The progress in functional genomics has been driven primarily by the development of new techniques that are used in a few dedicated research centres. Focusing on selected advances in genomic technologies, we assess the results that have been obtained so far, highlight the challenges faced by these new tools and suggest ways in which they can be overcome. We argue that progress in functional genomics will depend on developing high-throughput technologies that can easily be moved away from dedicated centres and into individual laboratories. | ||||||||||
| May 10,2004 | Autocrine and paracrine actions of natriuretic peptides in the heart | |||||||||
| The natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), are a family of polypeptide mediators exerting numerous actions in cardiovascular homeostasis. ANP and BNP are cardiac derived, being secreted and up-regulated in myocardium in response to many pathophysiological stimuli. CNP is an endothelium-derived mediator. The classical endocrine effects of ANP and BNP on fluid homeostasis and blood pressure, especially in conditions characterised by left ventricular dysfunction, are well recognised and extensively researched. However, there is accumulating evidence that, in addition to endocrine actions, ANP and BNP exhibit important autocrine and paracrine functions within the heart and coronary circulation. | ||||||||||
| May 9,2004 | The role of Bcl-2 family members in tumorigenesis | |||||||||
| The Bcl-2 family consists of about 20 homologues of important pro- and anti-apoptotic regulators of programmed cell death. The established mode of function of the individual members is to either preserve or disturb mitochondrial integrity, thereby inducing or preventing release of apoptogenic factors like Cytochrome c (Cyt c) from mitochondria. Recent findings also indicate further Bcl-2-controlled mitochondria-independent apoptosis pathways. Bcl-2 represents the founding member of the new and growing class of cell death inhibiting oncoproteins. In this review, we try to briefly summarize current models of Bcl-2 family function and to outline the work demonstrating the influence of deregulated Bcl-2 family member expression on tumorigenesis and cancer therapy. | ||||||||||
| May 8,2004 | A CENSUS OF HUMAN CANCER GENES | |||||||||
| A central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis (‘cancer genes’). After two decades of searching, how many have been identified and how do they compare to the complete gene set that has been revealed by the human genome sequence? We have conducted a ‘census’ of cancer genes that indicates that mutations in more than 1% of genes contribute to human cancer. The census illustrates striking features in the types of sequence alteration, cancer classes in which oncogenic mutations have been identified and protein domains that are encoded by cancer genes. | ||||||||||
| May 7,2004 | Socializing with the Neighbors:Stem Cells and Their Niche | |||||||||
| The potential of stem cells in regenerative medicine relies upon removing them from their natural habitat, propagating them in culture, and placing them into a foreign tissue environment. To do so, it is essential to understand how stem cells interact with their micro- environment, the so-called stem cell niche, to estab- lish and maintain their properties. In this review, we examine adult stem cell niches and their impact on stem cell biology. | ||||||||||
| May 6,2004 | Neurotransmitter transporters | |||||||||
| Plasma membrane transporters terminate the actions of several small molecule neurotransmitters, including glutamate, γ-aminobutyric acid, glycine, dopamine, serotonin and norepinephrine. The fact that anti-depressants, cocaine and amphetamines can have such profound behavioral effects by inhibiting the activity of some of these transporters underscores the importance of these molecules. Recent studies have begun to define the mechanisms that regulate these transporters. As these studies progress, it is becoming clear that the transporters form complexes both with themselves and with many other proteins that can regulate either transporter localization or activity. In most cases, the physiological and/or pathological relevance of these interactions is only beginning to emerge. | ||||||||||
| May 5,2004 | How DCs control cross-regulation between lymphocytes | |||||||||
| Dendritic cells (DCs) acquire and present a variety of antigens from a given pathogen. They orchestrate the development of the immune response by integrating and relaying various signals through interactions with T, B, natural killer (NK) and NKT cells. Owing to compartmentalization of these different cell types, sequential interactions often take place, for example, when innate immunity influences adaptive immunity. Lymphocytes within the DC cluster can instruct each other indirectly, by fine tuning of DC function, or directly, by local cytokine secretion, with presumably more pronounced effects when the interactions are concomitant rather than sequential and when the T cells are experienced. | ||||||||||
| May 4,2004 | Fixation biases affecting human SNPs | |||||||||
| Under neutrality all classes of mutation have an equal probability of becoming fixed in a population. In this article, we describe our analysis of the frequency distributions of >5000 human SNPs and provide evidence of biases in the process of fixation of certain classes of point mutation that are most likely to be attributable to biased gene conversion. The results indicate an increased fixation probability of mutations that result in the incorporation of a GC base pair. Furthermore, in transcribed regions this process exhibits strand asymmetry, and is biased towards preserving a G base on the coding strand. | ||||||||||
| May 3,2004 | Transforming Growth Factor β and Atherosclerosis | |||||||||
| The role of the anti-inflammatory cytokine transforming growth factor β(TGF-β) in atherosclerosis has been the subject of considerable debate for a decade. In the early 1990s, we postulated that TGF-β played an important role in maintaining normal vessel wall structure and that loss of this protective effect contributed to the development of atherosclerosis. We termed this the protective cytokine hypothesis. This proposal was slow to gain broad acceptance, however, because at that time there were little data available on the role of TGF-β during the development of atherosclerosis but much information about its role during trauma-induced neointima formation. | ||||||||||
| May 2,2004 | PARSING THE POLARITY CODE | |||||||||
| Cell polarization is used both to mediate physical fates, as, for example, in orientated cell migration, and to specify differential phenotypic fates, as in the asymmetric division of stem cells. Strikingly, the same sets of conserved proteins are used throughout the Metazoa for these purposes. The PAR proteins organize cell polarization in many contexts, and the PINS proteins control the orientation of mitosis. These proteins seem to function as components of a self-organizing network, and an important goal is to decode — or parse — the molecular language of this network. | ||||||||||
| May 1,2004 | Proteomic approaches in cancer risk and response assessment | |||||||||
| Proteomics is more than just a list-generating exercise where increases or decreases in protein expression are identified. Proteomic technologies will ultimately characterize information-flow through the protein circuitry that interconnects the extracellular microenvironment to the serum or plasma macroenvironment through intracellular signaling systems and their control of gene transcription. The nature of this information can be a cause or a consequence of disease processes and how patients respond to therapy. |
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