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| December 31,2005 | Signaling by Kit protein-tyrosine kinase—The stem cell factor receptor | |||||||||||||||||
| Signaling by stem cell factor and Kit, its receptor, plays important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a receptor protein-tyrosine kinase. The complete absence of stem cell factor or Kit is lethal. Deficiencies of either produce defects in red and white blood cell production, hypopigmentation, and sterility. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, and mastocytomas. | ||||||||||||||||||
| December 30,2005 | THE GENETIC BASIS FOR CARDIAC REMODELING | |||||||||||||||||
| Cardiomyopathies are primary disorders of cardiac muscle associated with abnormalities of cardiac wall thickness, chamber size, contraction, relaxation, conduction, and rhythm. They are a major cause of morbidity and mortality at all ages and, like acquired forms of cardiovascular disease, often result in heart failure. Over the past two decades, molecular genetic studies of humans and analyses of model organisms have made remarkable progress in defining the pathogenesis of cardiomyopathies. Hypertrophic cardiomyopathy can result from mutations in 11 genes that encode sarcomere proteins, and dilated cardiomyopathy is caused by mutations at 25 chromosome loci where genes encoding contractile, cytoskeletal, and calcium regulatory proteins have been identified. | ||||||||||||||||||
| December 29,2005 | Role of Cell-Cycle Regulators In Lung Cancer | |||||||||||||||||
| Lung cancer is the leading cause of cancer death worldwide. Histologically, 80% of lung cancers are classified as non-smallcell lung cancer (NSCLC), and the remaining 20% as small-cell lung cancer (SCLC). Lung carcinoma is the result of molecular changes in the cell, resulting in the deregulation of pathways controlling normal cellular growth, differentiation, and apoptosis. This review summarizes some of the most recent findings about the role of cell-cycle proteins in lung cancer pathogenesis and progression. | ||||||||||||||||||
| December 28,2005 | Intrahepatic immunity | |||||||||||||||||
| The intrahepatic immune environment is associated with the induction of tolerance, yet maintains the capacity to sustain effective responses against pathogens. The mechanisms underlying this dichotomy are unclear. Recent data indicate that activation of naǐve CD8+ T cells occurs within the liver. However, in contrast to efficient primary activation observed within the lymph nodes, this pathway is relatively ineffective, leading to reduced CD8+ T-cell cytotoxicity and survival. Thus, the outcome of intrahepatic CD8+ T-cell responses might be determined by whether primary activation occurs within the tolerogenic environment of the liver, or whether immunity is induced by initial antigen encounter within the lymph nodes. | ||||||||||||||||||
| December 27,2005 | Treatment of intracerebral haemorrhage | |||||||||||||||||
| Apart from management in a specialised stroke or neurological intensive care unit, until very recently no specific therapies improved outcome after intracerebral haemorrhage (ICH). In a recent phase II trial, recombinant activated factor VII (eptacog alfa) reduced haematoma expansion, mortality, and disability when given within 4 h of ICH onset; a phase III trial (the FAST trial) is now in progress. Ventilatory support, blood-pressure reduction, intracranial-pressure monitoring, osmotherapy, fever control, seizure prophylaxis, and nutritional supplementation are the cornerstones of supportive care in intensive care units. Ventricular drainage should be considered in all stuporous or comatose patients with intraventricular haemorrhage and acute hydrocephalus. | ||||||||||||||||||
| December 26,2005 | RNA interference and potential therapeutic applications of short interfering RNAs | |||||||||||||||||
| RNA interference is an endogenous gene-silencing mechanism that involves double-stranded RNA-mediated sequence-specific mRNA degradation. The discovery of this pathway together with the elucidation of the structure and function of short interfering RNAs — the effector molecules of RNA interference — has had an enormous impact on experimental biology. RNA interference technologies are currently the most widely utilized techniques in functional genomic studies. Furthermore, there is an intense research effort aimed at developing short interfering RNAs for therapeutic purposes. A number of proof-of-principle experiments have demonstrated the clinical potential of appropriately designed short interfering RNAs in various diseases including viral infections, cancer and neurodegenerative disorders. | ||||||||||||||||||
| December 25,2005 | Tumoral Drug Metabolism: Overview and Its Implications for Cancer Therapy | |||||||||||||||||
| Drug-metabolizing enzymes (DME) in tumors are capable of biotransforming a variety of xenobiotics, including antineoplastics, resulting in either their activation or detoxification. Many studies have reported the presence of DME in tumors; however, heterogenous detection methodology and patient cohorts have not generated consistent, firm data. Nevertheless, various gene therapy approaches and oral prodrugs have been devised, taking advantage of tumoral DME. With the need to target and individualize anticancer therapies, tumoral processes such as drug metabolism must be considered as both a potential mechanism of resistance to therapy and a potential means of achieving optimal therapy. This review discusses cytotoxic drug metabolism by tumors, through addressing the classes of the individual DME, their relevant substrates, and their distribution in specific malignancies. | ||||||||||||||||||
| December 24,2005 | Adiponectin – journey from an adipocyte secretory protein to biomarker of the metabolic syndrome | |||||||||||||||||
| Trujillo ME, Scherer PE (Albert Einstein College of Medicine, Bronx, NY, USA). Adiponectin – journey from an adipocyte secretory protein to biomarker of the metabolic syndrome (Review). | ||||||||||||||||||
| December 23,2005 | Genetical genomics: combining genetics with gene expression analysis | |||||||||||||||||
| The biological mechanisms that link genetic variation and its phenotypic outcome stand as a central puzzle in biology. Geneticists have usually approached this problem by trying to identify genetic variants that underlie the trait in question. Ten years ago, microarray technology opened a second front by making it possible to compare expression levels for most active genes under a variety of genetic and environmental conditions. A typical study reveals up- or down-regulation of genes or pathways associated with a phenotype (case/ control) or condition (treated/untreated). In the past few years, a number of groups have started to combine gene expression studies with genetic linkage analysis, leading to a new synergy between these approaches. | ||||||||||||||||||
| December 22,2005 | 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. | ||||||||||||||||||
| December 21,2005 | Cell migration in 3D matrix | |||||||||||||||||
| The ability of cells to migrate within the extracellular matrix and to remodel it depends as much on the physical and biochemical characteristics of a particular matrix as on cellular properties. Analyzing the different modes of migration of cells in matrices, and how cells switch between these modes, is vital for understanding a variety of physiological and pathological processes. Recent work provides new insights, but also raises some debates about the mechanisms and regulation of cell migration in three-dimensional matrices. | ||||||||||||||||||
| December 20,2005 | Cellular lipidomics | |||||||||||||||||
| The cellular lipidome comprises over 1000 different lipids. Most lipids look similar having a polar head and hydrophobic tails. Still, cells recognize lipids with exquisite specificity. The functionality of lipids is determined by their local concentration, which varies between organelles, between the two leaflets of the lipid bilayer and even within the lateral plane of the membrane. To incorporate function, cellular lipidomics must not only determine which lipids are present but also the concentration of each lipid at each specific intracellular location in time and the lipid’s interaction partners. Moreover, cellular lipidomics must include the enzymes of lipid metabolism and transport, their specificity, localization and regulation. Finally, it requires a thorough understanding of the physical properties of lipids and membranes, especially lipid–lipid and lipid–protein interactions. | ||||||||||||||||||
| December 19,2005 | Novel therapeutic opportunities for Alzheimer’s disease | |||||||||||||||||
| Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder with dementia in the elderly. The AD brain pathology is characterized by deposits of amyloid-β (Aβ) peptides and neurofibrillary tangles but also (among other aspects) by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. Classical targets of NSAIDs include cycloxygenase, nuclear factor κB, and peroxisome proliferator-activated receptors. Modulation of these pathways, all of which have been implicated in AD pathogenesis, could explain the NSAID effect on AD progression. | ||||||||||||||||||
| December 18,2005 | Ubiquitylation and cell signaling | |||||||||||||||||
| Ubiquitylation is an emerging mechanism implicated in a variety of nonproteolytic cellular functions. The attachment of a single ubiquitin (Ub) or poly-Ub (lysine 63) chains to proteins control gene transcription, DNA repair and replication, intracellular trafficking and virus budding. In these processes, protein ubiquitylation exhibits inducibility, reversibility and recognition by specialized domains, features similar to protein phosphorylation, which enable Ub to act as a signaling device. Here, we highlight several recent examples on how Ub regulates signaling and how signaling regulates ubiquitylation during physiological and pathological cellular processes. | ||||||||||||||||||
| December 17,2005 | Calcium Antagonists: Effects on Cardio-Renal Risk in Hypertensive Patients | |||||||||||||||||
| Calcium antagonists comprise 2 main subclasses, dihydropyridines and nondihydropyridines, and have been studied extensively in hypertensive patients. Early meta-analyses suggested that short-acting calcium antagonists were associated with higher mortality rates resulting from cardiovascular events and other etiologies. Recent meta-analyses failed to show any substantive difference between long acting calcium antagonists and other antihypertensive drug classes with regard to cardiovascular outcomes in those with low to moderate cardiovascular risk or kidney disease progression among those with stage 2 or 3 nonproteinuric kidney diseases. The data from calcium antagonist trials are consistent in that they decrease stroke incidence but fail to protect against new-onset heart failure. | ||||||||||||||||||
| December 16,2005 | Recent concepts in non-alcoholic fatty liver disease | |||||||||||||||||
| Non-alcoholic fatty liver disease (NAFLD) is present in up to one-third of the general population and in the majority of patients with metabolic risk factors such as obesity and diabetes. Insulin resistance is a key pathogenic factor resulting in hepatic fat accumulation. Recent evidence demonstrates NAFLD in turn exacerbates hepatic insulin resistance and often precedes glucose intolerance. Once hepatic steatosis is established, other factors, including oxidative stress, mitochondrial dysfunction, gut-derived lipopolysaccharide and adipocytokines, may promote hepatocellular damage, inflammation and progressive liver disease. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies, however, staging the disease requires a liver biopsy. | ||||||||||||||||||
| December 15,2005 | DNA Methyltransferase Inhibitors and the Development of Epigenetic Cancer Therapies | |||||||||||||||||
| Epimutations, such as the hypermethylation and epigenetic silencing of tumor suppressor genes, play a role in the etiology of human cancers. In contrast to DNA mutations, which are passively inherited through DNA replication, epimutations must be actively maintained because they are reversible. In fact, the reversibility of epimutations by small-molecule inhibitors provides the foundation for the use of such inhibitors in novel cancer therapy strategies. Among the compounds that inhibit epigenetic processes, the most extensively studied are DNA methyltransferase inhibitors. In this review, we examine the literature on DNA methyltransferase inhibitors and discuss the effi cacy of such compounds as antitumor agents, as evaluated in phase I – III clinical trials. | ||||||||||||||||||
| December 14,2005 | Immunology of ischemic vascular disease: plaque to attack | |||||||||||||||||
| Interest and studies focused on the role of immune and inflammatory mechanisms in vascular disease have advanced in synchrony with the advances in the understanding of innate immune system regulation and the interplay between innate and adaptive immunity. Clinical studies have implicated immune and inflammatory mechanisms in stroke and acute coronary syndromes. Analyses of genetically modified mice and in vitro and in vivo preclinical ischemia models have yielded insights into pathobiological mechanisms. Deciphering the role of innate immune mechanisms that confer tolerance to ischemia might guide translation of more effective therapies. Antigen-targeted and other forms of focused immunomodulation that can suppress vessel activation and protect ischemic tissue might ultimately find a niche in the prevention and treatment of vascular disease. | ||||||||||||||||||
| December 13,2005 | Kidney stone disease | |||||||||||||||||
| About 5% of American women and 12% of men will develop a kidney stone at some time in their life, and prevalence has been rising in both sexes. Approximately 80% of stones are composed of calcium oxalate (CaOx) and calcium phosphate (CaP); 10% of struvite (magnesium ammonium phosphate produced during infection with bacteria that possess the enzyme urease), 9% of uric acid (UA); and the remaining 1% are composed of cystine or ammonium acid urate or are diagnosed as drug-related stones. Stones ultimately arise because of an unwanted phase change of these substances from liquid to solid state. Here we focus on the mechanisms of pathogenesis involved in CaOx, CaP, UA, and cystine stone formation, including recent developments in our understanding of related changes in human kidney tissue and of underlying genetic causes, in addition to current therapeutics. | ||||||||||||||||||
| December 12,2005 | Nutrigenomics and nutrigenetics: the emerging faces of nutrition | |||||||||||||||||
| The recognition that nutrients have the ability to interact and modulate molecular mechanisms underlying an organism’s physiological functions has prompted a revolution in the field of nutrition. Performing population-scaled epidemiological studies in the absence of genetic knowledge may result in erroneous scientific conclusions and misinformed nutritional recommendations. To circumvent such issues and more comprehensively probe the relationship between genes and diet, the field of nutrition has begun to capitalize on both the technologies and supporting analytical software brought forth in the post-genomic era. The creation of nutrigenomics and nutrigenetics, two fields with distinct approaches to elucidate the interaction between diet and genes but with a common ultimate goal to optimize health through the personalization of diet, provide powerful approaches to unravel the complex relationship between nutritional molecules, genetic polymorphisms, and the biological system as a whole. | ||||||||||||||||||
| December 11,2005 | Cardiac Stem and Progenitor Cell Biology for Regenerative Medicine | |||||||||||||||||
| Stem cell therapy is a new and promising treatment of heart disease. However, the race is still on to find the "best" cell to reconstitute the myocardium and improve function after myocardial damage. The recent discovery in the adult mammalian myocardium of a small cell population with the phenotype, behavior, and regenerative potential of cardiac stem and progenitor cells has proposed these cells as the most appropriate for cell therapy. The existence of these cells has provided an explanation for the hitherto unexplained existence of a subpopulation of immature cycling myocytes in the adult myocardium. These findings have placed the heart squarely among other organs with regenerative potential despite the fact that the working myocardium is mainly constituted of terminally differentiated cells. | ||||||||||||||||||
| December 10,2005 | Management of Newly Diagnosed HIV Infection | |||||||||||||||||
| As part of a routine examination for insurance coverage, a 25-year-old previously healthy woman is found to have a positive test for human immunodeficiency virus type 1 (HIV-1) antibody. Heterosexual contact is her only risk factor for HIV acquisition. She is asymptomatic and has a normal physical examination. The results of hematologic and other routine laboratory tests are normal. Her CD4 cell count is 325 cells per cubic millimeter, and her plasma HIV-1 RNA level is 60,000 copies per milliliter (both confirmed on repeated testing). How should her case be managed? | ||||||||||||||||||
| December 9,2005 | Intracellular protein degradation | |||||||||||||||||
| Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve, it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely nonlysosomal, but the mechanisms involved remained obscure. The discovery of the ubiquitin–proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. | ||||||||||||||||||
| December 8,2005 | Laser Microdissection in Clinical Cardiovascular Research | |||||||||||||||||
| Laser microdissection (LMD) is an accurate and fast method to procure pure populations of cells from complex, heterogeneous tissues under direct microscopic visualization. It can be applied to a wide range of cell preparation, including paraffin-embedded material. The morphology of the captured cells is retained, and DNA, RNA, and proteins can be extracted for molecular analysis. The potential applications of LMD to human cardiovascular research are multiple, including viral/autoimmune myocarditis and arteritis, atherosclerotic lesions, and myocardial and vascular cell proliferation and death. Molecular and genetic analysis of LMD-procured cells in cardiac and vascular tissues may provide a better understanding of several cardiac diseases. | ||||||||||||||||||
| December 7,2005 | Cell migration in tumors | |||||||||||||||||
| Invasion of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. This requires chemotactic migration of cancer cells, steered by protrusive activity of the cell membrane and its attachment to the extracellular matrix. Recent advances in intravital imaging and the development of an in vivo invasion assay have provided new insights into how cancer cell migration is regulated by elements of the local microenvironment, including the extracellular matrix architecture and other cell types found in primary tumors. These results, combined with new findings from in vitro studies, have led to new insights into the molecular mechanisms of cell protrusive activity and chemotactic migration during invasion and metastasis. | ||||||||||||||||||
| December 6,2005 | Diagnostic and Therapeutic Applications of Epigenetics | |||||||||||||||||
| Epigenetic abnormalities, such as aberrant methylation of CpG islands, are inherited over cell divisions, and play important roles in carcinogenesis. Aberrant methylation ofCpGislands specific to tumor cells can be used as a marker to detect cancer cells or cancer-derived DNA, taking advantage of the high sensitivity of methods to detect aberrant methylation. Methylations of specific genes or methylation patterns of groups of genes were found to be associated with responses to chemotherapeutics and prognosis. Methylation in non-cancerous tissues is now attracting attention as a tumor risk marker, and is emerging as a target for cancer prevention. Epigenetic alterations are potentially reversible. | ||||||||||||||||||
| December 5,2005 | Combination Pharmacotherapy for Cardiovascular Disease | |||||||||||||||||
| Cardiovascular disease (CVD) is the major cause of death in developed countries and is rapidly becoming the major cause of death in the developing world. The increasing rates of obesity and type 2 diabetes, however, may slow the current favorable trends for deaths attributable to CVD in many developed countries. To improve control of risk factors for CVD, Wald and Law proposed a “polypill,” containing a statin, a diuretic, a β-blocker, an angiotensin- converting enzyme inhibitor, aspirin, and folic acid. This combination pharmacotherapy (CP) could be made widely available without treating specific risk factors or individuals. A workshop sponsored by the Centers for Disease Control and Prevention reviewed the concept of CP for both primary and secondary prevention. | ||||||||||||||||||
| December 4,2005 | Alpha cell function in health and disease: influence of glucagon-like peptide-1 | |||||||||||||||||
| Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. | ||||||||||||||||||
| December 3,2005 | Autophagy in innate and adaptive immunity | |||||||||||||||||
| Recently, several groups made a nearly simultaneous discovery that autophagic degradation represents a previously unrecognized effector of innate and adaptive immunity. Despite the fact that hints to these phenomena hail back to earlier sporadic reports, autophagy has, until now, received attention primarily as a fundamental cellular homeostasis pathway, whereby cytoplasm portions get sequestered by the membrane for delivery to lysosomes. This process leads to the removal of damaged or surplus organelles and digests stable, longlived macromolecules. Autophagy has been implicated previously in both health-promoting and diseaseassociated states, in cancer, neurodegeneration, development and aging. | ||||||||||||||||||
| December 2,2005 | Peroxisome Proliferator-Activated Receptor-Alpha and Atherosclerosis | |||||||||||||||||
| Atherosclerosis is an inflammatory process, triggered by the presence of lipids in the vascular wall, and encompasses a complex interaction among inflammatory cells, vascular elements, and lipoproteins through expression of several adhesion molecules and cytokines. Activation of the nuclear receptor, peroxisome proliferator- activated receptor-α (PPAR-α), has been demonstrated to modulate many aspects of lipoprotein metabolism and inflammation in vitro as well as in animal and human studies. The tissue distribution of PPAR-α is extensive, and it is abundantly present in the vascular wall where it may mediate many of antiinflammatory and antiatherogenic effects. Major clinical trials such as the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), the Helsinki Heart Study, and the Diabetes Atherosclerosis Intervention Study (DAIS) have demonstrated the beneficial effects of synthetic agonists of PPAR-α, specifically fibric acid derivatives, on cardiovascular disease outcome. | ||||||||||||||||||
| December 1,2005 | Notch promotes survival of pre–T cells at the β-selection checkpoint by regulating cellular metabolism | |||||||||||||||||
| Notch signals are necessary for the functional outcomes of T cell receptor β-selection, including differentiation, proliferation and rescue from apoptosis. The mechanism underlying this requirement for T cell development is unknown. Here we show that Notch receptor and Delta-like 1 ligand interactions promoted the survival of CD4ˉCD8ˉre–T cells through the maintenance of cell size, glucose uptake and metabolism. Furthermore, the trophic effects of Notch signaling were mediated by the pathway of phosphatidylinositol-3-OH kinase and the kinase Akt, such that expression of active Akt overcame the requirement for Notch in β-selection. Collectively, our results demonstrate involvement of Notch receptor–ligand interactions in the regulation of cellular metabolism, thus enabling the autonomous signaling capacity of the pre–T cell receptor complex. |
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