每日一文(0310)

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 September August July June May April March February January 2002 2001

October 31,2003 Tumour suppressors hamartin and tuberin: intracellular signalling
  Tumour suppressors hamartin and tuberin, encoded by tuberous sclerosis complex 1(TSC1) and TSC2 genes, respectively, are critical regulators of cell growth and proliferation. Mutations in TSC1 and TSC2 genes are the cause of an autosomal dominant disorder known as tuberous sclerosis complex (TSC). Another genetic disorder, lymphangioleiomyomatosis (LAM), is also associated with mutations in the TSC2 gene. Hamartin and tuberin control cell growth by negatively regulating S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), potentially through their upstream modulator mammalian target of rapamycin (mTOR). Growth factors and insulin promote Akt/PKB-dependent phosphorylation of tuberin, which in turn, releases S6K1 from negative regulation by tuberin and results in the activation of S6K1. Although much has been written regarding the molecular genetics of TSC and LAM, which is associated with either the loss of or mutation in the TSC1 and TSC2 genes, few reviews have addressed the intracellular signalling pathways regulated by hamartin and tuberin.
October 30,2003 Spectral imaging and its applications in live cell microscopy
  In biological microscopy, the ever expanding range of applications requires quantitative approaches that analyze several distinct orescent molecules at the same time in the same sample. However, the spectral properties of the orescent proteins and dyes presently available set an upper limit to the number of molecules that can be detected simultaneously with common microscopy methods. Spectral imaging and linear unmixing extends the possibilities to discriminate distinct orophores with highly overlapping emission spectra and thus the possibilities of multicolor imaging. This method also ors advantages for fast multicolor time-lapse microscopy and orescence resonance energy transfer measurements in living samples. Here we discuss recent progress on the technical implementation of the method, its limitations and applications to the imaging of biological samples.
October 29,2003 Search for new cyclic AMP-binding proteins
  Today, there is evidence that the cAMP-dependent kinases (PKA) are not the only intracellular receptors involved in intracellular cAMP signalling in eukaryotes. Other cAMPbinding proteins have been recently identified, including some cyclic nucleotide-gated channels and Epac (exchange protein directly activated by cAMP) proteins. All these proteins bind cAMP through conserved cyclic nucleotide monophosphatebinding domains. However, all putative cAMP-binding proteins having such domains, as revealed by computer analysis, do not necessarily bind cAMP, indicating that their presence is not a su.cient criteria to predict cAMP-binding property for a protein.
October 28,2003 Protein kinase D: a family affair
  The protein kinase D family of enzymes consists of three isoforms: PKD1/PKCW, PKD2 and PKD3/PKCX.They all share a similar architecture with regulatory sub-domains that play speci亼c roles in the activation, translocation and function of the enzymes.The PKD enzymes have recently been implicated in very diverse cellular functions, including Golgi organization and plasma membrane directed transport, metastasis, immune responses, apoptosis and cell proliferation.
October 27,2003 The ‘magic tail’ of G protein-coupled receptors: an anchorage for functional protein networks
  All cell types express a great variety of G proteincoupled receptors (GPCRs) that are coupled to only a limited set of G proteins. This disposition favors cross-talkbetween transduction pathways. However, GPCRs are organized into functional units. They promote speci亼city and thus avoid unsuitable cross-talk. New methodologies (mostly yeast two-hybrid screens and proteomics) have been used to discover more than 50 GPCR-associated proteins that are involved in building these units. In addition, these protein networks participate in the tra.cking, targeting, signaling, 亼ne-tuning and allosteric regulation of GPCRs. To date, proteins that interact with the GPCR C-terminus are the most abundant and are the focus of this review.
October 26,2003 The ins and outs of leptin receptor activation
  The adipocyte-derived hormone leptin signals the status of body energy stores by activating its receptor in hypothalamic nuclei. In contrast to the initial expectations, leptin treatment of human obesity was largely unsuccessful. One explanation for this is the marked leptin resistance, which likely operates in part at the receptor level. The leptin receptor is a member of the class I cytokine receptor family, which uses the Janus kinase/signal transducer and activator of transcription pathway as a major signaling route. In this review, we focus on the molecular mechanisms underlying leptin receptor activation. Dirent modes of leptin-induced clustering of the ectodomains and the subsequent signaling events will be discussed.
October 25,2003 Update on estrogen signaling
  Our understanding of estrogen signaling has undergone a true paradigm shift over recent years, following the discovery in 1995 of a second estrogen receptor, estrogen receptor L (ERβ). In many contexts ERβ appears to antagonize the actions of ERα(yin/yang relationship)although there also exist genes that are speci￠cally regulated by one of the two receptors. Studies of ERβ knockout mice have shown that ERβ exerts important functions in the ovary, central nervous system, mammary gland, prostate gland, hematopoiesis, immune system, vessels and bone. The use of ERL-speci￠c ligands against certain forms of cancer represents one of the many pharmaceutical possibilities that have been created thanks to the discovery of ERβ.
October 24,2003 Phosphoinositide signaling disorders in human diseases
  Phosphoinositides (PIs) play an essential role in diverse cellular functions. Their intracellular level is strictly regulated by speci亼c PI kinases, phosphatases and phospholipases. Recent discoveries indicate that dysfunctions in the control of their level often lead to pathologies. This revieww ill focus on some human diseases whose etiologies involve PI-metabolizing enzymes. The role of PTEN (phosphatase and tensin homolog deleted on chromosome ten) in cancer, the impact of the Src homology 2-containing inositol-5-phosphatase phosphatases in acute myeloid leukemia or diabetes, the involvement of myotubularin family members in genetic diseases and the implication of OCRL1 in Lowe syndrome will be emphasized. We will also reviewhow some bacterial pathogens have evolved strategies to speci亼cally manipulate the host cell PI metabolism to e.ciently infect them.
October 23,2003 Regulation of Tiam1-Rac signalling
  The GTPases of the Rho family are molecular switches that play an important role in a wide range of cellular processes and are increasingly implicated in tumourigenesis. Unlike what was found for the Ras oncogenes in tumours, hardly any activating mutations have been found in the genes encoding Rho proteins. In the past, we have identid Tiam1 (T-lymphoma invasion and metastasis) as a speci activator for the Rholike GTPase Rac. In vivo, Tiam1 deiency protects against Ras-induced skin carcinogenesis, underscoring the consequences of deregulated signalling for the onset and progression of tumours. Thus, an important level of regulation of signalling via the Rho-like GTPases comes from the speci control of their activators. In this paper, we review what is known on the speci  regulation of Tiam1 signalling towards Rac.
October 22,2003 Control of Ras cycling by Ca2+
  Ras GTPases are binary switches, cycling between an inactive GDP-bound form and an active GTP-bound form at the membrane. They transduce signals into the cytoplasm via effector pathways that regulate cell growth, direntiation and apoptosis. Ras activation is enhanced by guanine nucleotide exchange factors (GEFs); deactivation is accelerated by GTPase- activating proteins (GAPs). Recently, new roles for Ca2+ and diacylglycerol (DAG) in the control of Ras cycling have emerged with the discovery of a series of novel GEFs and GAPs. These regulators of Ras cycling are likely to play a key role in the information processing of Ca2+ and DAG signals.
October 21,2003 Tumour suppressors-a fly's perspective
  For a century, the little fruit.y Drosophila melanogaster has taught generations of geneticists about how genes control the development of a multicellular organism. More recently, Drosophila has begun to contribute more directly towards our understanding of human disease [Bernards A, Hariharan IK. Of .ies and men-studying human disease in Drosophila. Curr Opin Genet Dev 2001, 11, 274�278]. It is capable of doing this because it shares many disease-related genes with us. For example, the Drosophila genome sequencing project has revealed that two thirds of the genes implicated in human cancers have a counterpart in the .y genome [Adams MD, Celniker SE, Holt RA, et al.
October 20,2003 Biology of the TRANCE axis
  As the TNF and TNFR superfamilies have grown to more than two dozen combined members over the past 30 years, their involvement in interactions between immune cells, with regard to the events governing cellular differentiation, activation, and survival have been well established. The recently identified TNF superfamily cytokine, TRANCE (RANKL/OPGL/ODF/TNFSF11), which interacts with two receptors—one functional, TRANCE-R (RANK/TNFRSF11A), and one decoy, OPG (TNFRSF11B)—is a survival factor for activated dendritic cells, and may also be important for the maintenance of immune tolerance. TRANCE is also the key cytokine involved in osteoclast differentiation and activation, making TRANCE signaling crucial for proper bone homeostasis, and a potential therapeutic target in diseases such as osteoporosis, osteolytic metastatic cancer, arthritis, and periodontitis. Importantly, the positive role that TRANCE has in activating the immune system, appears to significantly contribute to pathologic bone loss. These observations have spurred intense study of the various ways in which the immune system can influence bone. Furthermore, TRANCE has also been demonstrated to play essential roles in the developmental processes leading to both lymph node formation, and the expansion and function of mammary glands during pregnancy and lactation. Thus, TRANCE is quickly emerging as a cytokine of significant importance to further understanding unique aspects of mammalian biology.
October 19,2003 Biology of FasL
  FasL (CD95L) is a well-known and well-characterized death-inducing ligand. Spontaneous mutations in FasL and its cognate receptor Fas (CD95) have helped understand the role of these molecules in the disease. Once thought to be mainly involved in the homeostasis of immune system, the territory of FasL regulation has been expanded to angiogenesis and tumor progression. Here, we review what is currently known about the role of FasL in many areas of biology.
October 18,2003 Control of glycogen deposition
  Traditionally, glycogen synthase (GS) has been considered to catalyze the key step of glycogen synthesis and to exercise most of the control over this metabolic pathway.However, recent advances have shown that other factors must be considered.Moreover, the control of glycogen deposition does not follow identical mechanisms in muscle and liver.Glucose must be phosphorylated to promote activation of GS.Glucose- 6-phosphate (Glc-6-P) binds to GS, causing the allosteric activation of the enzyme probably through a conformational rearrangement that simultaneously converts it into a better substrate for protein phosphatases, which can then lead to the covalent activation of GS.The potency of Glc-6-P for activation of liver GS is determined by its source, since Glc-6-P arising from the catalytic action of glucokinase (GK) is much more ective in mediating the activation of the enzyme than the same metabolite produced by hexokinase I (HK I).As a result, hepatic glycogen deposition from glucose is subject to a system of control in which the 'ontroller', GS, is in turn controlled by GK.In contrast, in skeletal muscle, the control of glycogen synthesis is shared between glucose transport and GS.The characteristics of the two pairs of isoenzymes, liver GS/GK and muscle GS/HK I, and the relationships that they establish are tailored to suit speci metabolic roles of the tissues in which they are expressed. The key enzymes in glycogen metabolism change their intracellular localization in response to glucose.The changes in the intracellular distribution of liver GS and GK triggered by glucose correlate with stimulation of glycogen synthesis.The translocation of GS, which constitutes an additional mechanism of control, causes the orderly deposition of hepatic glycogen and probably represents a functional advantage in the metabolism of the polysaccharide.
October 17,2003 Site of Functional Interaction of Release Factor 1 with the Ribosome
  Ribosomal protein L11 consists of a C-terminal and an N-terminal domain. To determine the importance of each domain for interaction with release factor 1, which works specifically at the UAG termination codon, we constructed Escherichia coli strains lacking either the entire L11 protein or just the N-terminal portion. Strains lacking L11 exhibited UAG suppression, defective growth, and high-temperature lethality, phenotypes that were reversed by expression of L11 protein from a plasmid. Strains lacking only the N-terminal portion of L11 grew well at physiological temperatures and survived at high temperature, but they were defective in UAG-dependent termination. Our results show for the first time that it is precisely the N-terminal part of ribosomal protein L11 that is required for the functional interaction of release factor 1 with the ribosome in the cell.
October 16,2003 Serum response factor:toggling between disparate programs of gene expression
  Serum response factor (SRF) is a widely expressed transcription factor involved in orchestrating disparate programs of gene expression linked to muscle differentiation and cellular growth. Vascular smooth muscle cell (SMC) differentiation, for example, is marked by the coordinate expression of several contractile and cytoskeletal genes regulated directly by SRF through one or more CArG-box elements in the immediate vicinity of transcription start sites. In vascular disease, this CArG-dependent program of SMC differentiation is compromised and numerous CArG-dependent early growth-response genes are activated. Thus, SRF must toggle between programs of SMC differentiation and growth depending on local environmental cues. Moreover, SRF must distinguish between a course of SMC differentiation and programs of cardiac and skeletal muscle differentiation. Several mechanisms exist to ensure context- and cell-specific programs of SRF-dependent gene expression. These include regulated expression, DNA binding, and alternative splicing of SRF, flanking sequences adjacent to and chromatin remodeling of CArG boxes, RhoA-mediated alterations in the cytoskeleton, and association of SRF with a variety of cell-restricted cofactors including the recently discovered myocardin coactivator.Although many SMC-differentiation genes require critical evolutionarily conserved CArG boxes for SMC-restricted promoter activity in cultured cells and transgenic mice, the expression of a growing number of similarly restricted genes appears to be independent of SRF. Thus, parallel circuits of gene transcription have evolved for the appropriate expression of all genes that define mammalian SMC lineages. The purpose of this review is to summarize the history and progress made in SRF research with emphasis on the role this transcription factor plays in facilitating a program of SMC-restricted gene expression.
October 15,2003 LKB1, a protein kinase regulating cell proliferation and polarity
  LKB1 is a serine-threonine protein kinase mutated in patients with an autosomal dominantly inherited cancer syndrome predisposing to multiple benign and malignant tumours, termed Peutz^Jeghers syndrome.Since its discovery in 1998, much research has focused on identi￠cation and characterisation of its cellular roles and analysing how LKB1 might be regulated. In this review we discuss exciting recent advances indicating that LKB1 functions as a tumour suppressor perhaps by controlling cell polarity.We also outline the current understanding of the molecular mechanisms by which LKB1 is regulated in vivo, through interaction with other proteins as well as by protein phosphorylation and prenylation.
October 14,2003 Effects of histamine on Th1/Th2 cytokine balance
  Atopic asthma is a chronic inflammatory disorder of the airways where upon exposure to allergens, the body mounts an immune response. This disease is associated with an increase in the number of Th2 (T helper type 2) cells and Th2 cytokines and a decrease in the number of Th1 (T helper type 1) cells and Th1 cytokines. Histamine plays an important role in the pathogenesis of atopic asthma through differential regulation of T helper lymphocytes. Histamine enhances the secretion of Th2 cytokines such as IL-4 (interleukin-4), IL-5, IL-10 and IL-13 and inhibits the production of Th1 cytokines IL-2 and IFNγ (interferon-γ) and monokine IL-12. It has been shown that histamine can modulate the cytokine network through upregulation of PGE2 (prostaglandin E2) and NO (nitric oxide). Histamine also affects cytokine production via H2 receptors and through the activation of PKA (protein kinase A). We have also demonstrated that the Jak-STAT (Janus kinase-signal transducers and activators of transcription) pathway is involved in histamine-mediated regulation of Th2 cytokines IL-5, IL-10, IL-13 and Th1 cytokine IFNγ.
October 13,2003 BAFF and the regulation of B cell survival
  The TNF family member BAFF is a fundamental survival factor for B cells. BAFF binds to three receptors, only one of which, BAFF-R, does not cross-react with the BAFF-related ligand APRIL. The survival function of BAFF on B cells is mediated mainly by BAFF-R and is particularly effective in transitional B cells. BAFF depletion leads to a considerable decrease in mature B cells, without apparent effect on B cell genesis. Consistently, BAFF overexpression results in an expanded B cell compartment and autoimmunity in mice. Elevated amounts of BAFF can be found in the serum of patients suffering from autoimmune diseases. The BAFF system is a promising target for the treatment of autoimmune diseases.
October 12,2003 Cross-talk between JNK/SAPK and ERK/MAPK Pathways
  Mixed lineage kinases (MLKs) are a family of serine/ threonine kinases that function in the SAPK signaling cascade. MLKs activate JNK/SAPK in vivo by directly phosphorylating and activating the JNK kinase SEK-1 (MKK4 and -7). Importantly, the MLK member MLK3/ SPRK has been shown recently to be a direct target of ceramide and tumor necrosis factor- (TNF-) and to mediate the TNF- and ceramide-induced JNK activation in Jurkat cells. Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells. Surprisingly, this induction of MEK phosphorylation does not result in ERK activation in vivo. Rather, in cells expressing active MLK3, ERK becomes resistant to activation by growth factors and mitogens. This restriction in ERK activation requires MLK3 kinase activity, is independent of Raf activation, and is reversed by JNK pathway inhibition either at the level of SEK-1, JNK, or Jun. These results demonstrate that sustained JNK activation uncouples ERK activation from MEK in a manner requiring Jun-mediated gene transcription. This in turn points to the existence of a negative cross-talk relationship between the stressactivated JNK pathway and the mitogen-activated ERK pathway. Thus, our findings imply that some of the biological functions of JNK activators, such as TNF- and ceramide, may be attributed to their ability to block cell responses to growth and survival factors acting through the ERK/MAPK pathway.
October 11,2003 Trends in Prevalence, Awareness, Treatment, and Control of Hypertension in the United States, 1988-2000
  Context: Prior analyses of National Health and Nutrition Examination Survey (NHANES) data through 1991 have suggested that hypertension prevalence is declining, but more recent self-reported rates of hypertension suggest that the rate is increasing. Objective :To describe trends in the prevalence, awareness, treatment, and control of hypertension in the United States using NHANES data. Design, Setting, and Participants : Survey using a stratified multistage probability sample of the civilian noninstitutionalized population. The most recent NHANES survey, conducted in 1999-2000 (n = 5448), was compared with the 2 phases of NHANES III conducted in 1988-1991 (n = 9901) and 1991-1994 (n = 9717). Individuals aged 18 years or older were included in this analysis. Main Outcome Measures: Hypertension, defined as a measured blood pressure of 140/90 mm Hg or greater or reported use of antihypertensive medications. Hypertension awareness and treatment were assessed with standardized questions. Hypertension control was defined as treatment with antihypertensive medication and a measured blood pressure of less than 140/90 mm Hg. Results : In 1999-2000, 28.7% of NHANES participants had hypertension, an increase of 3.7% (95% confidence interval [CI], 0%-8.3%) from 1988-1991. Hypertension prevalence was highest in non-Hispanic blacks (33.5%), increased with age (65.4% among those aged 60 years), and tended to be higher in women (30.1%). In a multiple regression analysis, increasing age, increasing body mass index, and non-Hispanic black race/ethnicity were independently associated with increased rates of hypertension. Overall, in 1999-2000, 68.9% were aware of their hypertension (nonsignificant decline of -0.3%; 95% CI, -4.2% to 3.6%), 58.4% were treated (increase of 6.0%; 95% CI, 1.2%-10.8%), and hypertension was controlled in 31.0% (increase of 6.4%; 95% CI, 1.6%-11.2%). Women, Mexican Americans, and those aged 60 years or older had significantly lower rates of control compared with men, younger individuals, and non-Hispanic whites. Conclusions : Contrary to earlier reports, hypertension prevalence is increasing in the United States. Hypertension control rates, although improving, continue to be low. Programs targeting hypertension prevention and treatment are of utmost importance.
October 10,2003 Factors Regulating Arteriogenesis
  Growth of collateral vessels is potentially able to preserve structure and a variable degree of function in subtended tissues in the presence of arterial occlusions. The process of transformation of a small arteriole into much larger conductance artery is called arteriogenesis. Small arterioles that interconnect side branches proximal from the arterial occlusion with distal ones experience increased fluid shear stress because of the increased blood flow velocity attributable to the pressure gradient along the bridging collaterals. This activates the endothelium and leads to monocyte adhesion and infiltration with the subsequent production of growth factors and proteases. Preexistent arterioles are essential. Their presence is genetically determined. Arteriogenesis is not organ- or species-specific; coronary or peripheral collateral vessels develop following the same design principles in mice, rats, rabbits, or dogs. In contrast to angiogenesis, arteriogenesis is not dependent on the presence of hypoxia/ischemia.
October 9,2003 Molecular Basis of Platelet Granule Secretion
  The energy-dependent release of granule contents from activated platelets is a well-established component of normal hemostasis and thrombosis. A role for membrane fusion in this process has been presumed for decades, but only recently have the mechanisms of platelet membrane fusion been investigated at the molecular level. Such studies have demonstrated that platelet membrane fusion is controlled by lipid components of the membrane bilayer, by transmembrane proteins termed SNARE proteins, and by chaperone proteins that interact with SNARE proteins. This core membrane fusion machinery is controlled by activation-dependent changes in cytoskeletal organization, intracellular calcium levels, kinase activity, and intracellular protease activity. Through these mechanisms, interactions of ligands with their cognate cell-surface receptors are transmitted to the membrane fusion machinery to facilitate membrane fusion and secretion of granule contents from platelets.
October 8,2003 Caveolin, Caveolae, and Endothelial Cell Function
  Caveolae are 50- to 100-nm cell-surface plasma membrane invaginations observed in terminally differentiated cells. They are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking and signal transduction. The use of caveolin-1– deficient mice has provided many new insights into the roles of caveolae and caveolin-1 in the regulation of endothelial cell function. These novel findings suggest an important role for caveolin-1 in the pathogenesis of cancer, atherosclerosis, and vascular disease.
October 7,2003 Recent Advances and Future Frontiers in Treating Age-Related Cataracts
  Cataracts,which are the leading cause of blindness worldwide,affect approximately 6 million individuals annually.Cataracts surgery is the most frequently performed surgical procedure in the United States with more than 1.5 million operations annually.More than half of the population older than 65 years develops age-related cataracts with visual disability related to cataracts,accounting for more than 8 million physician office visits each year.
October 6,2003 Prediction of Sudden Cardiac Death Appraisal of the Studies and Methods Assessing the Risk of Sudden Arrhythmic Death
  Since the recognition of the high incidence of cardiac arrest as the mechanism of sudden cardiac death (SCD), medical scientists and clinicians have sought methods to predict and prevent these events. Significant progress has already been made in the prediction and prevention of life-threatening arrhythmias during the last decade. This progress is highlighted by the outcomes of 4 recently published randomized studies demonstrating that the implantable cardioverter defibrillator (ICD) provides a mortality benefit compared with conventional drug therapy in highly specific subsets of patients. In parallel with intervention studies, several observational studies and reports have raised an optimistic notion that arrhythmic death can be predicted by methods potentially useful for widespread screening programs.
October 5,2003 Genes, Environment, and Cardiovascular Disease
  In this essay, we call to attention what every medical researcher knows about the etiology of cardiovascular disease but most deny, or choose to ignore, when designing, carrying out, and reporting genetic studies. Medical research is entering an era of synthesis that will take advantage of the successes of reductionism over the past decade in defining and describing human genome variations. Meaningful insights into the role of such variation requires a biological model of genome-phenotype relationships that incorporates interactions between subsets of possible genetic and environmental agents as causations in particular contexts indexed by time and space. We make recommendations for what needs to be done to cope with these complexities.
October 4,2003 Endothelial Progenitor Cells Isolation and Characterization
  Bone marrow of adults contains a subtype of progenitor cells that have the capacity to differentiate into mature endothelial cells and have therefore been termed endothelial progenitor cells (EPCs). Of the three cell markers (CD133, CD34, and the vascular endothelial growth factor receptor 2) that characterize the early functional EPCs, located predominantly in the bone marrow, EPCs obviously lose CD133/CD34 and start to express CD31, vascular endothelial cadherin, and von Willebrand factor when migrating to the circulation. Various isolation procedures of EPCs from different sources by using adherence culture or magnetic microbeads have been described, but published findings with regard to the number of EPCs in the peripheral circulation of healthy adults are scanty and no data regarding the lifetime of EPCs in vivo exist. Clinical studies employing EPCs for neovascularization of ischemic organs have just been started; however, the mechanisms stimulating or inhibiting the differentiation of bone marrow-derived EPCs in vivo and the signals causing their adhesion, migration, and homing to sites of injured tissue are largely unknown at present.
October 3,2003 The present view of the mechanism of protein folding
  We can track the positions and movements of all the atoms in small proteins as they fold and unfold by combining experimental studies with atomic-resolution molecular dynamics simulations. General principles as to how such complex architectures form so rapidly are now emerging from in-depth studies of a few proteins.Protein folding is one of the most perplexing problems in molecular biology.The problem has two parts — the prediction of the threedimensional, biologically active, native structure of a protein from its sequence and how it reaches this native structure from its denatured state.
October 2,2003 Immunocytokines: amplification of anti-cancer immunity
  Many cancers elicit an anti-tumor immune response, which is nevertheless unable to protect the patient. One approach to boost anti-tumor immunity is to target immunostimulatory cytokines to the tumor. Such targeting can be achieved by generating chimeric proteins (immunocytokines) in which the cytokine in question is fused to the C-terminus of a tumor-speci.c antibody. Immunocytokines containing interleukin-2 (IL-2) have been e.cacious in mouse tumor models and have entered clinical trials. Numerous enhancements of immunocytokines are possible, including use of additional stimulatory cytokines, alternate modes of tumor targeting, structural modi.cations to improve pharmacokinetics, and removal of potentially immunogenic sequences from the fusion protein. In addition, immunocytokines are likely to be e.cacious in combination with other therapies, including some forms of chemotherapy and cancer vaccines.
October 1,2003 DNA microarrays in clinical practice: past, present, and future
  Gene expression is a central concept in molecular biology and forms part of our knowledge of the role of genes in human diseases. Genome-wide monitoring of gene expression using DNA microarrays (allowing the simultaneous assessment of the transcription of tens of thousands of genes, and of their relative expression between normal cells and pathological cells) represents one of the latest breakthroughs in experimental molecular biology and provides unprecedented opportunity to explore the biological processes underlying human diseases by providing a comprehensive survey of a cell's transcriptional landscape. This revolutionary technology ultimately leads to the discovery of new biomarkers for disease diagnosis and prognosis prediction, and of new therapeutic tools. This paper provides an overview of microarray technology and describes some of its recent applications in medicine.

September August July June May April March February January 2002 2001