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 January 2003 2002 2001

February 29,2004 Molecular Mechanisms and Potential Targets for Treatment
  Significant advances have been made over the past few years concerning the cellular and molecular events underlying ischemic cell death. The brain succumbs to ischemic injury as a result of loss of metabolic stores, excessive intracellular calcium accumulation, oxidative stress, and potentiation of the inflammatory response. Neurons can also die via necrotic or apoptotic mechanisms, depending on the nature and severity of the insult. While it has been widely held that ischemia is notable for cessation of protein synthesis, brain regions with marginal reduction in blood supply are especially capable of expressing a variety of genes, the functions of many of which are only beginning to be understood.
February 28,2004 nuclear localization of the regulators of G protein signaling
  The regulators of G protein signaling (RGS) are an extraordinary class of diverse multifunctional signaling proteins best known for their potent capacity to down-regulate the activity of Ga subunits at the plasma membrane. In certain circumstances, some RGS proteins undergo translocation to the nucleus or plasma membrane from the cytoplasm. Translocation demonstrates a potentially dynamic alternative mechanism for Ga subunit or effector regulation. The nuclear localization of the regulators of G protein signaling proteins further suggests these proteins possess even greater functional heterogeneity than that envisioned previously, as regulators of transcription and cell cycle control.
February 27,2004 Cyclic GMP–Dependent Protein Kinases and the Cardiovascular System
  Signaling cascades initiated by nitric oxide (NO) and natriuretic peptides (NPs) play an important role in the maintenance of cardiovascular homeostasis. It is currently accepted that many effects of these endogenous signaling molecules are mediated via stimulation of guanylyl cyclases and intracellular production of the second messenger cGMP. Indeed, cGMP-elevating drugs like glyceryl trinitrate have been used for more than 100 years to treat cardiovascular diseases. However, the molecular mechanisms of NO/NP signaling downstream of cGMP are not completely understood.
February 26,2004 Caveolin regulation of endothelial function
  Caveolae are the sites in the cell membrane responsible for concentrating an array of signaling molecules critical for cell function. Recent studies have begun to identify the functions of caveolin-1, the 22-kDa caveolar protein that oligomerizes and inserts into the cytoplasmic face of the plasma membrane. Caveolin-1 appears to regulate caveolar internalization by stabilizing caveolae at the plasma membrane rather than controlling the shape of the membrane invagination. Because caveolin-1 is a scaffolding protein, it has also been hypothesized to function as a "master regulator" of signaling molecules in caveolae.
February 25,2004 Drug resistance reversal—are we getting closer?
  Clinical drug resistance is a major barrier to overcome before chemotherapy can become curative for most patients presenting with metastatic cancer. Rational attempts to tackle clinical drug resistance need to be based on an understanding of the mechanisms involved; these are likely to be complex and multifactorial, and may be due to inadequate drug exposure or alterations in the cancer cell itself. This article reviews a number of strategies used to tackle drug resistance, focussing on work in our institution related to the treatment of ovarian cancer and resistance to platinum and taxane-based chemotherapy.
February 24,2004 Electroporation: theory and methods, perspectives for drug delivery, gene therapy and research
  Electroporation designates the use of short high-voltage pulses to overcome the barrier of the cell membrane. By applying an external electric field, which just surpasses the capacitance of the cell membrane, transient and reversible breakdown of the membrane can be induced. This transient, permeabilized state can be used to load cells with a variety of different molecules, either through simple diffusion in the case of small molecules, or through electrophoretically driven processes allowing passage through the destabilized membrane - as is the case for DNA transfer.
February 23,2004 Topical Review Renin: origin, secretion and synthesis
  Renin is a central hormone in the control of blood pressure and various other physiological functions. In spite of the very early discovery of renin over 100 years ago, we have only recently gained a deeper understanding of the origin of renin-producing cells and of the mechanisms responsible for renin synthesis and secretion. The main source of renin is the juxtaglomerular cells (JGCs), which release renin from storage granules. Besides the renin–angiotensin system (RAS) in the JGCs, there exist local RASs in various tissues.
February 22,2004 REGULATION OF JAK–STAT SIGNALLING IN THE IMMUNE SYSTEM
  The cytokine-activated Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway has an important role in the control of immune responses. Dysregulation of JAK–STAT signalling is associated with various immune disorders. The signalling strength, kinetics and specificity of the JAK–STAT pathway are modulated at many levels by distinct regulatory proteins. Here, we review recent studies on the regulation of the JAK–STAT pathway that will enhance our ability to design rational therapeutic strategies for immune diseases.
February 21,2004 New Markers of Inflammation and Endothelial Cell Activation Part I
  Current views regard atherosclerosis as a dynamic and progressive disease arising from the combination of endothelial dysfunction and inflammation.1-6 The vascular endothelium, located at the interface of blood and tissue, is able to sense changes in hemodynamic forces and bloodborne signals and react by synthesizing and releasing vasoactive substances. Vascular homeostasis is maintained by a balance between endothelium-derived relaxing and contracting factors. With disruption of this balance, mediated by inflammatory and traditional cardiovascular risk factors, the vasculature becomes susceptible to atheroma formation.
February 20,2004 Nongenic transcription, gene regulation and action at a distance
  In eukaryotes, motifs such as silencers, enhancers and locus control regions act over thousands of base pairs to regulate adjacent genes; insulators limit such effects, and barriers confine repressive heterochromatin to particular chromosomal segments. Recent results show that many of these motifs are nongenic transcription units, and two of them directly contact their targets lying further down the chromosome to loop the intervening DNA: the barriers (scs and scs’) flanking the 87A7 heat-shock locus in the fly contact each other, and a locus control region touches the β-globin gene in the mouse. I hypothesize that the act of transcription underlies the function of these regulators; active polymerizing complexes tend to cluster into ‘factories’ and this facilitates molecular contact between the transcribed regulator and its distant (and transcribed) target.
February 19,2004 Cell signaling and cancer
  During the course of tumor progression, cancer cells acquire a number of characteristic alterations.These include the capacities to proliferate independently of exogenous growth-promoting or growth-inhibitory signals, to invade surrounding tissues and metastasize to distant sites, to elicit an angiogenic response, and to evade mechanisms that limit cell proliferation, such as apoptosis and replicative senescence.These properties reflect alterations in the cellular signaling pathways that in normal cells control cell proliferation, motility, and survival. Many of the proteins currently under investigation as possible targets for cancer therapy are signaling proteins that are components of these pathways. The nature of these signaling pathways and their roles in tumorigenesis were the subject of a recent Beatson International Cancer Conference.
February 18,2004 Production of therapeutic antibodies in plants
  Antibodies are versatile tools for the diagnosis treatment of many diseases. Their use has increased dramatically with the advent of recombinant antibody (rAb) technology,allowing the production of immunological reagents with improved and novel prperties.The main challenge now lies in achieving cost-effective production on a large scale.Over the past 15 years, the potential of plants for the production of pharmaceutical proteins has become well-established. Plants represent an inexpensive,efficient and safe alternative to traditional systems used for the commercial-scale synthesis of rAbs.
February 17,2004 Endothelial Protection by High-Density Lipoproteins
  There are several potential mechanisms by which HDLs protect against the development of vascular disease. One relates to the unique ability of these lipoproteins to remove cholesterol from the arterial wall. Another is the ability of HDL to prevent and eventually correct endothelial dysfunction, a key variable in the pathogenesis of atherosclerosis and its complications. HDLs help maintain endothelial integrity, facilitate vascular relaxation, inhibit blood cell adhesion to vascular endothelium, reduce platelet aggregability and coagulation, and may favor fibrinolysis.
February 16,2004 Our fragmentary knowledge of the regulatory functions of ANG II “fragments”: are we beginning to see the light?
  The control of total body sodium and water by the kidney has a pivotal role in the long-term control of mean arterial blood pressure (MAP; ). Whereas the function of the arterial baroreceptor reflex seems to be limited to the sensing and the correction of rapid short-term pressure changes around long-term MAP , the cardiopulmonary receptors in the low-pressure system provide important information on the degree of vascular filling .
February 15,2004 Disruption of TGF-β signaling in T cells accelerates atherosclerosis
  Increasing evidence suggests that atherosclerosis is an inflammatory disease promoted by hypercholesterolemia. The role of adaptive immunity has been controversial, however. We hypothesized that proatherogenic T cells are controlled by immunoregulatory cytokines. Among them, TGF-β has been implied in atherosclerosis, but its mechanism of action remains unclear. We crossed atherosclerosisprone ApoE-knockout mice with transgenic mice carrying a dominant negative TGF-β receptor II in T cells.
February 14,2004 Regulating histone acetyltransferases and deacetylases
  Histone acetyltransferases and histone deacetylases regulate the acetylation of histones and transcription factors, and in doing so have major roles in the control of cell fate. Many recent results have indicated that their function is strictly regulated in cells through the modulation of their levels, activity and availability for interaction with specific transcription factors. In this review, we present the various molecular mechanisms that bring about this tight regulation and discuss how these regulatory events influence cellular responses to environmental changes.
February 13,2004 The Biology of the Ets1 Proto-Oncogene
  The Ets1 proto-oncoprotein is a member of the Ets family of transcription factors that share a unique DNA binding domain, the Ets domain. The DNA binding activity of Ets1 is controlled by kinases and transcription factors. Some transcription factors, such as AML-1, regulate Ets1 by targeting its autoinhibitory module. Others, such as Pax-5, alter Ets1 DNA binding properties. Ets1 harbors two phosphorylation sites, threonine-38 and an array of serines within the exon VII domain. Phosphorylation of threonine-38 by ERK1/2 activates Ets1, whereas phosphorylation of the exon VII domain by CaMKII or MLCK inhibits Ets1 DNA binding activity. Ets1 is expressed by numerous cell types. In haemotopoietic cells, it contributes to the regulation of cellular differentiation. In a variety of other cells, including endothelial cells, vascular smooth muscle cells and epithelial cancer cells, Ets1 promotes invasive behavior. Regulation of MMP1, MMP3, MMP9 and uPA as well as of VEGF and VEGF receptor gene expression has been ascribed to Ets1. In tumors, Ets1 expression is indicative of poorer prognosis.
February 12,2004 Regulation of L-type Ca2+ channels in the heart: Overview of recent advances
  Regulation of L-type Ca2+ channels is complex, because many factors, such as phosphorylation, divalent cations, and proteins, specified or unspecified, have been shown to affect the channel activities. An additional complication is that these factors interact with one another to achieve final outcomes. Recent molecular technologies have helped to shed light on the mechanisms governing the activity of L-type Ca2+ channels. In this review article, three major topics concerning regulation of L-type Ca2+ channels in the heart are discussed, i.e. c-AMP dependent channel phosphorylation, role of magnesium (Mg2+), and the phenomenon of channel run-down.
February 11,2004 The War on ‘‘Anti-Aging Medicine’’
  Leading members of the gerontological community have recently launched a war on anti-aging medicine, seeking to discredit what they judge to be fraudulent and harmful products and therapies, and to distinguish their research from what they regard as the pseudoscience of the anti-aging movement. This article interprets the contemporary war on anti-aging medicine as largely an attempt by established gerontological researchers to preserve their hardwon scientific and political legitimacy, as well as to maintain and enhance funding for research on the basic biological mechanisms of aging.
February 10,2004 Regulation of matrix metalloproteinases: An overview
  Matrix metalloproteinases (MMPs) are a major group of enzymes that regulate cell-matrix composition. MMP genes show a highly conserved modular structure. Ample evidence exists on the role of MMPs in normal and pathological processes, including embryogenesis, wound healing, inflammation, arthritis, cardiovascular diseases, pulmonary diseases and cancer. The expression patterns of MMPs have interesting implications for the use of MMP inhibitors as therapeutic agents.
February 9,2004 REGULATING ANTIGEN-RECEPTOR GENE ASSEMBLY
  The genes encoding antigen receptors are unique because of their high diversity and their assembly in developing lymphocytes from gene segments through a series of site-specific DNA recombination reactions known as V(D)J rearrangement. This review focuses on our understanding of how recombination of immunoglobulin and T-cell receptor gene segments is tightly regulated despite being catalysed by a common lymphoid recombinase, which recognizes a widely distributed conserved recombination signal sequence.
February 8,2004 Human Chromosome 17 in Essential Hypertension
  Hypertension affects up to 30% of the adult population in Western societies and is a major risk factor for kidney disease, stroke and coronary heart disease. It is a complex trait thought to be influenced by a number of genes and environmental factors, although the precise aetiology remains unknown at this time. A number of methods have been successfully used to identify mutations that cause Mendelian traits and these are now being applied to the investigation of complex diseases.
February 7,2004 Antisense technology in molecular and cellular bioengineering
  Antisense technology is finding increasing application not only in clinical development, but also for cellular engineering. Several types of antisense methods (e.g. antisense oligonucleotides, antisense RNA and small interfering RNA) can be used to inhibit the expression of a target gene. These antisense methods are being used as part of metabolic engineering strategies to downregulate enzymes controlling undesired pathways with regard to product formation.
February 6,2004 A big step in the study of small cell lung cancer
  A rationally designed, conditional p53and Rballele-based and lung-targeted mouse model of human small cell lung cancer (SCLC) provides the cancer research community with a valid and important new tool to use in translational research against this deadly disease.
February 5,2004 Written in blood
  The blood contains a treasure trove of previously unstudied biomarkers that could reflect the ongoing physiologic state of all tissues. Every cell in the body leaves a record of its physiological state in the products it sheds to the blood, either as waste or as signals to neighbouring cells. What some may view as a cellular refuse is really a diagnostic gold mine.
February 4,2004 Molecular Evolution of the SARS Coronavirus During the Course of the SARS Epidemic in China
  Sixty-three SARS coronavirus genomic sequences derived from the early, middle and late phases of the severe acute respiratory syndrome (SARS) epidemic were analyzed. Genotypes characteristic of each phase were discovered and the earliest genotypes were similar to animal SARSlike coronaviruses. Major deletions were observed in the Orf8 region, both at the start and the end of the epidemic. The neutral mutation rate of the viral genome was constant but the amino acid substitution rate of the coding sequences slowed during the course of the epidemic. The spike protein initially showed the strongest responses to positive selection pressures followed by subsequent purifying selection and eventual stabilization.
February 3,2004 New and emerging drug therapies for the management of acute heart failure
  In recent times, there have been many developments in therapies for acute heart failure, in contrast to the preceding 20 years. These have been mainly fuelled by new and expanding knowledge about the pathophysiology of heart failure, which has allowed for insight into potential therapeutic strategies. This review will examine the key emerging therapies for acute heart failure, in light of available pathophysiological and clinical evidence.
February 2,2004 Effects of different angiotensins during acute, double blockade of the renin system in conscious dogs
  Evidence of biological activity of fragments of ANG II is accumulating. Fragments considered being inactive degradation products might mediate actions previously attributed to ANG II. The study aimed to determine whether angiotensin fragments exert biological activity when administered in amounts equimolar to physiological doses of ANG II. Cardiovascular, endocrine, and renal effects of ANG II, ANG III, ANG IV, and ANG-(1-7) (6 pmol . kg-1 . min-1) were investigated in conscious dogs during acute inhibition of angiotensin I-converting enzyme (enalaprilate) and aldosterone (canrenoate).
February 1,2004 The FRK/RAK-SHB Signaling Cascade: A Versatile Signal- Transduction Pathway that Regulates Cell Survival, Differentiation and Proliferation
  Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling.

January 2003 2002 2001