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May 31,2006 Adducin and hypertension
  Adducin is a heterodimeric cytoskleton protein consisting of an α-subunit and either a β-or γ-subunit.In rats and humans,mutation of the α-adducin subunit leads to the stimulation of the sodium(Na+),potassium (K+)-adenosine triphosphate(ATP)-ase activity in renal tubular cells,increased renal Na+ reabsorption,and,subsequently,hypertension. Ouabain is a hormone that is released the hypothalamus and,possibly,the adrenal glands.In renal tubular cells it modulates Na+/K+-ATPase activity and regulates natriuresis. Plasma ouabain levels increase with the number of copies of the mutated α-adducin allele.
May 30,2006 Advances in chronic viral hepatitis
  Chronic liver disease due to hepatitis B virus or hepatitis C virus infection results in cirrhosis and hepatocellular carcinoma. Successful eradication or suppression of viral replication may lead to clinical improvement and better prognosis. Important discoveries have been made in recent years on the management of these diseases. This article aims at reviewing important publications of the past year that contribute to better understanding and treatment of chronic viral hepatitis.
May 29,2006 Foundations for engineering biology
  Engineered biological systems have been used to manipulate information, construct materials, process chemicals, produce energy, provide food, and help maintain or enhance human health and our environment. Unfortunately, our ability to quickly and reliably engineer biological systems that behave as expected remains quite limited. Foundational technologies that make routine the engineering of biology are needed. Vibrant, open research communities and strategic leadership are necessary to ensure that the development and application of biological technologies remains overwhelmingly constructive.
May 28,2006 Complicating the complexity of p53
  Recent studies have suggested that the straightforward role of p53 as a transcription factor that functions by inducing apoptotic target genes to eliminate developing tumor cells is only part of a much more complicated story. There is now a firm body of evidence supporting a transcriptionally independent activity of p53 as a functional, if not structural, homologue of the BH3-only proteins. Although this information adds another nuance to the mechanism by which p53 can induce apoptosis, further studies indicate that the apoptotic function of p53 represents only a part of its tumor suppressive activity. Although complicating our understanding of p53, these new insights may also provide some exciting new targets for the design of therapeutics that can reactivate p53 in cancers.
May 27,2006 STATINS AND CANCER PREVENTION
  Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy- 3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer.
May 26,2006 Mechanisms of Disease: inflammatory mediators and cancer prevention
  Discovery of molecular pathways critical to carcinogenesis is revolutionizing the treatment and prevention of cancer. Traditional chemotherapeutic approaches usually cause ‘global’ cytotoxicity to both normal and carcinoma cells. Over the past decade, however, investigators have developed compounds that inhibit tumor formation more selectively by targeting specific signaling pathways, including those involving the epidermal growth factor receptor (EGFR) and cyclooxygenase 2 (COX2). COX2-derived bioactive lipids, including prostaglandin E2, are potent inflammatory mediators that promote tumor growth and metastasis through stimulation of cell proliferation, invasion, and angiogenesis.
May 25,2006 Cell therapy for cardiovascular disease: what cells, what diseases and for whom?
  Experimental and human data suggesting progenitor cells possess the capacity to regenerate tissue and augment repair in injured organs has generated widespread interest in the basic research and clinical communities. Nowhere have these findings been more tantalizing than in human cardiovascular disease, in which vasculogenesis and myocardial regeneration logically and understandably remain as attractive therapeutic targets. Burgeoning experimental evidence attests to the proangiogenic, vasculogenic and tissue reparative capabilities of a broad range of progenitor cells derived from the bone marrow, circulation and a number of other tissues in vivo.
May 24,2006 Cancer Stem Cells: An Old Idea—A Paradigm Shift
  Although the concept that cancers arise from ‘‘stem cells’’ or ‘‘germ cells’’ was first proposed about 150 years ago, it is only recently that advances in stem cell biology have given new impetus to the ‘‘cancer stem cell hypothesis.’’ Two important related concepts of this hypothesis are that (a) tumors originate in either tissue stem cells or their immediate progeny through dysregulation of the normally tightly regulated process of self-renewal. As a result of this, (b) tumors contain a cellular subcomponent that retains key stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation albeit aberrant that contributes to cellular heterogeneity. Recent experimental evidence in a variety of tumors has lent strong support to the cancer stem cell hypothesis that represents a paradigm shift in our understanding of carcinogenesis and tumor cell biology.
May 23,2006 Transcription-independent pro-apoptotic functions of p53
  Induction of apoptosis is one of the central activities by which p53 exerts its tumor-suppressing function. Aside from its primary function as a transcription factor, it can promote apoptosis independent of transcription. Recent studies have started to define the mechanisms of non-transcriptional pro-apoptotic p53 activities operating within the intrinsic mitochondria-mediated pathway of apoptosis. So far, two different mechanisms have been described, each of which was assigned to a specific localization of the p53 protein, either in the cytosol or directly at the mitochondria. Although mechanistically different, both transcription-independent modes of apoptosis induction converge, as they both initiate permeabilization of the outer mitochondrial membrane via activation of the pro-apoptotic Bcl-2 family members Bax or Bak.
May 22,2006 Proteomic analysis of high-density lipoprotein
  Plasma lipoproteins, such as high-density lipoprotein (HDL), can serve as carriers for a wide range of proteins that are involved in processes such as lipid metabolism, thrombosis, inflammation and atherosclerosis. The identification of HDL-associated proteins is essential with regards to understanding these processes at the molecular level. In this study, a combination of proteomic approaches including 1-DE and 2-DE MALDI-TOF, isotope-coded affinity tag and Western blot analysis were employed to identify proteins associated with human HDL. To minimize potential losses of HDL-associated proteins during isolation, a one-step ultracentrifugation technique was applied and the quality of purified HDL was confirmed by nephelometry, highperformance gel chromatography, and Western blot analysis.
May 21,2006 The amazing complexity of transcription factories
  Multicellular eukaryotes orchestrate immensely complex patterns of gene expression in order to define numerous specialised cell types. Patterns of expression are regulated at the level of DNA modification, chromatin structure, genome architecture and nuclear organisation. Each aspect of these features of regulation is controlled by complex nuclear systems, and each of the systems must interact to define a coherent regulatory network. In proliferating cells, and particularly during development, patterns of gene expression must be preserved in cells that have active DNA repair mechanisms and efficiently duplicate both DNA and the associated chromatin status— the histone code. The systems that regulate DNA synthesis and genome stability are integrated with those that regulate the efficacy of RNA synthesis, such that patterns of gene expression are maintained.
May 20,2006 Multifactor dimensionaliy reducion for detecting geng-geng and geng-environment interactions in pharmacogenomics studies
  In the quest for discovering disease susceptibility genes,the realiy of gene-gene and gene-environment interactions creates difficult challenges for many current statistical approaches.In an attempt to overcome limitations with current disease geng detection methods,the multifactor dimensionality reduction(MDR)approach was previously developed.In brief,MDR is a method that reduces the dimensionslity of multilocus information to dientify polymorphisms associated with an increased risk of disease.This approach takes multilocus genotypes and develops a model for defining diseasa risk by pooling high-risk genotype combinations into one group and low-risk combinations into another.
May 19,2006 Oxidative Stress Profiling
  Many of the most serious human diseases have a strong association with the steady-state level of oxidative damage in tissues. On an individual level this damage is defined as the patient’s oxidative stress status (OSS). OSS is associated with many of the major age-related diseases such as cancer, heart disease, diabetes, and Alzheimer’s disease, as well as with the aging process itself. In general, the greater the OSS of the individual, the higher the risk for disease development. To further understand the role that OSS has as a causative or an associated factor for these diseases, and to develop more effective personalized therapy to minimize OSS, requires a reliable means to measure the many different components contributing to an individual’s OSS.
May 18,2006 Cytokine Therapy
  Cytokines are a unique class of intercellular regulatory proteins that play a crucial role in initiating, maintaining, and regulating immunologic homeostatic and inflammatory processes. Indeed, measurement of cytokine profiles in patients provides a useful indication of disease status. Due to their multiple functions, including regulatory and effector cellular function in many diseases, these molecules, their receptors, and their signal transduction pathways are promising candidates for therapeutic interference. The therapeutic administration of cytokines, modulation of cytokine action, or at times gene therapy is being used for a wide range of infectious and autoimmune diseases, in immunocompromised patients with AIDS, and in neoplasia.
May 17,2006 G Protein-Coupled Receptor List
  NC-IUPHAR and its subcommittees provide authoritative reports on the nomenclature and pharmacology of G protein-coupled receptors (GPCRs) that summarize their structure, pharmacology, and roles in physiology and pathology. These reports are published in Pharmacological Reviews and through the International Union of Pharmacology (IUPHAR) Receptor Database web site . The essentially complete sequencing of the human genome has allowed the cataloging of all of the human gene sequences potentially encoding GPCRs. The IUPHAR Receptor List presents this catalog giving IUPHAR-approved nomenclature (where available), known ligands, and gene names for all of these potential receptors together with links to curated sequence, descriptive information, and additional links in the Entrez Gene database.
May 16,2006 Mitochondria and Ischemia/Reperfusion Injury
  Cardiac ischemia/reperfusion injury results in a variable mixture of apoptotic, necrotic, and normal tissue that depends on both the duration and severity of ischemia. Injury can be abrogated by activation of protective pathways via ischemic and pharmacologic preconditioning. Mitochondria serve as final arbiters of life and death of the cell as these organelles not only are required to generate ATP but also can trigger apoptosis or necrosis. A key mechanism of mitochondrial injury is by the mitochondrial permeability transition (MPT) that has been shown to occur at reperfusion.
May 15,2006 Advances in clinical cancer proteomics
  For most cancers, survival rates depend on the early detection of the disease. So far, no biomarkers exist to cope with this difficult task. New proteomic technologies have brought the hope of discovering novel early cancer-specific biomarkers in complex biological samples and/ or of the setting up of new clinically relevant test systems. Novel mass spectrometry-(MS) based technologies in particular, such as surface-enhanced laser desorption/ionisation time of flight (SELDI-ToF-MS), have shown promising results in the recent literature. Here, proteomic profiles of control and disease states are compared to find biomarkers for diagnosis. This paper aims to address the authors’ own work and that of other groups in clinical cancer proteomics based on SELDI-ToF-MS. Shortcomings and hopes for the future are discussed.
May 14,2006 Pitfalls of Quantitative Real- Time Reverse-Transcription Polymerase Chain Reaction
  Polymerase chain reaction (PCR)-based assays can target either DNA (the genome) or RNA (the transcriptome).Targeting the genome generates robust data that are informative and, most importantly, generally applicable. This is because the information contained within the genome is contextindependent; i.e., generally, every normal cell contains the same DNA sequence—the same mutations and polymorphisms. The transcriptome, on the other hand, is contextdependent; i.e., the mRNA complement and level varies with physiology, pathology, or development.This makes the information contained within the transcriptome intrinsically flexible and variable.
May 13,2006 The Year in Heart Failure 2005
  Another year has come and gone, and this again gives us the opportunity to pick what we consider the most important stories in the field of heart failure. 2005 was not a banner year for new breakthroughs. Although there were some important advances, most were more incremental in nature and some of the top stories reflect disappointments and controversies. As a result, we have not used the ‘‘Top 10’’ approach of previous years, but rather have grouped stories into categories. This list represents only the views of the authors. Even without dramatic breakthroughs, heart failure remains an area of dynamic growth, discovery, and innovation.
May 12,2006 The relationship between chromatin structure and transcriptional activity in mammalian genomes
  In cells, chromatin is folded into a 30 nm fibre. Recent genome-wide studies have shown that DNaseI-sensitive sites are present in both transcribed and non-transcribed genes and are enriched in the gene-dense regions of the human genome. The distribution of open chromatin has also been shown to correlate with gene density rather than transcription. In this review it is suggested that open chromatin corresponds to a 30 nm fibre interspersed with discontinuities, and that blocks of open chromatin might facilitate gene transcription, but are neither necessary nor sufficient. The nature of these discontinuities is not known but could correspond to alterations in chromatin fibre structure caused by irregular nucleosome positioning, nucleosome remodelling activities, variant histones or the binding of specific transcription factors.
May 11,2006 Pharmacogenetics of opioid receptors and addiction
  It is generally assumed that combinations of polymorphic alleles of different genes contribute to polygenetic disorders. Variants of the opioid receptors are the obvious candidates underlying addiction. Most research has focused on the coding variation A118G of the mu opioid receptor (MOPr), which replaces asparagine at position 40 by aspartate (Asn40Asp). However, to date, no conclusive evidence exists regarding which physiological effects this mutation may cause. Other rare polymorphisms in the MOPr cause marked effects (e.g. impairment of G-protein coupling) but, due to their low frequency, their role in addiction is questionable. A large number of polymorphic sites have been found in the putative promoter region of the mu opioid receptor.
May 10,2006 Strategies for Modifying High-Density Lipoprotein Cholesterol: A Role for Nicotinic Acid
  Summary. Statin-mediated lowering of low-density lipoprotein cholesterol (LDL-C) is regarded as the foundation of lipid-modifying therapy. However, the residual cardiovascular risk for statin-treated patients remains high, indicating the need for therapeutic intervention against other lipid targets as well as non-lipid risk factors. Low levels of high-density lipoprotein cholesterol (HDL-C) are established as a strong independent risk factor for cardiovascular disease. Intervention studies have also demonstrated clinical benefits associated with HDL-C raising. Although lifestyle modification does play an important role in raising HDL-C, most patients with a low HDL-C and at high risk of coronary events also require pharmacological treatment to achieve the target.
May 9,2006 The Use of Genetic SNPs as New Diagnostic Markers in Preventive Medicine
  Using an automated mass spectrometric genotyping platform, we have completed more than ten whole-genome SNP scans on phenotypically stratified population pools. The pools are usually constructed to represent one ethnicity, one gender, and one phenotype, classified as strictly as possible. From 28,000 to 91,000 different SNPs are used for each study, and the pools typically contain DNA from 300 different individuals. Significant correlations between SNP allele and phenotype are first reproduced in the pools, then replicated on individual DNA samples (deconvolution of the pools), and then where possible replicated in completely independent populations.
May 8,2006 Transcription Factor Decoys: A New Model for Disease Intervention
  Transcription factor proteins regulate gene expression via binding to specific DNA sequences found in the promoter/enhancer regions of the genes they control. Although most transcription factor binding has been associated with an increase in gene expression, gene suppression has also been described. Transcription factor decoys are molecules that mimic the binding sites for transcription factor proteins, and compete with promoter regions to absorb this binding activity in the cell nucleus. By blocking transcription factor– chromosomal DNA interaction, these molecules provide a powerful means to manipulate the regulation of gene expression, particularly as transcription factors are increasingly understood to alter gene activation during the course of normal and pathologic processes in cell biology.
May 7,2006 Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications
  Over the last decade, studies have unraveled many aspects of endogenous production and physiological functions of carbon monoxide (CO). The majority of endogenous CO is produced in a reaction catalyzed by the enzyme heme oxygenase (HO). Inducible HO (HO-1) and constitutive HO (HO-2) are mostly recognized for their roles in the oxidation of heme and production of CO and biliverdin, whereas the biological function of the third HO isoform, HO-3, is still unclear. The tissue type-specific distribution of these HO isoforms is largely linked to the specific biological actions of CO on different systems. CO functions as a signaling molecule in the neuronal system, involving the regulation of neurotransmitters and neuropeptide release, learning and memory, and odor response adaptation and many other neuronal activities. The vasorelaxant property and cardiac protection effect of CO have been documented.
May 6,2006 Lactoferrin – A Novel Bone Growth Factor
  Lactoferrin is an iron-binding glycoprotein that belongs to the transferrin family. It is present in breast milk, in epithelial secretions, and in the secondary granules of neutrophils. In healthy subjects lactoferrin circulates at concentrations of 2-7 x 10-6 g/ml. Lactoferrin is a pleiotropic factor with potent antimicrobial and immunomodulatory activities. Recently,we have shown that lactoferrin can also promote bone growth. At physiological concentrations, lactoferrin potently stimulates the proliferation and differentiation of primary osteoblasts and also acts as a survival factor inhibiting apoptosis induced by serum withdrawal. Lactoferrin also affects osteoclast formation and, in murine bone marrow culture, lactoferrin potently inhibits osteoclastogenesis.
May 5,2006 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.
May 4,2006 The Need for Anti-aging Medicine: The Challenges Faced to Incorporate Preventative Medicine into the Clinic and into Society
  The world’s population is getting older and this fact is made clear by the aging demographics of both developed and developing countries. Projections estimate that there will be very sharp rises in the numbers of people over the age of 50, and very small increases expected in those under 15. From these facts, we judge that the costs of traditional health care based on the current “nationalistic” model will struggle to be met unless they undergo a radical alteration. A number of possible solutions are debated, ending in a conclusion that a liberal society is likely to choose preventative medicine as the next health care model for the twenty-first century.
May 3,2006 What makes a gene name? Named entity recognition in the biomedical literature
  The recognition of biomedical concepts in natural text (named entity recognition, NER) is a key technology for automatic or semi-automatic analysis of textual resources. Precise NER tools are a prerequisite for many applications working on text, such as information retrieval, information extraction or document classification. Over the past years, the problem has achieved considerable attention in the bioinformatics community and experience has shown that NER in the life sciences is a rather difficult problem. Several systems and algorithms have been devised and implemented. In this paper, the problems and resources in NER research are described, the principal algorithms underlying most systems sketched, and the current state-of-the- art in the field surveyed.
May 2,2006 Ca2+-Sensitisers—A Promising Option to Treat Heart Failure?
  Summary. Because the number of transplants is still fewer than the number of patients waiting for a donor organ, new concepts of therapy are needed that allow patients to bridge the time gap until heart transplantation or even to improve symptoms while on treatment. Ca2+-sensitisers are agents that directly influence myofilaments and/or the cross-bridge-cycle. Depending on the molecular mechanisms underlying their action, Ca2+-sensitisers have been divided into three classes. While, a number of Ca2+-sensitising drugs have been described, currently only the Ca2+-sensitisers pimobendan and levosimendan are in clinical use. This review provides a survey on the molecular mechanisms and the therapeutic effectiveness of Ca2+-sensitisers for the treatment of human heart failure.
May 1,2006 Recruitment of Hsp70 chaperones: a crucial part of viral survival strategies
  Virus proliferation depends on the successful recruitment of host cellular components for their own replication, protein synthesis, and virion assembly. In the course of virus particle production a large number of proteins are synthesized in a relatively short time, whereby protein folding can become a limiting step. Most viruses therefore need cellular chaperones during their life cycle. In addition to their own protein folding problems viruses need to interfere with cellular processes such as signal transduction, cell cycle regulation and induction of apoptosis in order to create a favorable environment for their proliferation and to avoid premature cell death.

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