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 November October September August July June May April March February January 2006 2005 2004 2003 2002 2001

Dec 31, 2007 Models, mechanisms and clinical evidence for cancer dormancy
  Patients with cancer can develop recurrent metastatic disease with latency periods that range from years even to decades. This pause can be explained by cancer dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic. Cancer dormancy is poorly understood, resulting in major shortcomings in our understanding of the full complexity of the disease. Here, I review experimental and clinical evidence that supports the existence of various mechanisms of cancer dormancy including angiogenic dormancy, cellular dormancy (G0-G1 arrest) and immunosurveillance. The advances in this field provide an emerging picture of how cancer dormancy can ensue and how it could be therapeutically targeted.
Dec 30, 2007 Chromosomal passengers: conducting cell division
  Mitosis and meiosis are remarkable processes during which cells undergo profound changes in their structure and physiology. These events are orchestrated with a precision that is worthy of a classical symphony, with different activities being switched on and off at precise times and locations throughout the cell. One essential 'conductor' of this symphony is the chromosomal passenger complex (CPC), which comprises Aurora-B protein kinase, the inner centromere protein INCENP, survivin and borealin (also known as Dasra-B). Studies of the CPC are providing insights into its functions, which range from chromosome-microtubule interactions to sister chromatid cohesion to cytokinesis, and constitute one of the most dynamic areas of ongoing mitosis and meiosis research.
Dec 29, 2007 HIV controllers: how do they tame the virus?
  HIV controllers are rare, chronically HIV-1-infected patients in whom viral replication is undetectable in the absence of antiretroviral treatment. Most such patients are nonetheless infected by replication-competent viruses. An effective, multifunctional HIV-specific CD8(+) T-cell response is thought to be central to viral control in these individuals. The mechanisms underlying this spontaneous control of HIV infection and the particular characteristics of the CD8(+) T-cell response in HIV controllers are the focus of intensive investigations, because they should help to unravel the pathogenesis of AIDS and to provide new clues for the design of effective vaccine strategies. In this review, we examine recent findings from these studies.
Dec 28, 2007 Immunotherapy for Alzheimer’s disease: attacking amyloid-β from the inside
  Although extracellular Abeta plaques are a hallmark of Alzheimer's disease, it remains to be determined whether extracellular or intracellular Abeta accumulation initiates the disease process. A recent paper from Gunnar Gouras' group showed that Abeta antibodies lead to reduced intracellular Abeta levels in neurons via antibody internalization after binding to the Abeta domain of amyloid precursor protein (APP) at the plasma membrane. This work suggests novel avenues for the immunotherapy of Alzheimer's disease.
Dec 27, 2007 Splicing in disease: disruption of the splicing code and the decoding machinery
  Human genes contain a dense array of diverse cis-acting elements that make up a code required for the expression of correctly spliced mRNAs. Alternative splicing generates a highly dynamic human proteome through networks of coordinated splicing events. Cis- and trans-acting mutations that disrupt the splicing code or the machinery required for splicing and its regulation have roles in various diseases, and recent studies have provided new insights into the mechanisms by which these effects occur. An unexpectedly large fraction of exonic mutations exhibit a primary pathogenic effect on splicing. Furthermore, normal genetic variation significantly contributes to disease severity and susceptibility by affecting splicing efficiency.
Dec 26, 2007 Hypertension and genes
  Hypertension is a complex multifactorial disorder with many genetic, environmental and demographic factors contributing to this disorder.1 As recently reviewed by Tanira and Balushi,1 the genetic element contribution to blood pressure variation ranges from 30 to 50%. There is therefore a viewpoint that identifying hypertension susceptibility genes would contribute to understanding the pathophysiology of the disorder, as well as targeted preventative strategies.
Dec 25, 2007 Signaling crossroads: The function of Raf kinase inhibitory protein in cancer, the central nervous system and reproduction
  The Raf kinase inhibitory protein 1 (RKIP-1) and its orthologs are conserved throughout evolution and widely expressed in eukaryotic organisms. In its non-phosphorylated form RKIP-1 negatively regulates the Raf/MEK/ERK pathway by interfering with the activity of Raf-1. In its phosphorylated state, RKIP-1 dissociates from Raf-1 and inhibits GRK-2, a negative regulator of G-protein coupled receptors (GPCRs). Available data indicate that the phosphorylation of RKIP-1 by PKC can stimulate both the Raf/MEK/ERK and GPCR pathways. RKIP-1 has also been implicated as a negative regulator of the NF-kappaB pathway. Recent studies have shown that phosphorylated RKIP-1 binds to the centrosomal and kinetochore regions of metaphase chromosomes, where it may be involved in regulating the partitioning of chromosomes and the progression through mitosis. The collective evidence indicates that RKIP-1 regulates the activity and mediates the crosstalk between several important cellular signaling pathways. A variety of ablative interventions suggest that reduced RKIP-1 function may influence metastasis, angiogenesis, resistance to apoptosis, and genome integrity. Attenuation of RKIP-1 may also affect cardiac and neurological functions, spermatogenesis, sperm decapacitation, and reproductive behavior. In this review, the role of RKIP-1 in cellular signaling, and especially its functions revealed using a mouse knockout model, are discussed.
Dec 24, 2007 Molecular basis of ageing
  The 94th Annual Boehringer Ingelheim Fonds International Titisee Conference brought scientists from around the world together to discuss recent progress in studies of the basic biology of ageing (biogerontology). The field of biogerontology has seen a marked growth in scientific and popular interest over the past few years, leading to an influx of new investigators working on diverse aspects of cellular and organismal ageing.
Dec 23, 2007 The design and application of effective written instructional material: a review of published work
  This review will consider the evidence base for the format of educational material drawing on academic papers and the practice of the design industry. The core issues identified from the review are drawn together in guidelines for educational posters, text and web based material. The review deals with the design of written material both for use in leaflets and books as well as the impact of factors such as font type and size as well as colour on poster design. It sets these aspects of educational material within a research framework, which looks at impact on learning and subsequent change in practice. These issues are examined through a practical example of a poster designed for a regional gastroenterology meeting.
Dec 22, 2007 Targeting the mTOR signaling network in cancer
  The mammalian target of rapamycin (mTOR) is an unconventional protein kinase that is centrally involved in the control of cancer cell metabolism, growth and proliferation. The mTOR pathway has attracted broad scientific and clinical interest, particularly in light of the ongoing clinical cancer trials with mTOR inhibitors. The mixed clinical results to date reflect the complexity of both cancer as a disease target, and the mTOR signaling network, which contains two functionally distinct mTOR complexes, parallel regulatory pathways, and feedback loops that contribute to the variable cellular responses to the current inhibitors. In this review, we discuss the regulatory pathways that govern mTOR activity, and highlight clinical results obtained with the first generation of mTOR inhibitors to reach the oncology clinics.
Dec 21, 2007 Controlling Mutation: Intervening in Evolution as a Therapeutic Strategy
  Mutation is the driving force behind many processes linked to human disease, including cancer, aging, and the evolution of drug resistance. Mutations have traditionally been considered the inevitable consequence of replicating large genomes with polymerases of finite fidelity. Observations over the past several decades, however, have led to a new perspective on the process of mutagenesis. It has become clear that, under some circumstances, mutagenesis is a regulated process that requires the induction of pro-mutagenic enzymes and that, at least in bacteria, this induction may facilitate evolution. Herein, we review what is known about induced mutagenesis in bacteria as well as evidence that it contributes to the evolution of antibiotic resistance. Finally, we discuss the possibility that components of induced mutation pathways might be targeted for inhibition as a novel therapeutic strategy to prevent the evolution of antibiotic resistance.
Dec 20, 2007 Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins
  A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.
Dec 19, 2007 Neural stem cells, tumour stem cells and brain tumours: Dangerous relationships?
  Neural stem cells (NSC) have been implicated not only in brain development and neurogenesis but also in tumourigenesis. Brain tumour stem cells (BTSC) have been isolated from several paediatric or adult human brain tumours, however their origin is still disputed. This review discusses the normal role of NSC in the adult mammalian brain and their anatomical location. It compares the molecular characteristics and the biological behaviour of NSC/BTSC, and describes the molecular pathways involved in controlling self-renewal and maintenance of adult NSC/BTSC and brain tumour development. It also assesses the current hypotheses about the origin of BTSC and the clinical consequences.
Dec 18, 2007 Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting
  The realization that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs to create more effective vaccines. Early clinical trials exploring autologous DCs that were loaded with antigens ex vivo to induce T-cell responses have provided proof of principle. Here, we discuss how direct targeting of antigens to DC surface receptors in vivo might replace laborious and expensive ex vivo culturing, and facilitate large-scale application of DC-based vaccination therapies.
Dec 17, 2007 MicroRNAs in the Human Heart-A Clue to Fetal Gene Reprogramming in Heart Failure
  BACKGROUND: Chronic heart failure is characterized by left ventricular remodeling and reactivation of a fetal gene program; the underlying mechanisms are only partly understood. Here we provide evidence that cardiac microRNAs, recently discovered key regulators of gene expression, contribute to the transcriptional changes observed in heart failure. METHODS AND RESULTS: Cardiac transcriptome analyses revealed striking similarities between fetal and failing human heart tissue. Using microRNA arrays, we discovered profound alterations of microRNA expression in failing hearts. These changes closely mimicked the microRNA expression pattern observed in fetal cardiac tissue. Bioinformatic analysis demonstrated a striking concordance between regulated messenger RNA expression in heart failure and the presence of microRNA binding sites in the respective 3' untranslated regions. Messenger RNAs upregulated in the failing heart contained preferentially binding sites for downregulated microRNAs and vice versa. Mechanistically, transfection of cardiomyocytes with a set of fetal microRNAs induced cellular hypertrophy as well as changes in gene expression comparable to the failing heart. CONCLUSIONS: Our data support a novel mode of regulation for the transcriptional changes in cardiac failure. Reactivation of a fetal microRNA program substantially contributes to alterations of gene expression in the failing human heart.
Dec 16, 2007 New pancreas from old: microregulators of pancreas regeneration
  MicroRNAs (miRNAs) are 18-22 nucleotide RNA molecules that mediate post-transcriptional gene silencing, primarily by binding to the 3' untranslated region of their target mRNA. Several studies have demonstrated the role of miRNAs in mouse pancreas development (miR-124a, miR-503, miR-541, miR-214) as well as in insulin secretion (miR-375, miR-9). Pancreatic transcription factors that are temporally expressed during early pancreas development are re-expressed during pancreas regeneration following pancreatectomy in mice. The only exception to this is Neurogenin3 (NGN3). Here, we discuss recent evidence for miRNA-mediated silencing of ngn3, which inhibits endocrine cell development via the classical 'stem cell pathway' during mouse pancreatic regeneration, thereby favoring beta-cell regeneration.
Dec 15, 2007 Regulatory T cells and infection: a dangerous necessity
  Surviving a given infection requires the generation of a controlled immune response. Failure to establish or restore homeostatic conditions during or following the onset of an infection can lead to tissue damage. Investigation of the immunoregulatory network that arises in response to the infectious process or that is induced by the pathogen itself should provide insight into therapeutic approaches for the control of infection and any subsequent immunopathology. In this Review, I discuss current hypotheses and points of polemic associated with the origin, mode of action and antigen specificity of the various populations of regulatory T cells that arise during infection.
Dec 14, 2007 Time to Treatment in Primary Percutaneous Coronary Intervention
  Early administration of reperfusion therapy improves survival in patients with ST-elevation myocardial infarction by reestablishing coronary blood flow within the occluded infarct-related artery.1 Primary percutaneous coronary intervention (PCI) is superior to fibrinolytic therapy when performed rapidly by expert teams,2 but its effectiveness may be limited by delays in delivery.
Dec 13, 2007 Celiac disease
  Celiac disease is a unique autoimmune disorder, unique because the environmental precipitant is known. The disorder was previously called celiac sprue, based on the Dutch word sprue, which was used to describe a disease similar to tropical sprue that is characterized by diarrhea, emaciation, aphthous stomatitis, and malabsorption.1,2 Celiac disease is precipitated, in genetically predisposed persons, by the ingestion of gluten, the major storage protein of wheat and similar grains.3 Originally considered a rare malabsorption syndrome of childhood, celiac disease is now recognized as a common condition that may be diagnosed at any age and that affects many organ systems. The therapy for the disease is a gluten-free diet; however, the response to therapy is poor in up to 30% of patients, and dietary nonadherence is the chief cause of persistent or recurrent symptoms. Small intestinal adenocarcinoma, refractory sprue, and enteropathy-associated T-cell lymphoma are complications of celiac disease that must be ruled out when alarming symptoms such as abdominal pain, diarrhea, and weight loss develop despite a strict gluten-free diet.
Dec 12, 2007 Cell and molecular biology of Notch
  Notch signalling is a cell-cell communication process, which allows the establishment of patterns of gene expression and differentiation, regulates binary cell fate choice and the maintenance of stem cell populations. So far, the data published has elucidated the main players in the Notch signalling pathway. However, its regulatory mechanisms are exhibiting an increasing complexity which could account for the multitude of roles it has during development and in adult organisms. In this review, we will describe the multiple roles of Notch and how various factors can regulate Notch signalling.
Dec 11, 2007 How telomeres are replicated
  The replication of the ends of linear chromosomes, or telomeres, poses unique problems, which must be solved to maintain genome integrity and to allow cell division to occur. Here, we describe and compare the timing and specific mechanisms that are required to initiate, control and coordinate synthesis of the leading and lagging strands at telomeres in yeasts, ciliates and mammals. Overall, it emerges that telomere replication relies on a strong synergy between the conventional replication machinery, telomere protection systems, DNA-damage-response pathways and chromosomal organization.
Dec 10, 2007 miRNomics-The bioinformatics of microRNA genes
  MicroRNAs (miRNAs) are tiny genetic rheostats in plants, animals, and viruses, regulating the expression of messenger RNAs by targeting transcripts for cleavage or translational repression. Their regulatory impact is even more pervasive as a potential therapeutic tool. Since inception, computational methods have been an invaluable tool complementing experimental approaches. Here, we outline miRNA-bioinformatics highlighting the biological and therapeutic repertoire of miRNAs, in silico prediction of miRNA genes and their targets, along with a glimpse of the bioinformatic challenges that lie ahead.
Dec 9, 2007 Cellular signaling in normal and cancerous stem cells
  Chemokines are not only found in the immune system or expressed in inflammatory conditions: they are constitutively present in the brain in both glial cells and neurons. Recently, the possibility has been raised that they might act as neurotransmitters or neuromodulators. Although the evidence is incomplete, emerging data show that chemokines have several of the characteristics that define neurotransmitters. Moreover, their physiological actions resemble those of neuromodulators in the sense that chemokines usually have few effects by themselves in basal conditions, but modify the induced release of neurotransmitters or neuropeptides. These findings, together with the pharmacological development of agonists and antagonists that are selective for chemokine receptors and can cross the blood-brain barrier, open a new era of research in neuroscience.
Dec 8, 2007 TAT transduction: the molecular mechanism and therapeutic prospects
  Research into the mechanism of protein transduction has undergone a renaissance in the past five years as many groups have sought to understand the behavior of transducing peptides to harness their enormous therapeutic and diagnostic potential. The field has benefited greatly from rigorous cell biological and biophysical studies of the mechanism used by cell penetrating peptides to enter cells and deliver their cargo. The recent identification of fluid phase endocytosis as the mode of cellular entry for TAT and other protein transduction domains has enhanced our understanding of how transduction facilitates intracellular delivery. Many outstanding questions and contradictions still remain to be resolved in the field. Nevertheless, the current body of work regarding the mechanism of uptake gives a much clearer picture of how these macromolecules enter cells and how we might enhance the bioavailability to take advantage of them clinically.
Dec 7, 2007 Cellular signaling in normal and cancerous stem cells
  Self-renewing divisions of normal and cancerous stem cells are responsible for the initiation and maintenance of normal and certain cancerous tissues, respectively. Recent findings suggest that tumor surveillance mechanisms can reduce regenerative capacity and frequency of normal stem cells, thereby contributing to tissue aging. Signaling pathways promoting self-renewal of stem cells can also drive proliferation in cancer. The BMI-1 proto-oncogene is required for the maintenance of tissue-specific stem cells and is involved in carcinogenesis within the same tissues. BMI-1 promotes self-renewal of stem cells largely by interfering with two central cellular tumor suppressor pathways, p16(Ink4a)/retinoblastoma protein (Rb) and ARF/p53, whose disruption is a hallmark of cancer. Nucleolin, an Rb-associated protein, is abundant in proliferating cancerous cells and likely contributes to the maintenance of human CD34-positive stem/progenitor cells of hematopoiesis. Elucidation of the involvement of proto-oncogenes and tumor suppressors in the maintenance of stem cells might have therapeutic implications.
Dec 6, 2007 MicroRNA regulation of human protein protein interaction network
  Since the functional state of a protein-protein interaction network depends on gene expression, a fundamental question is what relationships exist between protein interaction network and gene regulation. In particular, microRNAs have recently emerged as a major class of post-transcriptional regulators that influences a large proportion of genes in higher eukaryotes. Here we show that protein connectivity in the human protein-protein interaction network is positively correlated with the number of microRNA target-site types in the 3' untranslated regions of the gene encoding the protein and that interacting proteins tend to share more microRNA target-site types than random pairs. Moreover, our results demonstrate that microRNA targeting propensity for genes in different biological processes can be largely explained by their protein connectivity. Finally, we show that for hub proteins, microRNA regulation complexity is negatively correlated with clustering coefficient, suggesting that microRNA regulation is more important to inter-modular hubs than to intramodular ones. Taken together, our study provides the first evidence for global correlation between microRNA repression and protein-protein interactions.
Dec 5, 2007 Ribozymes, riboswitches and beyond: regulation of gene expression without proteins
  Although various functions of RNA are carried out in conjunction with proteins, some catalytic RNAs, or ribozymes, which contribute to a range of cellular processes, require little or no assistance from proteins. Furthermore, the discovery of metabolite-sensing riboswitches and other types of RNA sensors has revealed RNA-based mechanisms that cells use to regulate gene expression in response to internal and external changes. Structural studies have shown how these RNAs can carry out a range of functions. In addition, the contribution of ribozymes and riboswitches to gene expression is being revealed as far more widespread than was previously appreciated. These findings have implications for understanding how cellular functions might have evolved from RNA-based origins.
Dec 4, 2007 Functions and dysfunctions of mitochondrial dynamics
  Recent findings have sparked renewed appreciation for the remarkably dynamic nature of mitochondria. These organelles constantly fuse and divide, and are actively transported to specific subcellular locations. These dynamic processes are essential for mammalian development, and defects lead to neurodegenerative disease. But what are the molecular mechanisms that control mitochondrial dynamics, and why are they important for mitochondrial function? We review these issues and explore how defects in mitochondrial dynamics might cause neuronal disease.
Dec 3, 2007 Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics
  Mantle cell lymphoma (MCL) is a well-defined lymphoid malignancy characterized by a rapid clinical evolution and poor response to current therapeutic protocols. The genetic and molecular mechanisms involved in its pathogenesis combine the dysregulation of cell proliferation and survival pathways with a high level of chromosome instability that seems related to the disruption of the DNA damage response pathway. Understanding these mechanisms and how they affect tumour behaviour is providing the rationale for the identification of reliable predictors of clinical evolution and the design of innovative therapeutic strategies that could open new avenues for the treatment of patients with MCL.
Dec 2, 2007 Flying under the radar: the new wave of BCR–ABL inhibitors
  The introduction of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec; Novartis) revolutionized the treatment of chronic myeloid leukaemia (CML). However, most patients with CML receiving imatinib still harbour molecular residual disease and some develop resistance associated with ABL kinase domain mutations. The second-generation BCR-ABL inhibitors nilotinib (Tasigna; Novartis) and dasatinib (Sprycel; Bristol-Myers Squibb) have shown significant activity after imatinib failure in clinical trials, but still face similar obstacles to imatinib, including negligible activity against the frequent BCR-ABL T315I mutation and modest effects in advanced phases of CML. Various medicinal chemistry efforts, in part aided by structural studies of the ABL kinase-imatinib complex have resulted in the synthesis of a new generation of BCR-ABL inhibitors, some of which have shown encouraging preliminary activity in clinical trials, including against T315I mutants. Here, we discuss these emerging therapies, which have the potential to improve the outcome of patients with CML.
Dec 1, 2007 Visceral leishmaniasis: what are the needs for diagnosis, treatment and control
  Visceral leishmaniasis (VL) is a systemic protozoan disease that is transmitted by phlebotomine sandflies. Poor and neglected populations in East Africa and the Indian sub-continent are particularly affected. Early and accurate diagnosis and treatment remain key components of VL control. In addition to improved diagnostic tests, accurate and simple tests are needed to identify treatment failures. Miltefosine, paromomycin and liposomal amphotericin B are gradually replacing pentavalent antimonials and conventional amphotericin B as the preferred treatments in some regions, but in other areas these drugs are still being evaluated in both mono- and combination therapies. New diagnostic tools and new treatment strategies will only have an impact if they are made widely available to patients.

November October September August July June May April March February January 2006 2005 2004 2003 2002 2001