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 June May April March February January 2003 2002 2001

July 31,2004 Role of MRI in clinical cardiology
  Rapid progress has been made in cardiac MRI (CMRI) over the past decade, which has firmly established it as a reliable and clinically important technique for assessment of cardiac structure, function, perfusion, and myocardial viability. Its versatility and accuracy is unmatched by any other individual imaging modality. CMRI is non-invasive and has high spatial resolution and avoids use of potentially nephrotoxic contrast agent or radiation. It has been extensively studied against other established non-invasive imaging modalities and has been shown to be superior in many scenarios, particularly with respect to assessment of cardiac and great vessel morphology and left ventricular function.
July 30,2004 THE THREE ES OFCANCER IMMUNOEDITING
  After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models—together with compelling data from human patients— indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop.The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed “cancer immunoediting.”
July 29,2004 Neuroendocrine Transcriptome in Genetic Hypertension
  The genetic basis of hypertension in the genetically/hereditary hypertensive (BPH/2) mouse strain is incompletely understood, although a recent genome scan uncovered evidence for several susceptibility loci. To probe the neuroendocrine transcriptome in this disease model, 12 488 probe set microarray experiments were performed on mRNA transcripts from adrenal glands of juvenile (prehypertensive) and adult BPH/2 (hypertensive), as well as the genetically/hereditary low-blood pressure (BPL/1), strains at both time points.
July 28,2004 CD1: Antigen Presentation and T Cell Function
  This review summarizes the major features of CD1 genes and proteins, the patterns of intracellular trafficking ofCD1molecules, and howthey sample different intracellular compartments for self- and foreign lipids.We describe how lipid antigens bind to CD1 molecules with their alkyl chains buried in hydrophobic pockets and expose their polar lipid headgroup whose fine structure is recognized by the TCR of CD1-restricted T cells. CD1-restricted T cells carry out effector, helper, and adjuvantlike functions and interact with other cell types including macrophages, dendritic cells, NK cells, T cells, and B cells, thereby contributing to both innate and adaptive immune responses.
July 27,2004 A probabilistic view of gene function
  Cells are controlled by the complex and dynamic actions of thousands of genes. With the sequencing of many genomes, the key problem has shifted from identifying genes to knowing what the genes do; we need a framework for expressing that knowledge. Even the most rigorous attempts to construct ontological frameworks describing gene function ultimately rely on manual curation and are thus labor-intensive and subjective. But an alternative exists: the field of functional genomics is piecing together networks of gene interactions, and although these data are currently incomplete and error-prone, they provide a glimpse of a new, probabilistic view of gene function. We outline such a framework, which revolves around a statistical description of gene interactions derived from large, systematically compiled data sets.
July 26,2004 KATP Channel Openers
  ATP-sensitive potassium channels (KATP channels) are heteromeric complexes of poreforming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. KATP channels were identified in a variety of tissues including muscle cells, pancreatic β-cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening. Functionally, KATP channels provide a means of linking the electrical activity of a cell to its metabolic state.
July 25,2004 DISEASE-RELATEDMISASSEMBLY OF MEMBRANE PROTEINS
  Medical genetics so far has identified ~16,000 missense mutations leading to single amino acid changes in protein sequences that are linked to human disease. A majority of these mutations affect folding or trafficking, rather than specifically affecting protein function. Many disease-linked mutations occur in integral membrane proteins, a class of proteins about whose folding we know very little. We examine the phenomenon of disease-linked misassembly of membrane proteins and describe model systems currently being used to study the delicate balance between proper folding and misassembly.
July 24,2004 Chronic obstructive pulmonary disease
  Chronic obstructive pulmonary disease is a leading cause of death and disability, but has only recently been extensively explored from a cellular and molecular perspective. There is a chronic in. ammation that leads to . xed narrowing of small airways and alveolar wall destruction (emphysema). This is characterised by increased numbers of alveolar macrophages, neutrophils and cytotoxic T-lymphocytes, and the release of multiple in. ammatory mediators . A high level of oxidative stress may amplify this in. ammation. There is also increased elastolysis and evidence for involvement of several elastolytic enzymes, including serine proteases, cathepsins and matrix metalloproteinases.
July 23,2004 Physiological basis and image processing in functional magnetic resonance imaging
  Functional magnetic resonance imaging (fMRI) is recently developing as imaging modality used for mapping hemodynamics of neuronal and motor event related tissue blood oxygen level dependence (BOLD) in terms of brain activation. Image processing is performed by segmentation and registration methods. Segmentation algorithms provide brain surface-based analysis, automated anatomical labeling of cortical fields in magnetic resonance data sets based on oxygen metabolic state. Registration algorithms provide geometric features using two or more imaging modalities to assure clinically useful neuronal and motor information of brain activation.
July 22,2004 INTEGRINS AND T CELL–MEDIATED IMMUNITY
  Integrin receptors mediate adhesive events that are critical for a specific and effective immune response to foreign pathogens. Integrin-dependent interactions of lymphocytes and antigen-presenting cells (APCs) to endothelium regulate the ef- ficiency and specificity of trafficking into secondary lymphoid organs and peripheral tissue. Within these sites, integrins facilitate cell movement via interactions with the extracellular matrix, and promote and stabilize antigen-specific interactions between T lymphocytes and APCs that are critical for initiating T cell–activation events.
July 21,2004 Cardiac Myosin Binding Protein C
  Myosin binding protein-C (MyBP-C) is a thick filament–associated protein localized to the crossbridgecontaining C zones of striated muscle sarcomeres. The cardiac isoform is composed of eight immunoglobulin I–like domains and three fibronectin 3–like domains and is known to be a physiological substrate of cAMP-dependent protein kinase. MyBP-C contributes to thick filament structure via interactions at its C-terminus with the light meromyosin section of the myosin rod and with titin. The protein also has a role in the regulation of contraction, due to the binding of its N-terminus to the subfragment-2 portion of myosin, which reduces actomyosin ATPase activity; phosphorylation abolishes this interaction, resulting in release of the “brake” on crossbridge cycling.
July 20,2004 Cancer of pancreas
  Cancer of the pancreas is the tenth most frequent cancer in Europe, accounting for some 3% of cancer in both sex. Smoking has been clearly established as a major risk factor affecting the carcinogenesis of pancreatic carcinoma. Diet has also been associated with pancreatic cancer, although no conclusive data are yet available. Different genetic alterations have been observed in pancreatic neoplasms. Typical symptoms of pancreatic cancer are: jaundice, abdominal pain and weight loss. The prognosis of pancreatic carcinoma depends mainly on radical surgery and the presence of negative resection margins, as well as on the biological tumour stage, which also influences the treatment strategy.
July 19,2004 Hepatocyte transplantation
  Transplantation of the whole liver, or a portion of the liver, has been remarkably effective in the treatment of liver failure and liver-based inherited metabolic diseases. In spite of spectacular technical advances, significant morbidity and mortality remains. Furthermore, demand for transplantable livers is progressively outpacing the supply of donated cadaver organs, resulting in longer waiting times and increased mortality for prospective transplant recipients [1]. The expanding use of adult living donors may abate the organ shortage to some extent, but this procedure is not without significant risk to the donor and recipient [2].
July 18,2004 MODIFIED ADENOVIRUSES FOR CANCER GENE THERAPY
  Adenoviral gene therapy is an exciting novel approach for treating cancers resistant to currently available therapies. However, currently there is little evidence supporting significant clinical benefits with replication-incompetent adenoviruses. Recent data suggest that expression of the primary receptor, the coxsackie-adenovirus receptor (CAR), may be highly variable on tumor cells, resulting in resistance to infection. Consequently, various strategies have been evaluated to modify adenovirus tropism in order to circumvent CAR deficiency, including retargeting complexes or genetic capsid modifications. To improve tumor penetration and local amplifiation on the antitumor effect, selectively oncolytic agents, i.e., conditionally replicating adenoviruses, have been constructed.
July 17,2004 VIRAL-BASEDMYOCARDIAL GENE THERAPY APPROACHES TO ALTER CARDIAC FUNCTION
  In recent years there has been a rapid expansion in our understanding of the molecular biology that underpins human physiology. In the heart, elegant molecular pathways have been elucidated, and derangements in these pathways have been identified as factors in cardiac disease. However, as our understanding has grown, we have recognized that there exist only relatively crude tools to effect changes in molecular pathophysiology. The ultimate promise of gene therapy is to correct the molecular derangements that cause illness.
July 16,2004 Apoptosis initiated by dependence receptors
  A distinct group of receptors including DCC, UNC5, RET and Ptc1 is known to function in ligand-dependent neuronal growth and differentiation or axon guidance. Acting as "dependence receptors", theymay also regulateneuronal cell survival by inducing apoptosis in the absence of cognate ligand. Receptor-initiated apoptosis requires proteolytic (caspase) cleavage and exposure of a proapoptotic region in the cytoplasmic domains of the receptors. In contrast, classical apoptosis induced by growth factor or cytokine deprivation involves loss of survival signaling without receptor cleavage.DCC,UNC5,RETand Ptc1 are downregulated or mutated in diverse cancers, and show properties characteristic of tumor suppressors, consistent with their ability to promote neuronal cell death.
July 15,2004 DNA and the chromosome – varied targets for chemotherapy
  The nucleus of the cell serves to maintain, regulate, and replicate the critical genetic information encoded by the genome. Genomic DNA is highly associated with proteins that enable simple nuclear structures such as nucleosomes to form higher-order organisation such as chromatin fibres. The temporal association of regulatory proteins with DNA creates a dynamic environment capable of quickly responding to cellular requirements and distress. The response is often mediated through alterations in the chromatin structure, resulting in changed accessibility of specific DNA sequences that are then recognized by specific proteins. Anti-cancer drugs that target cellular DNA have been used clinically for over four decades, but it is only recently that nuclease specific drugs have been developed to not only target the DNA but also other components of the nuclear structure and its regulation.
July 14,2004 LYSOPHOSPHOLIPID RECEPTORS
  Lysophospholipids (LPs), such as lysophosphatidic acid and sphingosine 1-phosphate, are membrane-derived bioactive lipid mediators. LPs can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes that include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis. In recent years, identification of multiple cognate G protein-coupled receptors has provided a mechanistic framework for understanding how LPs play such diverse roles.
July 13,2004 Manipulating angiogenesis in medicine
  Blood vessels nourish organs with vital nutrients and oxygen and, thus, new vessels form when the embryo needs to grow or wounds are to heal. However, forming new blood vessels is a complex and delicate process, which, unfortunately, is often derailed. Thus, when insufficient vessels form, the tissue becomes ischaemic and stops to function adequately. Conversely, when vessels grow excessively, malignant and inflamed tissues grow faster.It is now becoming increasingly evident that abnormal vessel growth contributes to the pathogenesis of numerous malignant, ischaemic, inflammatory, infectious and immune disorders.
July 12,2004 How do proteins avoid becoming too stable?
  The vast majority of theoretical and experimental folding studies have shown that as a protein folds, it attempts to adopt a conformation that occurs at its lowest free energy minimum. However, studies on a small number of proteins have now shown that this is a generality. In this review we discuss recent data on how two proteins, α-lytic protease and α1-antitrypsin, successfully fold to their metastable native states, whilst avoiding more stable but inactive conformations. protein becomes trapped in a non-native conformation that forces it through an alternative folding pathway.
July 11,2004 New Clinical Markers Predictive of Cardiovascular Disease
  Identification of persons at risk for developing cardiovascular disease has focused attention on blood pressure, smoking, and serum cholesterol levels. Modification of these factors has resulted in reduction of overall morbidity and mortality within the population. While significant, these risk factors do not predict all cardiovascular events, because the causes of cardiovascular disease are multifactorial and the risk associated with any given factor is compounded by the presence of other risk factors. Additional risk factors that may also identify risk for cardiovascular disease may include inflammatory mediators such as C-reactive protein, interleukin 6, cell adhesion molecules, and fibrinogen.
July 10,2004 Dendritic cell biology and cancer therapy
  Dendritic cells (DCs) are nature's best antigenpresenting cells. They possess attributes that allow them to effectively fulfill the requirements for priming/activating T cells and mediating tumor-specific immune responses. In this review, emphasis is placed on those aspects of DC biology that best illustrate their usefulness in immunotherapy of cancer. Culture, maturation, and polarization conditions for human DC are discussed, as are strategies for antigen-loading of DCs and for their delivery to patients with cancer. A concise recommendation for monitoring of DC-based vaccination trails is provided.
July 9,2004 Proteomics in postgenomic neuroscience
  Proteomics is complementary to genomic approaches anchored in DNA and RNA.Global characterization of proteins is providing new insights into general biological structures as well as synapses,receptor complexes and other neuronal and glial features.Current challenges for proteomics of the nervous system include problems relating to sample preparation,brain complexity,limited databases and informatics tools.The combination of proteomics with other global functional genomic approaches at the levels of genome and transcriptome,together with network biology,will provide important bridges between genes,physiology and pathology.
July 8,2004 Apoptosis pathways in cancer and cancer therapy
  Activation of apoptosis pathways is a key mechanism by which cytotoxic drugs kill tumor cells. Also immunotherapy of tumors requires an apoptosis sensitive phenotype of target cells. Defects in apoptosis signalling contribute to resistance of tumors. Activation of apoptosis signalling following treatment with cytotoxic drugs has been shown to lead to activation of the mitochondrial (intrinsic) pathway of apoptosis. In addition, signalling through the death receptor (extrinsic) pathways, contributes to sensitivity of tumor cells towards cytotoxic treatment. Both pathways converge .nally at the level of activation of caspases, the e.ector molecules in most forms of cell death.
July 7,2004 Sirolimus-Eluting Coronary Stents
  Despite major technological advances in the practice of percutaneous coronary intervention, restenosis of the treated arteries remains a challenge for many interventional cardiologists. Sirolimus is a macrolide antibiotic with potent antifungal, immunosuppressive, and antimitotic activities. Sirolimus inhibits in-stent restenosis via 2 major mechanisms of action: by blocking the process of neointimal hyperplasia by inhibiting smooth muscle cell proliferation and by inhibiting inflammatory cell activity. In pivotal clinical trials, the sirolimus-eluting stent has demonstrated significant improvements in angiographic and clinical outcomes compared with bare metal stents in patients with de novo lesions in native coronary arteries.
July 6,2004 SHAPING THE NUCLEAR ACTION OF NF-κB
  The NF-κB/REL family of transcription factors pivotally control the inflammatory and immune responses, as well as other genetic programmes that are central to cell growth and survival. The cytoplasmic regulation of NF-κB is well characterized and, recently, significant progress has been made in understanding how its nuclear action is regulated. Post-translational modification of the NF-κB subunits as well as histones surrounding the NF-κB target genes has a key role in this regulation. Here, we review the important advances that constitute this new and exciting chapter in NF-κB biology.
July 5,2004 Novel functions of thrombomodulin in inflammation
  The objective of this study was to review the mechanisms by which thrombomodulin (TM) may modulate inflammation. The data were taken from published research performed by other laboratories and our own experimental results. TM is a transmembrane glycoprotein receptor and cofactor for thrombin in the protein C anticoagulant system. Recent studies have revealed that TM has activities, both dependent and independent of either protein C or thrombin, that affect biological systems beyond the coagulation pathway. This review highlights recent insights, provided by in vitro and in vivo analyses, into how the unique structural domains of TM effectively modify coagulation, fibrinolysis, and inflammation in health and disease.
July 4,2004 Local drug delivery in restenosis injury
  The success of percutaneous transluminal coronary angioplasty in treatment of acute coronary syndromes has been compromised by the incidence of restenosis. The physical insult of balloon insertion can damage or remove the endothelial monolayer, thereby generating a prothrombotic surface. The resulting inappropriate response to injury can also lead to penetration of inflammatory cells, conversion of the underlying media to a synthetic phenotype, deposition of extracellular matrix, constrictive remodeling, and neointimal hyperplasia. While stent implantation at the time of balloon insertion has offset some of these events, inflammatory responses to the implanted biomaterial (stent) and intimal hyperplasia are still prominent features of the procedure, leading in 20–30% of cases to in-stent restenosis within a year.
July 3,2004 The development of proteasome inhibitors as anticancer drugs
  The ubiquitin-proteasome pathway plays a central role in the targeted destruction of cellular proteins, including cell cycle regulatory proteins. Because these pathways are critical for the proliferation and survival of all cells, and in particular cancerous cells, proteasome inhibition is a potentially attractive anticancer therapy. Based on encouraging cytotoxic activity, bortezomib was the first proteasome inhibitor to be evaluated in clinical trials. Efficacy and safety results from a phase 2 clinical trial contributed to approval of bortezomib for use in patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies and have demonstrated disease progression on their last therapy.
July 2,2004 Clinical Research
  I would like to begin by expressing my deep appreciation to the Clinical Council for honoring me this year with the annual James B. Herrick Award. As a longstanding maverick cardiovascular investigator, I recognize the unfortunate fate of many mavericks who more often face sanction than accolades, and I am therefore particularly grateful that the Council has seen fit to honor me for a lifetime of effort that has often challenged traditional thinking.
July 1,2004 Clinical applications of dendritic cell vaccination in the treatment of cancer
  Dendritic cell (DC) immunotherapy has shown significant promise in animal studies as a potential treatment for cancer. Its application in the clinic depends on the results of human trials. Here, we review the published clinical trials of cancer immunotherapy using exogenously antigen-exposed DCs. We begin with a short review of general properties and considerations in the design of such vaccines. We then review trials by disease type. Despite great e.orts on the part of individual investigative groups, most trials to date have not yielded data from which .rm conclusions can be drawn.

June May April March February January 2003 2002 2001