Showing papers by "University of Geneva published in 2007"

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Abstract: For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Abstract: We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

Evolution of genes and genomes on the Drosophila phylogeny.

Abstract: Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

The Myofibroblast: One Function, Multiple Origins

Abstract: The crucial role played by the myofibroblast in wound healing and pathological organ remodeling is well established; the general mechanisms of extracellular matrix synthesis and of tension production by this cell have been amply clarified. This review discusses the pattern of myofibroblast accumulation and fibrosis evolution during lung and liver fibrosis as well as during atheromatous plaque formation. Special attention is paid to the specific features characterizing each of these processes, including the spectrum of different myofibroblast precursors and the distinct pathways involved in the formation of differentiated myofibroblasts in each lesion. Thus, whereas in lung fibrosis it seems that most myofibroblasts derive from resident fibroblasts, hepatic stellate cells are the main contributor for liver fibrosis and media smooth muscle cells are the main contributor for the atheromatous plaque. A better knowledge of the molecular mechanisms conducing to the appearance of differentiated myofibroblasts in each pathological situation will be useful for the understanding of fibrosis development in different organs and for the planning of strategies aiming at their prevention and therapy.

Device-independent security of quantum cryptography against collective attacks.

Abstract: We present the optimal collective attack on a quantum key distribution protocol in the "device-independent" security scenario, where no assumptions are made about the way the quantum key distribution devices work or on what quantum system they operate. Our main result is a tight bound on the Holevo information between one of the authorized parties and the eavesdropper, as a function of the amount of violation of a Bell-type inequality.

Rosuvastatin in Older Patients with Systolic Heart Failure

Abstract: As compared with the placebo group, patients in the rosuvastatin group had de- creased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001) and of high-sensitivity C-reactive protein (difference between groups, 37.1%; P<0.001). During a median follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval (CI), 0.83 to 1.02; P = 0.12), and 728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P = 0.31). There were no significant differences between the two groups in the coronary outcome or death from cardiovascular causes. In a prespecified secondary analysis, there were fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001). No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group. Conclusions Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems. (ClinicalTrials.gov number, NCT00206310.)

Future extreme events in European climate: an exploration of regional climate model projections

Abstract: This paper presents an overview of changes in the extreme events that are most likely to affect Europe in forthcoming decades. A variety of diagnostic methods are used to determine how heat waves, heavy precipitation, drought, wind storms, and storm surges change between present (1961–90) and future (2071–2100) climate on the basis of regional climate model simulations produced by the PRUDENCE project. A summary of the main results follows. Heat waves – Regional surface warming causes the frequency, intensity and duration of heat waves to increase over Europe. By the end of the twenty first century, countries in central Europe will experience the same number of hot days as are currently experienced in southern Europe. The intensity of extreme temperatures increases more rapidly than the intensity of more moderate temperatures over the continental interior due to increases in temperature variability. Precipitation – Heavy winter precipitation increases in central and northern Europe and decreases in the south; heavy summer precipitation increases in north-eastern Europe and decreases in the south. Mediterranean droughts start earlier in the year and last longer. Winter storms – Extreme wind speeds increase between 45°N and 55°N, except over and south of the Alps, and become more north-westerly than cuurently. These changes are associated with reductions in mean sea-level pressure, leading to more North Sea storms and a corresponding increase in storm surges along coastal regions of Holland, Germany and Denmark, in particular. These results are found to depend to different degrees on model formulation. While the responses of heat waves are robust to model formulation, the magnitudes of changes in precipitation and wind speed are sensitive to the choice of regional model, and the detailed patterns of these changes are sensitive to the choice of the driving global model. In the case of precipitation, variation between models can exceed both internal variability and variability between different emissions scenarios.

A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1

Abstract: Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)-B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.

Proteasome-Independent Functions of Ubiquitin in Endocytosis and Signaling

Abstract: Ubiquitination is a reversible posttranslational modification of cellular proteins, in which a 76-amino acid polypeptide, ubiquitin, is primarily attached to the epsilon-amino group of lysines in target proteins. Ubiquitination is a major player in regulating a broad host of cellular processes, including cell division, differentiation, signal transduction, protein trafficking, and quality control. Aberrations in the ubiquitination system are implicated in pathogenesis of some diseases, certain malignancies, neurodegenerative disorders, and pathologies of the inflammatory immune response. Here, we discuss the proteasome-independent roles of ubiquitination in signaling and endocytosis.

Genome sequence of Aedes aegypti, a major arbovirus vector

Abstract: We present a draft sequence of the genome of Aedes aegypti, the primary vector for yellow fever and dengue fever, which at approximately 1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae. Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of approximately 4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster. Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of approximately 2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.

The world of emotions is not two-dimensional.

Abstract: For more than half a century, emotion researchers have attempted to establish the dimensional space that most economically accounts for similarities and differences in emotional experience. Today, many researchers focus exclusively on two-dimensional models involving valence and arousal. Adopting a theoretically based approach, we show for three languages that four dimensions are needed to satisfactorily represent similarities and differences in the meaning of emotion words. In order of importance, these dimensions are evaluation-pleasantness, potency-control, activation-arousal, and unpredictability. They were identified on the basis of the applicability of 144 features representing the six components of emotions: (a) appraisals of events, (b) psychophysiological changes, (c) motor expressions, (d) action tendencies, (e) subjective experiences, and (f) emotion regulation.

Strain Tuning of Ferroelectric Thin Films

Abstract: Predictions and measurements of the effect of biaxial strain on the properties of epitaxial ferroelectric thin films and superlattices are reviewed. Results for single-layer ferroelectric films of biaxially strained SrTiO3, BaTiO3, and PbTiO3 as well as PbTiO3/SrTiO3 and BaTiO3/SrTiO3 superlattices are described. Theoretical ap- proaches, including first principles, thermodynamic analysis, and phase-field models, are applied to these biaxially strained materials, the assumptions and limitations of each technique are explained, and the predictions are compared. Measurements of the effect of biax- ial strain on the paraelectric-to-ferroelectric transition temperature (TC) are shown, demonstrating the ability of percent-level strains to shift TC by hundreds of degrees in agreement with the predic- tions that predated such experiments. Along the way, important ex- perimental techniques for characterizing the properties of strained ferroelectric thin films and superlattices, as well as appropriate sub- strates on which to grow them, are mentioned.

Ultrashort filaments of light in weakly ionized, optically transparent media

Abstract: Modern laser sources nowadays deliver ultrashort light pulses reaching few cycles in duration and peak powers exceeding several terawatt (TW). When such pulses propagate through optically transparent media, they first self-focus in space and grow in intensity, until they generate a tenuous plasma by photo-ionization. For free electron densities and beam intensities below their breakdown limits, these pulses evolve as self-guided objects, resulting from successive equilibria between the Kerr focusing process, the chromatic dispersion of the medium and the defocusing action of the electron plasma. Discovered one decade ago, this self-channeling mechanism reveals a new physics, widely extending the frontiers of nonlinear optics. Implications include long-distance propagation of TW beams in the atmosphere, supercontinuum emission, pulse shortening as well as high-order harmonic generation. This review presents the landmarks of the 10-odd-year progress in this field. Particular emphasis is laid on the theoretical modeling of the propagation equations, whose physical ingredients are discussed from numerical simulations. The dynamics of single filaments created over laboratory scales in various materials such as noble gases, liquids and dielectrics reveal new perspectives in pulse shortening techniques. Far-field spectra provide promising diagnostics. Attention is also paid to the multifilamentation instability of broad beams, breaking up the energy distribution into small-scale cells along the optical path. The robustness of the resulting filaments in adverse weathers, their large conical emission exploited for multipollutant remote sensing, nonlinear spectroscopy and the possibility of guiding electric discharges in air are finally addressed on the basis of experimental results.

Scanning tunneling spectroscopy of high-temperature superconductors

Abstract: Tunneling spectroscopy has played a central role in the experimental verification of the microscopic theory of superconductivity in classical superconductors. Initial attempts to apply the same approach to high-temperature superconductors were hampered by various problems related to the complexity of these materials. The use of scanning tunneling microscopy and spectroscopy (STM and STS) on these compounds allowed the main difficulties to be overcome. This success motivated a rapidly growing scientific community to apply this technique to high-temperature superconductors. This paper reviews the experimental highlights obtained over the last decade. The crucial efforts to gain control over the technique and to obtain reproducible results are first recalled. Then a discussion on how the STM and STS techniques have contributed to the study of some of the most unusual and remarkable properties of high-temperature superconductors is presented: the unusually large gap values and the absence of scaling with the critical temperature, the pseudogap and its relation to superconductivity, the unprecedented small size of the vortex cores and its influence on vortex matter, the unexpected electronic properties of the vortex cores, and the combination of atomic resolution and spectroscopy leading to the observation of periodic local density of states modulations in the superconducting and pseudogap states and in the vortex cores.

Fast rotating massive stars and the origin of the abundance patterns in galactic globular clusters

Abstract: Aims. We propose the Wind of Fast Rotating Massive Stars scenario to explain the origin of the abundance anomalies observed in globular clusters. Methods. We compute and present models of fast rotating stars with initial masses between 20 and 120 M ⊙ for an initial metallicity Z = 0.0005 ([Fe/H] ≃ -1.5). We discuss the nucleosynthesis in the H-burning core of these objects and present the chemical composition of their ejecta. We consider the impact of uncertainties in the relevant nuclear reaction rates. Results. Fast rotating stars reach critical velocity at the beginning of their evolution and remain near the critical limit during the rest of the main sequence and part of the He-burning phase. As a consequence they lose large amounts of material through a mechanical wind which probably leads to the formation of a slow outflowing disk. The material in this slow wind is enriched in H-buming products and presents abundance patterns similar to the chemical anomalies observed in globular cluster stars. In particular, the C, N, O, Na and Li variations are well reproduced by our model. However the rate of the 24 Mg(p, y) has to be increased by a factor 1000 around 50 x 10 6 K in order to reproduce the amplitude of the observed Mg-Al anticorrelation. We discuss how the long-lived low-mass stars currently observed in globular clusters could have formed out of the slow wind material ejected by massive stars.

Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern.

Abstract: Percutaneous coronary intervention has become the most frequently used method of myocardial revascularization.1,2 The advent of coronary stenting led to a significant decrease in the complications seen after balloon angioplasty, resulting in improved patient outcome.3,4 Yet, stented angioplasty has been plagued from the onset by early stent thrombosis (<30 days after index procedure) and late in-stent restenosis (ISR). Initially, stent thrombosis rates as high as 24% raised serious doubts as to the viability of the therapy.5 With the combined prescription of thienopyridines and aspirin for 4 to 8 weeks,6,7 together with proper stent deployment techniques,8 early stent thrombosis rates decreased to what was felt to be an unavoidable and acceptable 1% to 1.5%. At the same time, efforts to reduce the 30% late ISR rates through systemic pharmacological approaches remained unsuccessful until local radiation, a strong antiproliferative therapy, was applied to prevent or treat ISR.9–13 Vascular brachytherapy was the first illustration that delayed healing might portend an increased risk of thrombosis together with the expected reduction in restenosis. Indeed, stent thrombosis rates increased again up to 5.3%, and the time window of event occurrence was extended beyond 1 year so that the initial clinical benefit would eventually erode as time went by.13,14 Today, first-generation drug-eluting stents (gen1-DES: Cypher, Cordis, Johnson & Johnson, Miami Lakes, Fla [sirolimus-eluting stent, SES] and Taxus, Boston Scientific Corp, Natick, Mass [paclitaxel-eluting stent]) releasing an antiproliferative compound (sirolimus or paclitaxel, respectively) via a nonbioerodable polymer have been proved to reduce the incidence of ISR by up to 75%.15–39 Since the publication in 2002 of the first randomized trial16 comparing DES and bare metal stents (BMS) in highly selected patients and lesions, the use of DES in clinical practice has expanded to the majority of coronary lesion subsets …

Increased Number of Islet-Associated Macrophages in Type 2 Diabetes

Abstract: Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived inflammatory factors. Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat-fed C57BL/6J mice, the GK rat, and the db/db mouse. When cultured islets were exposed to a type 2 diabetic milieu or when islets were isolated from high-fat-fed mice, increased islet-derived inflammatory factors were produced and released, including interleukin (IL)-6, IL-8, chemokine KC, granulocyte colony-stimulating factor, and macrophage inflammatory protein 1alpha. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and beta-cell lines and was not mimicked by the induction of islet cell death. Further, this inflammatory response was found to be biologically functional, as conditioned medium from human islets exposed to a type 2 diabetic milieu could induce increased migration of monocytes and neutrophils. This migration was blocked by IL-8 neutralization, and IL-8 was localized to the human pancreatic alpha-cell. Therefore, islet-derived inflammatory factors are regulated by a type 2 diabetic milieu and may contribute to the macrophage infiltration of pancreatic islets that we observe in type 2 diabetes.

Re-equilibration of Zircon in Aqueous Fluids and Melts

Abstract: Natural zircon crystals often show complex secondary textures that cut across primary growth zones. In zircon showing structural damage caused by self-irradiation, such textures are the result of a diffusion-reaction process in which a hydrous species diffuses inwards and “catalyzes” structural recovery. Nanoscale pores develop, solvent elements such as Ca, Al and Fe are gained, and radiogenic Pb is lost. In both aqueous fluids and melts, replacement of zircon with undamaged structure by a coupled dissolution-reprecipitation process can produce similar textures. The reacted domains usually have lower trace element contents and may contain micrometer-sized pores and inclusions of uranium, thorium and/or yttrium phases, originally in solid solution. Both processes have considerable implications for zircon geochronology.

Society for Ambulatory Anesthesia guidelines for the management of postoperative nausea and vomiting.

Abstract: The present guidelines were compiled by a multidisciplinary international panel of individuals with interest and expertise in postoperative nausea and vomiting (PONV) under the auspices of The Society of Ambulatory Anesthesia. The panel critically evaluated the current medical literature on PONV to provide an evidence-based reference tool for the management of adults and children who are undergoing surgery and are at increased risk for PONV. In brief, these guidelines identify risk factors for PONV in adults and children; recommend approaches for reducing baseline risks for PONV; identify the most effective antiemetic monotherapy and combination therapy regimens for PONV prophylaxis; recommend approaches for treatment of PONV when it occurs; and provide an algorithm for the management of individuals at increased risk for PONV.

System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock

Abstract: The mammalian circadian timing system consists of a master pacemaker in neurons of the suprachiasmatic nucleus (SCN) and clocks of a similar molecular makeup in most peripheral body cells. Peripheral oscillators are self-sustained and cell autonomous, but they have to be synchronized by the SCN to ensure phase coherence within the organism. In principle, the rhythmic expression of genes in peripheral organs could thus be driven not only by local oscillators, but also by circadian systemic signals. To discriminate between these mechanisms, we engineered a mouse strain with a conditionally active liver clock, in which REV-ERBalpha represses the transcription of the essential core clock gene Bmal1 in a doxycycline-dependent manner. We examined circadian liver gene expression genome-wide in mice in which hepatocyte oscillators were either running or arrested, and found that the rhythmic transcription of most genes depended on functional hepatocyte clocks. However, we discovered 31 genes, including the core clock gene mPer2, whose expression oscillated robustly irrespective of whether the liver clock was running or not. By contrast, in liver explants cultured in vitro, circadian cycles of mPer2::luciferase bioluminescence could only be observed when hepatocyte oscillators were operational. Hence, the circadian cycles observed in the liver of intact animals without functional hepatocyte oscillators were likely generated by systemic signals. The finding that rhythmic mPer2 expression can be driven by both systemic cues and local oscillators suggests a plausible mechanism for the phase entrainment of subsidiary clocks in peripheral organs.

NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation

Abstract: NOX4 is an enigmatic member of the NOX (NADPH oxidase) family of ROS (reactive oxygen species)-generating NADPH oxidases. NOX4 has a wide tissue distribution, but the physiological function and activation mechanisms are largely unknown, and its pharmacology is poorly understood. We have generated cell lines expressing NOX4 upon tetracycline induction. Tetracycline induced a rapid increase in NOX4 mRNA (1 h) followed closely (2 h) by a release of ROS. Upon tetracycline withdrawal, NOX4 mRNA levels and ROS release decreased rapidly ( 100 muM). The pattern of NOX4-dependent ROS generation was unique: (i) ROS release upon NOX4 induction was spontaneous without need for a stimulus, and (ii) the type of ROS released from NOX4-expressing cells was H(2)O(2), whereas superoxide (O(2)(-)) was almost undetectable. Probes that allow detection of intracellular O(2)(-) generation yielded differential results: DHE (dihydroethidium) fluorescence and ACP (1-acetoxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine) ESR measurements did not detect any NOX4 signal, whereas a robust signal was observed with NBT. Thus NOX4 probably generates O(2)(-) within an intracellular compartment that is accessible to NBT (Nitro Blue Tetrazolium), but not to DHE or ACP. In conclusion, NOX4 has a distinct pharmacology and pattern of ROS generation. The close correlation between NOX4 mRNA and ROS generation might hint towards a function as an inducible NOX isoform.

Mitochondrial bioenergetics and structural network organization

Abstract: Mitochondria form a dynamic network, and it remains unclear how the alternate configurations interact with bioenergetics properties. The metabolic signals that link mitochondrial structure to its functional states have not been fully characterized. In this report, we analyze the bidirectional relationships between mitochondrial morphology and function in living human cells. First, we determined the effect of mitochondrial fission on energy production by using small interfering RNA (siRNA) targeting DRP1, which revealed the importance of membrane fluidity on the control of bioenergetics. Second, we followed the effect of rotenone, a specific inhibitor of respiratory chain complex I, which causes large structural perturbations, once a threshold was reached. Last, we followed changes in the mitochondrial network configuration in human cells that had been treated with modulators of oxidative phosphorylation, and in fibroblasts from two patients with mitochondrial disease where the respiratory rate, DeltaPsi and the generation of reactive oxygen species (ROS) were measured. Our data demonstrate that the relationship between mitochondrial network organization and bioenergetics is bidirectional, and we provide a model for analyzing the metabolic signals involved in this crosstalk.

Stability of feature selection algorithms: a study on high-dimensional spaces

Abstract: With the proliferation of extremely high-dimensional data, feature selection algorithms have become indispensable components of the learning process Strangely, despite extensive work on the stability of learning algorithms, the stability of feature selection algorithms has been relatively neglected This study is an attempt to fill that gap by quantifying the sensitivity of feature selection algorithms to variations in the training set We assess the stability of feature selection algorithms based on the stability of the feature preferences that they express in the form of weights-scores, ranks, or a selected feature subset We examine a number of measures to quantify the stability of feature preferences and propose an empirical way to estimate them We perform a series of experiments with several feature selection algorithms on a set of proteomics datasets The experiments allow us to explore the merits of each stability measure and create stability profiles of the feature selection algorithms Finally, we show how stability profiles can support the choice of a feature selection algorithm

Quantum repeaters with photon pair sources and multimode memories.

Abstract: We propose a quantum repeater protocol which builds on the well-known Duan-Lukin-Cirac-Zoller (DLCZ) protocol [L. M. Duan, M. D. Lukin, J. I. Cirac, and P. Zoller, Nature (London) 414, 413 (2001)10.1038/35106500], but which uses photon pair sources in combination with memories that allow to store a large number of temporal modes. We suggest to realize such multimode memories based on the principle of photon echo, using solids doped with rare-earth-metal ions. The use of multimode memories promises a speedup in entanglement generation by several orders of magnitude and a significant reduction in stability requirements compared to the DLCZ protocol.

Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways.

Abstract: Melanoma is one of the most aggressive cancers, and its incidence is increasing. These tumors derive from the melanocyte lineage and remain incurable after metastasis. Here we report that SONIC HEDGEHOG (SHH)-GLI signaling is active in the matrix of human hair follicles, and that it is required for the normal proliferation of human melanocytes in culture. SHH-GLI signaling also regulates the proliferation and survival of human melanomas: the growth, recurrence, and metastasis of melanoma xenografts in mice are prevented by local or systemic interference of HH-GLI function. Moreover, we show that oncogenic RAS-induced melanomas in transgenic mice express Gli1 and require Hh-Gli signaling in vitro and in vivo. Finally, we provide evidence that endogenous RAS-MEK and AKT signaling regulate the nuclear localization and transcriptional activity of GLI1 in melanoma and other cancer cells. Our data uncover an unsuspected role of HH-GLI signaling in melanocytes and melanomas, demonstrate a role for this pathway in RAS-induced tumors, suggest a general integration of the RAS/AKT and HH-GLI pathways, and open a therapeutic approach for human melanomas.

Response to Letter Regarding Article, “Stent Thrombosis Late After Implantation of First-Generation Drug-Eluting Stents: A Cause for Concern”

Abstract: We are grateful for the thorough comments by Agostoni et al and Kereiakes et al, which give us the opportunity to clarify our position. As Agostoni et al point out, important limitations exist in the measurements of luminal dimensions that may be magnified when the change in those dimensions are assessed by measurement of late loss (LL). Furthermore, there is variation in absolute quantitative coronary angiography (QCA) values according to core laboratories, which makes comparison of QCA data problematic.1 Regardless of these facts, QCA of lumen dimensions has long been the backbone of clinical studies in the field of restenosis.2 It has now become crucial to go beyond luminal measurements and to focus on both events that matter to the patient and their …