Showing papers by "University of Turin published in 2011"
National Institutes of Health1, Cardiff University2, Erasmus University Rotterdam3, VU University Amsterdam4, University of Manchester5, University College London6, University of Helsinki7, University of Oulu8, Johns Hopkins University9, Georgetown University10, Illumina11, University Hospital of Wales12, University of Eastern Finland13, University of Miami14, University of Turin15, University of Cagliari16, The Catholic University of America17, Microsoft18, University of Toronto19, University of Würzburg20, University of Washington21, Aneurin Bevan University Health Board22
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
3,784 citations
TL;DR: It is shown that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice and this work suggests that deficits in microglian function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.
Abstract: Microglia are highly motile phagocytic cells that infiltrate and take up residence in the developing brain, where they are thought to provide a surveillance and scavenging function. However, although microglia have been shown to engulf and clear damaged cellular debris after brain insult, it remains less clear what role microglia play in the uninjured brain. Here, we show that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice. These findings link microglia surveillance to synaptic maturation and suggest that deficits in microglia function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.
3,011 citations
Stephen Sawcer1, Garrett Hellenthal2, Matti Pirinen2, Chris C. A. Spencer2 +262 more•Institutions (67)
TL;DR: In this article, a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, they have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
2,511 citations
TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
1,829 citations
TL;DR: In this article, the CAPACITY program was designed to confirm the results of a phase 2 study that suggested that pirfenidone, a novel antifibrotic and anti-inflammatory drug, reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis.
1,685 citations
TL;DR: In this paper, a detailed characterization of structural, vibrational, and electronic properties of UiO-66 (Zr-BDC MOF) in its hydroxylated and dehydroxylating forms is presented.
Abstract: Through a combined use of experimental and theoretical approaches such as XRPD, EXAFS, IR, and UV−vis spectroscopies and ab initio periodic DFT calculations, we report a detailed characterization of structural, vibrational, and electronic properties of UiO-66 (Zr-BDC MOF) in its hydroxylated and dehydroxylated forms. The stability of the materials with respect to the most common solvents, acids, and bases is determined by combining XRPD and TGA/MS techniques. The structures of the two forms of UiO-66 are refined through an interactive XRPD/EXAFS approach and validated by ab initio calculations. Experimental and calculated IR spectra are reported and compared to enlighten the nature of vibrational modes upon dehydroxylation and to show the complete reversibility of the dehydration/hydration phenomenon. Experimental and calculated band gaps are also reported and compared. In this work, we show the necessity to combine, in a synergic way, different experimental techniques and periodic ab initio approaches to...
1,302 citations
TL;DR: NAFLD warrants screening for cardio-metabolic risk and for progressive liver disease and the combination of three noninvasive tests with LB may optimally individuate patients with NASH, with or without advanced fibrosis.
Abstract: BACKGROUND. NAFLD ranges from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH). The natural history of NAFLD and the optimal strategy to identify subjects with progressive liver disease are unclear. Objectives. To assess the evidence in: (1) natural history of NAFLD; and (2) non-invasive methods to differentiate NAFLD histological subtypes. DESIGN AND SETTING. Among 4185 articles published on MEDLINE, Cochrane Library, EMBASE, Pubmed, national and International meeting abstracts through July 2010, 40 articles assessing the natural history of NAFLD and 32 articles evaluating the diagnostic accuracy of non-invasive tests against liver biopsy (LB) were included. MEASUREMENTS. Two reviewers retrieved articles and evaluated study quality by appropriate scores. Main outcomes were pooled using random- or fixed-effects models. RESULTS. NAFLD has an increased overall mortality (OR: 1.57, 95% CI: 1.18-2.10), deriving from liver-related and cardiovascular disease, and a 2-fold risk of diabetes. Compared to SS, NASH has a higher liver-related (OR for NASH: 5.71, 2.31-14.13; OR for NASH with advanced fibrosis: 10.06, 4.35-23.25), but not cardiovascular mortality (OR: 0.91, 0.42-1.98). Three non-invasive methods received independent validation: pooled AUROC, sensitivity and specificity of cytokeratin-18 for NASH are 0.82 (0.78-0.88), 0.78 (0.64-0.92), 0.87 (0.77-0.98). For NASH with advanced fibrosis, pooled AUROC, sensitivity and specificity of NAFLD fibrosis score and Fibroscan are 0.85 (0.80-0.93), 0.90 (0.82-0.99), 0.97 (0.94-0.99) and 0.94 (0.90-0.99), 0.94 (0.88-0.99) and 0.95 (0.89-0.99). CONCLUSIONS. NAFLD warrants screening for cardio-metabolic risk and for progressive liver disease. The combination of three noninvasive tests with LB may optimally individuate patients with NASH, with or without advanced fibrosis.
1,145 citations
TL;DR: The Adaptive Calibration Model is presented, an evolutionary-developmental theory of individual differences in the functioning of the stress response system that extends the theory of biological sensitivity to context (BSC) and provides an integrative framework for future research in the field.
1,009 citations
TL;DR: This study identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and possess growth- and tumor-suppressive properties and presents a road map for the prediction and validation of ceRNA activity and networks and thus imparts a trans-regulatory function to protein- coding mRNAs.
907 citations
TL;DR: The BRAF V600E mutation was present in all patients with HCL who were evaluated, and may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL.
Abstract: Background Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. Methods We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL. Results Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with spl...
861 citations
Mayo Clinic1, University of Nantes2, Cedars-Sinai Medical Center3, Harvard University4, National and Kapodistrian University of Athens5, University of Barcelona6, Hackensack University Medical Center7, Icahn School of Medicine at Mount Sinai8, Lille University of Science and Technology9, Emory University10, University of Turin11, Wayne State University12, University of Hamburg13, United States Department of Veterans Affairs14, University of Salamanca15
TL;DR: It is proposed that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript, and detailed definitions for patient populations, lines of therapy, and specific endpoints are provided.
TL;DR: This work reports that a subset of tumor-initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma releases MVs that trigger angiogenesis and promote the formation of a premetastatic niche.
Abstract: Recent studies suggest that tumor-derived microvesicles (MV) act as a vehicle for exchange of genetic information between tumor and stromal cells, engendering a favorable microenvironment for cancer development. Within the tumor mass, all cell types may contribute to MV shedding, but specific contributions to tumor progression have yet to be established. Here we report that a subset of tumor-initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma releases MVs that trigger angiogenesis and promote the formation of a premetastatic niche. MVs derived only from CD105-positive cancer stem cells conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation after in vivo implantation in immunocompromised severe combined immunodeficient (SCID) mice. Furthermore, treating SCID mice with MVs shed from CD105-positive cells greatly enhanced lung metastases induced by i.v. injection of renal carcinoma cells. Molecular characterization of CD105-positive MVs defines a set of proangiogenic mRNAs and microRNAs implicated in tumor progression and metastases. Our results define a specific source of cancer stem cell-derived MVs that contribute to triggering the angiogenic switch and coordinating metastatic diffusion during tumor progression.
TL;DR: Ciardiello et al. as discussed by the authors found that HER2 amplification was a predictor of resistance to anti-epidermal growth factor receptor (EGFR) antibodies and response to combination therapies against HER2 in this tumor setting.
Abstract: Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples (“xenopatients”) to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype–response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2 -amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal cancer, whose medical treatment in the chemorefractory setting remains an unmet clinical need.
Significance: Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, combining the flexibility of preclinical analysis with the informative value of population-based studies. Our suite of patient-derived xenografts from metastatic colorectal carcinomas reliably mimicked disease response in humans, prospectively recapitulated biomarker-based case stratification, and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting. Cancer Discovery; 1(6) ; 508–23. ©2011 AACR .
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TL;DR: In this article, the transverse momentum balance in dijet and γ/Z+jets events is used to measure the jet energy response in the CMS detector, as well as the transversal momentum resolution.
Abstract: Measurements of the jet energy calibration and transverse momentum resolution in CMS are presented, performed with a data sample collected in proton-proton collisions at a centre-of-mass energy of 7TeV, corresponding to an integrated luminosity of 36pb−1. The transverse momentum balance in dijet and γ/Z+jets events is used to measure the jet energy response in the CMS detector, as well as the transverse momentum resolution. The results are presented for three different methods to reconstruct jets: a calorimeter-based approach, the ``Jet-Plus-Track'' approach, which improves the measurement of calorimeter jets by exploiting the associated tracks, and the ``Particle Flow'' approach, which attempts to reconstruct individually each particle in the event, prior to the jet clustering, based on information from all relevant subdetectors
TL;DR: It is found that a single administration of MVs, immediately after IRI, protects rats from AKI by inhibiting apoptosis and stimulating tubular epithelial cell proliferation, and suggests that MVs could be exploited as a potential new therapeutic approach.
Abstract: Background Several studies demonstrated that mesenchymal stem cells (MSCs) reverse acute kidney injury (AKI) by a paracrine mechanism rather than by MSC transdifferentiation. We recently demonstrated that microvesicles (MVs) released from MSCs may account for this paracrine mechanism by a horizontal transfer of messenger RNA and microRNA. Methods MVs isolated from MSCs were injected intravenously in rats (30 μg/rat) immediately after monolateral nephrectomy and renal artery and vein occlusion for 45 min. To evaluate the MV effects on AKI induced by ischaemia-reperfusion injury (IRI), the animals were divided into different groups: normal rats (n = 4), sham-operated rats (n = 6), IRI rats (n = 6), IRI + MV rats (n = 6), and IRI + RNase-MV rats (n = 6), and all animals were sacrificed at Day 2 after the operation. To evaluate the chronic kidney damage consequent to IRI, the rats were divided into different groups: sham-operated rats (n = 6) and IRI rats (n = 6), IRI + MV rats (n = 6), and all animal were sacrificed 6 months after the operation. Results We found that a single administration of MVs, immediately after IRI, protects rats from AKI by inhibiting apoptosis and stimulating tubular epithelial cell proliferation. The MVs also significantly reduced the impairment of renal function. Pretreatment of MVs with RNase to inactivate their RNA cargo abrogated these protective effects. Moreover, MVs by reducing the acute injury also protected from later chronic kidney disease. Conclusion MVs released from MSCs protect from AKI induced by ischaemia reperfusion injury and from subsequent chronic renal damage. This suggest that MVs could be exploited as a potential new therapeutic approach.
TL;DR: The authors' findings document two major complementary networks involving the ventral-anterior and dorsal-posterior insula: one network links the anterior insula to the middle and inferior temporal cortex and anterior cingulate cortex, and is primarily related to limbic regions which play a role in emotional aspects, and support the use of resting state functional analysis to investigate connectivity in the living human brain.
TL;DR: In this article, the authors present a review of the state-of-the-art in the area of observations, nuclear and atomic physics, and stellar modeling, and the corresponding interplay is illustrated by the general abundance patterns of the elements beyond iron and by the effect of sensitive branching points along the $s$-process path.
Abstract: Nucleosynthesis in the $s$ process takes place in the He-burning layers of low-mass asymptotic giant branch (AGB) stars and during the He- and C-burning phases of massive stars. The $s$ process contributes about half of the element abundances between Cu and Bi in solar system material. Depending on stellar mass and metallicity the resulting $s$-abundance patterns exhibit characteristic features, which provide comprehensive information for our understanding of the stellar life cycle and for the chemical evolution of galaxies. The rapidly growing body of detailed abundance observations, in particular, for AGB and post-AGB stars, for objects in binary systems, and for the very faint metal-poor population represents exciting challenges and constraints for stellar model calculations. Based on updated and improved nuclear physics data for the $s$-process reaction network, current models are aiming at an ab initio solution for the stellar physics related to convection and mixing processes. Progress in the intimately related areas of observations, nuclear and atomic physics, and stellar modeling is reviewed and the corresponding interplay is illustrated by the general abundance patterns of the elements beyond iron and by the effect of sensitive branching points along the $s$-process path. The strong variations of the $s$-process efficiency with metallicity bear also interesting consequences for galactic chemical evolution.
TL;DR: This study genetically identifies multiple putative microRNA decoys for PTEN, validates Z EB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAF V600E to promote melanomagenesis.
TL;DR: In this article, the authors studied the effect of collision centrality on the transverse momentum of PbPb collisions at the LHC with a data sample of 6.7 inverse microbarns.
Abstract: Jet production in PbPb collisions at a nucleon-nucleon center-of-mass energy of 2.76 TeV was studied with the CMS detector at the LHC, using a data sample corresponding to an integrated luminosity of 6.7 inverse microbarns. Jets are reconstructed using the energy deposited in the CMS calorimeters and studied as a function of collision centrality. With increasing collision centrality, a striking imbalance in dijet transverse momentum is observed, consistent with jet quenching. The observed effect extends from the lower cut-off used in this study (jet transverse momentum = 120 GeV/c) up to the statistical limit of the available data sample (jet transverse momentum approximately 210 GeV/c). Correlations of charged particle tracks with jets indicate that the momentum imbalance is accompanied by a softening of the fragmentation pattern of the second most energetic, away-side jet. The dijet momentum balance is recovered when integrating low transverse momentum particles distributed over a wide angular range relative to the direction of the away-side jet.
TL;DR: The evidence connecting gut microflora to obesity and to type 1 and type 2 diabetes is discussed, and potential mechanisms underlying this relationship are presented.
Abstract: Novel, culture-independent, molecular and metagenomic techniques have provided new insight into the complex interactions between the mammalian host and gut microbial species. It is increasingly evident that gut microbes may shape the host metabolic and immune network activity and ultimately influence the development of obesity and diabetes. We discuss the evidence connecting gut microflora to obesity and to type 1 and type 2 diabetes, and we present recent insights into potential mechanisms underlying this relationship: increased nutrient absorption from the diet, prolonged intestinal transit time, altered bile acid entero-hepatic cycle, increased cellular uptake of circulating triglycerides, enhanced de novo lipogenesis, reduced free fatty acid oxidation, altered tissue composition of biologically active polyunsaturated fatty acid, chronic low-grade inflammation triggered by the endotoxin toll-like receptor 4 axis, and altered intestinal barrier function.
K. Aamodt1, A. Abrahantes Quintana, Dagmar Adamová2, Andrew Marshall Adare3 +938 more•Institutions (80)
TL;DR: In this paper, the centrality dependence of the chargedparticle multiplicity density at midrapidity in Pb-Pb collisions at root s(NN) = 2: 76 TeV is presented.
Abstract: The centrality dependence of the charged-particle multiplicity density at midrapidity in Pb-Pb collisions at root s(NN) = 2: 76 TeV is presented. The charged-particle density normalized per participating nucleon pair increases by about a factor of 2 from peripheral (70%-80%) to central (0%-5%) collisions. The centrality dependence is found to be similar to that observed at lower collision energies. The data are compared with models based on different mechanisms for particle production in nuclear collisions.
TL;DR: Blocking CCL2 nitration in tumors promoted CD8+ influx and reduced tumor growth and prolonged survival in mice when combined with adoptive cell therapy.
Abstract: Tumor-promoted constraints negatively affect cytotoxic T lymphocyte (CTL) trafficking to the tumor core and, as a result, inhibit tumor killing. The production of reactive nitrogen species (RNS) within the tumor microenvironment has been reported in mouse and human cancers. We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy.
K. Aamodt1, A. Abrahantes Quintana, Dagmar Adamová2, Andrew Marshall Adare3 +909 more•Institutions (76)
TL;DR: In this article, the authors measured the transverse momentum spectra of primary charged particles in Pb-Pb collisions at root s(NN) = 2.76 TeV at the ALICE Collaboration at the LHC.
11 Jul 2011
TL;DR: The first measurement of the triangular v3, quadrangular v4, and pentagonal v5 charged particle flow in Pb-Pb collisions is reported, and a double peaked structure in the two-particle azimuthal correlations is observed, which can be naturally explained from the measured anisotropic flow Fourier coefficients.
Abstract: We report on the first measurement of the triangular nu(3), quadrangular nu(4), and pentagonal nu(5) charged particle flow in Pb-Pb collisions at root s(NN) = 2.76 TeV measured with the ALICE detector at the CERN Large Hadron Collider. We show that the triangular flow can be described in terms of the initial spatial anisotropy and its fluctuations, which provides strong constraints on its origin. In the most central events, where the elliptic flow nu(2) and nu(3) have similar magnitude, a double peaked structure in the two-particle azimuthal correlations is observed, which is often interpreted as a Mach cone response to fast partons. We show that this structure can be naturally explained from the measured anisotropic flow Fourier coefficients.
Columbia University1, Yale University2, Peking University3, Shanghai Jiao Tong University4, University of Alabama at Birmingham5, University of Tennessee6, Icahn School of Medicine at Mount Sinai7, Istituto Giannina Gaslini8, University of Calgary9, University of Parma10, University of Brescia11, University of Foggia12, University of Turin13
TL;DR: Three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance, explain 4–7% of the disease variance and up to a tenfold variation in interindividual risk.
Abstract: We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10⁻²⁶ and 4.84 × 10⁻⁹ and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.
TL;DR: Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported.
Duke University1, King's College London2, Stanford University3, University of Texas MD Anderson Cancer Center4, University of Melbourne5, Fox Chase Cancer Center6, University of Wisconsin-Madison7, Leiden University8, Boston University9, University of Florence10, University of Turin11, Complutense University of Madrid12, University of Paris13, University of Barcelona14, Northwestern University15, Medical University of Vienna16, University of São Paulo17, Okayama University18, University of Tokyo19, University of Zurich20, Mayo Clinic21, Emory University22, University of Pittsburgh23, University of California, Los Angeles24, Yale University25, University of Helsinki26, Memorial Sloan Kettering Cancer Center27, Medical University of Graz28, University of Nantes29, Johns Hopkins University30
TL;DR: In this article, consensus recommendations for the general conduct of clinical trials of patients with mycosis fungoides (MF) and Sezary syndrome (SS), as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, were presented.
Abstract: Mycosis fungoides (MF) and Sezary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin's lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated c...
University of Texas MD Anderson Cancer Center1, University of Turin2, State University of Campinas3, Sarah Cannon Research Institute4, Karolinska Institutet5, Karolinska University Hospital6, Singapore General Hospital7, University of Bologna8, Osaka City University9, Novartis10, University of Chicago11, Royal Adelaide Hospital12
TL;DR: At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the nilotinib groups than in the imatinib group, and there were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the nilotinib groups.
Abstract: Summary Background Nilotinib has shown greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase after a minimum follow-up of 12 months. We present data from the Evaluating Nilotinib Efficacy and Safety in clinical Trials–newly diagnosed patients (ENESTnd) study after a minimum follow-up of 24 months. Methods ENESTnd was a phase 3, multicentre, open-label, randomised study. Adult patients were eligible if they had been diagnosed with chronic phase, Philadelphia chromosome-positive CML within the previous 6 months. Patients were randomly assigned (1:1:1) to receive nilotinib 300 mg twice a day, nilotinib 400 mg twice a day, or imatinib 400 mg once a day, all administered orally, by use of a computer-generated randomisation schedule, using permuted blocks, and stratified according to Sokal score. Efficacy results are reported for the intention-to-treat population. The primary endpoint was major molecular response at 12 months, defined as BCR–ABL transcript levels on the International Scale (BCR–ABL IS ) of 0·1% or less by real-time quantitative PCR in peripheral blood. This study is registered with ClinicalTrials.gov, number NCT00471497. Findings 282 patients were randomly assigned to receive nilotinib 300 mg twice daily, 281 to receive nilotinib 400 mg twice daily, and 283 to receive imatinib. By 24 months, significantly more patients had a major molecular response with nilotinib than with imatinib (201 [71%] with nilotinib 300 mg twice daily, 187 [67%] with nilotinib 400 mg twice daily, and 124 [44%] with imatinib; p IS levels to ≤0·0032%) at any time than did those in the imatinib group (74 [26%] with nilotinib 300 mg twice daily, 59 [21%] with nilotinib 400 mg twice daily, and 29 [10%] with imatinib; p vs imatinib, p=0·0004 for nilotinib 400 mg twice daily vs imatinib). There were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the nilotinib groups than in the imatinib group (two with nilotinib 300 mg twice daily, five with nilotinib 400 mg twice daily, and 17 with imatinib; p=0·0003 for nilotinib 300 mg twice daily vs imatinib, p=0·0089 for nilotinib 400 mg twice daily vs imatinib). At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the nilotinib groups than in the imatinib group (five with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and ten with imatinib). Overall, the only grade 3 or 4 non-haematological adverse events that occurred in at least 2·5% of patients were headache (eight [3%] with nilotinib 300 mg twice daily, four [1%] with nilotinib 400 mg twice daily, and two [ Interpretation Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support nilotinib as a first-line treatment option for patients with newly diagnosed disease. Funding Novartis.
TL;DR: The epidemiological findings suggest that ALS phenotypes carry distinctive and easily distinguishable clinical and prognostic characteristics, strongly related to a complex interplay between gender and age.
Abstract: Background Different amyotrophic lateral sclerosis (ALS) phenotypes have been recognised, marked by a varying involvement of spinal and bulbar upper and lower motor neurons. However, the differential characteristics of these phenotypes are still largely unknown. Objective To define the epidemiology and outcome of ALS phenotypes in a population based setting. Methods All ALS cases incident in two Italian regions were prospectively collected from 1995 to 2004 in an epidemiological register. Cases were classified according to established ALS phenotypes: classic, bulbar, flail arm, flail leg, pyramidal, respiratory, pure lower motor neuron (PLMN) and pure upper motor neuron (PUMN). Results ALS phenotype were determined in 1332 out of 1351 incident patients (98.6%). Classic and bulbar phenotypes had similar mean annual incidence rates. Gender specific incidence rates showed a male preponderance in respiratory, flail arm, classic and PLMN phenotypes; in all other phenotypes, men and women had similar incidence rates. Age at onset was significantly lower in pyramidal, PLMN and PUMN phenotypes and higher in the bulbar phenotype. The best outcomes were observed in PUMN, pyramidal, PLMN and flail arm phenotypes and the worst in respiratory and bulbar phenotypes. Conclusions Our epidemiological findings suggest that ALS phenotypes carry distinctive and easily distinguishable clinical and prognostic characteristics, strongly related to a complex interplay between gender and age. The categorisation of ALS patients according to more homogenous clinical groups is relevant in identifying biological markers for ALS and should be considered for the design of clinical trials.
TL;DR: Application of ideal adsorbed solution theory in simulating breakthrough curves shows Fe(2)(dobdc) to be a promising material for the separation of O(2) from air at temperatures well above those currently employed in industrial settings.
Abstract: The air-free reaction between FeCl2 and H4dobdc (dobdc4– = 2,5-dioxido-1,4-benzenedicarboxylate) in a mixture of N,N-dimethylformamide (DMF) and methanol affords Fe2(dobdc)·4DMF, a metal–organic framework adopting the MOF-74 (or CPO-27) structure type. The desolvated form of this material displays a Brunauer–Emmett–Teller (BET) surface area of 1360 m2/g and features a hexagonal array of one-dimensional channels lined with coordinatively unsaturated FeII centers. Gas adsorption isotherms at 298 K indicate that Fe2(dobdc) binds O2 preferentially over N2, with an irreversible capacity of 9.3 wt %, corresponding to the adsorption of one O2 molecule per two iron centers. Remarkably, at 211 K, O2 uptake is fully reversible and the capacity increases to 18.2 wt %, corresponding to the adsorption of one O2 molecule per iron center. Mossbauer and infrared spectra are consistent with partial charge transfer from iron(II) to O2 at low temperature and complete charge transfer to form iron(III) and O22– at room temper...