Showing papers by "University of Milan published in 2009"
University of Udine1, International School for Advanced Studies2, National Research Council3, Massachusetts Institute of Technology4, University of Paris5, Princeton University6, University of Minnesota7, ParisTech8, University of Milan9, International Centre for Theoretical Physics10, University of Paderborn11, ETH Zurich12, École Polytechnique Fédérale de Lausanne13
TL;DR: QUANTUM ESPRESSO as discussed by the authors is an integrated suite of computer codes for electronic-structure calculations and materials modeling, based on density functional theory, plane waves, and pseudopotentials (norm-conserving, ultrasoft, and projector-augmented wave).
Abstract: QUANTUM ESPRESSO is an integrated suite of computer codes for electronic-structure calculations and materials modeling, based on density-functional theory, plane waves, and pseudopotentials (norm-conserving, ultrasoft, and projector-augmented wave). The acronym ESPRESSO stands for opEn Source Package for Research in Electronic Structure, Simulation, and Optimization. It is freely available to researchers around the world under the terms of the GNU General Public License. QUANTUM ESPRESSO builds upon newly-restructured electronic-structure codes that have been developed and tested by some of the original authors of novel electronic-structure algorithms and applied in the last twenty years by some of the leading materials modeling groups worldwide. Innovation and efficiency are still its main focus, with special attention paid to massively parallel architectures, and a great effort being devoted to user friendliness. QUANTUM ESPRESSO is evolving towards a distribution of independent and interoperable codes in the spirit of an open-source project, where researchers active in the field of electronic-structure calculations are encouraged to participate in the project by contributing their own codes or by implementing their own ideas into existing codes.
19,985 citations
TL;DR: This work surmises that CRI represents the seventh hallmark of cancer, and suggests that an additional mechanism involved in cancer-related inflammation (CRI) is induction of genetic instability by inflammatory mediators, leading to accumulation of random genetic alterations in cancer cells.
Abstract: Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumors that are not epidemiologically related to inflammation. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. In the tumor microenvironment, smoldering inflammation contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, reduced response to hormones and chemotherapeutic agents. Recent data suggest that an additional mechanism involved in cancer-related inflammation (CRI) is induction of genetic instability by inflammatory mediators, leading to accumulation of random genetic alterations in cancer cells. In a seminal contribution, Hanahan and Weinberg [(2000) Cell, 100, 57-70] identified the six hallmarks of cancer. We surmise that CRI represents the seventh hallmark.
2,475 citations
Harvard University1, University of Massachusetts Medical School2, Massachusetts Institute of Technology3, Rhode Island Hospital4, University of Kentucky5, Tufts University6, Université de Montréal7, University of Bologna8, Children's Hospital Oakland Research Institute9, Vanderbilt University10, Northwestern University11, University of Milan12
TL;DR: Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder Ten percent of cases are inherited; most involve unidentified genes We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders
2,387 citations
Université catholique de Louvain1, Centre national de la recherche scientifique2, Université de Montréal3, French Alternative Energies and Atomic Energy Commission4, École normale supérieure de Lyon5, European Synchrotron Radiation Facility6, University of Liège7, University of Basel8, Université de Namur9, University of Milan10, Spanish National Research Council11, Dalhousie University12
TL;DR: The present paper provides an exhaustive account of the capabilities of ABINIT, with adequate references to the underlying theory, as well as the relevant input variables, tests and, if available, ABinIT tutorials.
2,226 citations
TL;DR: It is found that most lysosomal genes exhibit coordinated transcriptional behavior and are regulated by the transcription factor EB (TFEB), providing a potential therapeutic target to enhance cellular clearing in lysOSomal storage disorders and neurodegenerative diseases.
Abstract: Lysosomes are organelles central to degradation and recycling processes in animal cells. Whether lysosomal activity is coordinated to respond to cellular needs remains unclear. We found that most lysosomal genes exhibit coordinated transcriptional behavior and are regulated by the transcription factor EB (TFEB). Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes. TFEB overexpression in cultured cells induced lysosomal biogenesis and increased the degradation of complex molecules, such as glycosaminoglycans and the pathogenic protein that causes Huntington's disease. Thus, a genetic program controls lysosomal biogenesis and function, providing a potential therapeutic target to enhance cellular clearing in lysosomal storage disorders and neurodegenerative diseases.
1,928 citations
TL;DR: A homogeneous X-rays analysis of all 318 gamma-ray bursts detected by the X-ray telescope (XRT) on the Swift satellite up to 2008 July 23 is presented; this represents the largest sample ofX-ray GRB data published to date.
Abstract: We present a homogeneous X-ray analysis of all 318 gamma-ray bursts detected by the X-ray telescope (XRT) on the Swift satellite up to 2008 July 23; this represents the largest sample of X-ray GRB data published to date. In Sections 2-3, we detail the methods which the Swift-XRT team has developed to produce the enhanced positions, light curves, hardness ratios and spectra presented in this paper. Software using these methods continues to create such products for all new GRBs observed by the Swift-XRT. We also detail web-based tools allowing users to create these products for any object observed by the XRT, not just GRBs. In Sections 4-6, we present the results of our analysis of GRBs, including probability distribution functions of the temporal and spectral properties of the sample. We demonstrate evidence for a consistent underlying behaviour which can produce a range of light-curve morphologies, and attempt to interpret this behaviour in the framework of external forward shock emission. We find several difficulties, in particular that reconciliation of our data with the forward shock model requires energy injection to continue for days to weeks.
1,613 citations
TL;DR: A series of routines that can be interfaced with the most popular classical molecular dynamics codes through a simple patching procedure, which leaves the possibility for the user to exploit many different MD engines depending on the system simulated and on the computational resources available.
1,423 citations
TL;DR: A Stata implementation of coarsened exact matching, a new method for improving the estimation of causal effects by reducing imbalance in covariates between treated and control groups, is introduced.
Abstract: In this article, we introduce a Stata implementation of coarsened exact matching, a new method for improving the estimation of causal effects by reduc- ing imbalance in covariates between treated and control groups. Coarsened exact matching is faster, is easier to use and understand, requires fewer assumptions, is more easily automated, and possesses more attractive statistical properties for many applications than do existing matching methods. In coarsened exact match- ing, users temporarily coarsen their data, exact match on these coarsened data, and then run their analysis on the uncoarsened, matched data. Coarsened exact matching bounds the degree of model dependence and causal effect estimation er- ror by ex ante user choice, is monotonic imbalance bounding (so that reducing the maximum imbalance on one variable has no effect on others), does not require a separate procedure to restrict data to common support, meets the congruence prin- ciple, is approximately invariant to measurement error, balances all nonlinearities and interactions in sample (i.e., not merely in expectation), and works with mul- tiply imputed datasets. Other matching methods inherit many of the coarsened exact matching method's properties when applied to further match data prepro- cessed by coarsened exact matching. The cem command implements the coarsened exact matching algorithm in Stata.
1,236 citations
TL;DR: The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes, which makes TAM an attractive target of novel biological therapies of tumors.
Abstract: The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes TAM, major players in the connection between inflammation and cancer, summarize a number of functions (eg, promotion of tumor cell proliferation and angiogenesis, incessant matrix turnover, repression of adaptive immunity), which ultimately have an important impact on disease progression Thus, together with other myeloid-related cells present at the tumor site (Tie2 macrophages and MDSCs), TAM represent an attractive target of novel biological therapies of tumors
1,225 citations
TL;DR: It is demonstrated here that these core-shell nanowires have high charge storage capacity with approximately 90% capacity retention over 100 cycles and show excellent electrochemical performance at high rate charging and discharging.
Abstract: Silicon is an attractive alloy-type anode material for lithium ion batteries because of its highest known capacity (4200 mAh/g). However silicon’s large volume change upon lithium insertion and extraction, which causes pulverization and capacity fading, has limited its applications. Designing nanoscale hierarchical structures is a novel approach to address the issues associated with the large volume changes. In this letter, we introduce a core−shell design of silicon nanowires for highpower and long-life lithium battery electrodes. Silicon crystalline-amorphous core−shell nanowires were grown directly on stainless steel current collectors by a simple one-step synthesis. Amorphous Si shells instead of crystalline Si cores can be selected to be electrochemically active due to the difference of their lithiation potentials. Therefore, crystalline Si cores function as a stable mechanical support and an efficient electrical conducting pathway while amorphous shells store Li+ ions. We demonstrate here that these...
1,201 citations
Harvard University1, Broad Institute2, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico3, McMaster University4, McGill University5, University of Leicester6, University of Lübeck7, University of Pennsylvania8, Vanderbilt University9, University of Missouri–Kansas City10, University of Münster11, University of Verona12, Queen's University Belfast13, University of Washington14, Boston University15, University of Helsinki16, National Institute for Health and Welfare17, Lund University18, University of Cambridge19, Vita-Salute San Raffaele University20, University of Ferrara21, University of Turin22, Hebrew University of Jerusalem23, University of Girona24, University of Milan25, University of Leeds26, University of Regensburg27, Ludwig Maximilian University of Munich28, University of Kiel29, Wellcome Trust Sanger Institute30, University of Paris31, MedStar Washington Hospital Center32, deCODE genetics33, University of Iceland34
TL;DR: SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with my Cardiovascular Infarction risk.
Abstract: We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls We carried out replication in an independent sample with an effective sample size of up to 19,492 SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations1, 2, 3, 4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9) We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10-3) We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk
TL;DR: Modalities for blood collection and processing are fully delineated and the choice of tests is limited to dRVVT and a sensitive aPTT and the interpretation of the results in general and in particular situations is reported.
TL;DR: Methodologies are compared along several dimensions, including the methodological phases and steps, the strategies and techniques, the data quality dimensions, the types of data, and, finally, thetypes of information systems addressed by each methodology.
Abstract: The literature provides a wide range of techniques to assess and improve the quality of data. Due to the diversity and complexity of these techniques, research has recently focused on defining methodologies that help the selection, customization, and application of data quality assessment and improvement techniques. The goal of this article is to provide a systematic and comparative description of such methodologies. Methodologies are compared along several dimensions, including the methodological phases and steps, the strategies and techniques, the data quality dimensions, the types of data, and, finally, the types of information systems addressed by each methodology. The article concludes with a summary description of each methodology.
TL;DR: Several quantities of interest in quantum information, including entanglement and purity, are nonlinear functions of the density matrix and cannot, even in principle, correspond to proper quantum information as discussed by the authors.
Abstract: Several quantities of interest in quantum information, including entanglement and purity, are nonlinear functions of the density matrix and cannot, even in principle, correspond to proper quantum o...
University of Milano-Bicocca1, University of Paris2, University of Brescia3, University of Bologna4, University of Lausanne5, Queen Mary University of London6, Ghent University7, University of Barcelona8, University of Glasgow9, Istanbul University10, Katholieke Universiteit Leuven11, Hannover Medical School12, University of Manchester13, University of Oslo14, Joseph Fourier University15, Gdańsk Medical University16, University of Copenhagen17, University of Münster18, University of Valencia19, Complutense University of Madrid20, University of Erlangen-Nuremberg21, Maastricht University22, University of Amsterdam23, University of Milan24
TL;DR: The objective of this study was to establish a baseline for the design of a systematic literature review of this type of treatment for high blood pressure using a simple, straightforward, and scalable procedure.
Abstract: Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Commit
TL;DR: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency and effective protection against infections and improvement in physical development made a normal lifestyle possible.
Abstract: Background We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxificati...
TL;DR: In this prematurely stopped and therefore underpowered study, there was a lack of clinical benefit of intensive insulin therapy, associated with an increased incidence of hypoglycaemia, as compared to a 7.8–10.0 mmol/L target.
Abstract: PURPOSE: An optimal target for glucose control in ICU patients remains unclear. This prospective randomized controlled trial compared the effects on ICU mortality of intensive insulin therapy (IIT) with an intermediate glucose control. METHODS: Adult patients admitted to the 21 participating medico-surgical ICUs were randomized to group 1 (target BG 7.8-10.0 mmol/L) or to group 2 (target BG 4.4-6.1 mmol/L). RESULTS: While the required sample size was 1,750 per group, the trial was stopped early due to a high rate of unintended protocol violations. From 1,101 admissions, the outcomes of 542 patients assigned to group 1 and 536 of group 2 were analysed. The groups were well balanced. BG levels averaged in group 1 8.0 mmol/L (IQR 7.1-9.0) (median of all values) and 7.7 mmol/L (IQR 6.7-8.8) (median of morning BG) versus 6.5 mmol/L (IQR 6.0-7.2) and 6.1 mmol/L (IQR 5.5-6.8) for group 2 (p < 0.0001 for both comparisons). The percentage of patients treated with insulin averaged 66.2 and 96.3%, respectively. Proportion of time spent in target BG was similar, averaging 39.5% and 45.1% (median (IQR) 34.3 (18.5-50.0) and 39.3 (26.2-53.6)%) in the groups 1 and 2, respectively. The rate of hypoglycaemia was higher in the group 2 (8.7%) than in group 1 (2.7%, p < 0.0001). ICU mortality was similar in the two groups (15.3 vs. 17.2%). CONCLUSIONS: In this prematurely stopped and therefore underpowered study, there was a lack of clinical benefit of intensive insulin therapy (target 4.4-6.1 mmol/L), associated with an increased incidence of hypoglycaemia, as compared to a 7.8-10.0 mmol/L target. (ClinicalTrials.gov # NCT00107601, EUDRA-CT Number: 200400391440).
TL;DR: It is found that the stability of the net ecosystem denitrification in the face of salinity stress was strongly influenced by the initial evenness of the community, therefore, when communities are highly uneven, or there is extreme dominance by one or a few species, their functioning is less resistant to environmental stress.
Abstract: Owing to the present global biodiversity crisis, the biodiversity-stability relationship and the effect of biodiversity on ecosystem functioning have become major topics in ecology. Biodiversity is a complex term that includes taxonomic, functional, spatial and temporal aspects of organismic diversity, with species richness (the number of species) and evenness (the relative abundance of species) considered among the most important measures. With few exceptions (see, for example, ref. 6), the majority of studies of biodiversity-functioning and biodiversity-stability theory have predominantly examined richness. Here we show, using microbial microcosms, that initial community evenness is a key factor in preserving the functional stability of an ecosystem. Using experimental manipulations of both richness and initial evenness in microcosms with denitrifying bacterial communities, we found that the stability of the net ecosystem denitrification in the face of salinity stress was strongly influenced by the initial evenness of the community. Therefore, when communities are highly uneven, or there is extreme dominance by one or a few species, their functioning is less resistant to environmental stress. Further unravelling how evenness influences ecosystem processes in natural and humanized environments constitutes a major future conceptual challenge.
International Agency for Research on Cancer1, Catholic University of the Sacred Heart2, Fred Hutchinson Cancer Research Center3, Universidade Federal do Rio Grande do Sul4, University of São Paulo5, National Institutes of Health6, Harvard University7, Brown University8, Oswaldo Cruz Foundation9, University of Milan10, Pennsylvania State University11, University of Lausanne12, University of Buenos Aires13, Universidade Federal de Pelotas14, Boston University15, University of North Carolina at Chapel Hill16, University of Iowa17, University of Texas MD Anderson Cancer Center18, Nofer Institute of Occupational Medicine19, Russian Academy20, Medical University of Warsaw21, University of California, Los Angeles22
TL;DR: It is confirmed that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk, however, a substantial proportion of head and head cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head andneck cancer among women and among young-onset cases.
Abstract: Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter ( ψ ) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk ( ψ = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases 60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541–50)
TL;DR: For several exposures, it has been proved that chemicals can alter epigenetic marks, and that the same or similar epigenetic alterations can be found in patients with the disease of concern or in diseased tissues.
Abstract: Purpose of review Epigenetics investigates heritable changes in gene expression occurring without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA expression, can change genome function under exogenous influence. Here, we review current evidence indicating that epigenetic alterations mediate toxicity from environmental chemicals. Recent findings In-vitro, animal, and human investigations have identified several classes of environmental chemicals that modify epigenetic marks, including metals (cadmium, arsenic, nickel, chromium, and methylmercury), peroxisome proliferators (trichloroethylene, dichloroacetic acid, and TCA), air pollutants (particulate matter, black carbon, and benzene), and endocrine-disrupting/reproductive toxicants (diethylstilbestrol, bisphenol A, persistent organic pollutants, and dioxin). Most studies conducted so far have been centered on DNA methylation, whereas only a few investigations have studied environmental chemicals in relation to histone modifications and microRNA. Summary For several exposures, it has been proved that chemicals can alter epigenetic marks, and that the same or similar epigenetic alterations can be found in patients with the disease of concern or in diseased tissues. Future prospective investigations are needed to determine whether exposed individuals develop epigenetic alterations over time and, in turn, which such alterations increase the risk of disease. Also, further research is needed to determine whether environmental epigenetic changes are transmitted transgenerationally.
TL;DR: The rationale for and discussed are the problems in proposing BDNF treatment as a beneficial and feasible therapeutic approach in the clinic, and the involvement of BDNF in a number of neurodegenerative diseases is reviewed.
Abstract: Changes in the levels and activities of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), have been described in a number of neurodegenerative disorders, including Huntington disease, Alzheimer disease and Parkinson disease. It is only in Huntington disease, however, that gain-of-function and loss-of-function experiments have linked BDNF mechanistically with the underlying genetic defect. Altogether, these studies have led to the development of experimental strategies aimed at increasing BDNF levels in the brains of animals that have been genetically altered to mimic the aforementioned human diseases, with a view to ultimately influencing the clinical treatment of these conditions. In this article, we will review the current knowledge about the involvement of BDNF in a number of neurodegenerative diseases, with particular emphasis on Huntington disease, and will provide the rationale for and discuss the problems in proposing BDNF treatment as a beneficial and feasible therapeutic approach in the clinic.
TL;DR: ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy, and early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy.
Abstract: Summary Background About a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome. Methods Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL. Findings 30 patients (12·6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a − , CD8 − , CD5 weak with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40–100] at 10 years vs 10% [4–16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25–89] at 2 years vs 14% [6–22] at 2 years for patients treated in the AIEOP trial). Interpretation ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy. Funding US National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC).
TL;DR: Recent data involving purinergic signalling in pathological conditions, including pain, trauma, ischaemia, epilepsy, migraine, psychiatric disorders and drug addiction are highlighted, which are expected to lead to the development of therapeutic strategies for these disorders with novel mechanisms of action.
TL;DR: In this article, the effects of albuminuria and reduced estimated GFR (eGFR) on the risk for cardiovascular and renal events among individuals with type 2 diabetes were investigated. But, there was no evidence of an interaction between the effect of higher eGFR and lower UACR.
Abstract: There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.
Mayo Clinic1, Medical University of Vienna2, University of Arkansas for Medical Sciences3, The Royal Marsden NHS Foundation Trust4, University of Minnesota5, University of Nantes6, University of Milan7, National Institutes of Health8, University of Ulm9, Columbia University10, Cedars-Sinai Medical Center11, Harvard University12, Charité13, Dalhousie University14, University of Alberta15
TL;DR: In this paper, the authors proposed a framework for the classification of myeloma subtypes and provided recommendations for genetic testing, which needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials.
Abstract: Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinicopathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor- B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials.
TL;DR: This review discusses recent findings derived from basic cell biology, clinical studies, and studies in animal models such as mice and zebrafish and their possible integration in a common picture of human pathologies.
Istituto Giannina Gaslini1, Boston Children's Hospital2, University of Milan3, Istanbul University4, University of Paris5, Hacettepe University6, University of Padua7, University of Duisburg-Essen8, Semmelweis University9, University of Marburg10, University of Mainz11, Charles University in Prague12, Pomeranian Medical University13, Charité14, University of Strasbourg15, University of Hamburg16, University of Rostock17, Heidelberg University18
TL;DR: Investigation of the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor revealed a substantial benefit with respect to renal function among children with chronic kidney disease.
Abstract: Background Although inhibition of the renin–angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting–enzyme (ACE) inhibitor. Methods After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m 2 of body-surface area) received ramipril at a dose of 6 mg per square meter of bodysurface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin–angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion. Results A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan– Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P = 0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease. Conclusions Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)
TL;DR: It is demonstrated that p53 regulates polarity of cell division in mammary SCs and suggested that loss of p53 favors symmetric divisions of cancer SCs, contributing to tumor growth.
University of Barcelona1, Guy's and St Thomas' NHS Foundation Trust2, Sheba Medical Center3, University of Copenhagen4, University of Debrecen5, University of Milan6, Utrecht University7, Sofia Medical University8, University of Pisa9, Université catholique de Louvain10, Dresden University of Technology11, Pierre-and-Marie-Curie University12
TL;DR: Patients with APS still develop significant morbidity and mortality despite current treatment, and it is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.
Abstract: Objectives: To identify the main causes of morbidity and mortality in patients with antiphospholipid syndrome (APS) during a 5-year period and to determine clinical and immunological parameters with prognostic significance. Methods: The clinical and immunological features of a cohort of 1000 patients with APS from 13 European countries who had been followed up from 1999 to 2004 were analysed. Results: 200 (20%) patients developed APS-related manifestations during the 5-year study period. Recurrent thrombotic events appeared in 166 (16.6%) patients and the most common were strokes (2.4% of the total cohort), transient ischaemic attacks (2.3%), deep vein thromboses (2.1%) and pulmonary embolism (2.1%). When the thrombotic events occurred, 90 patients were receiving oral anticoagulants and 49 were using aspirin. 31/420 (7.4%) patients receiving oral anticoagulants presented with haemorrhage. 3/121 (2.5%) women with only obstetric APS manifestations at the start of the study developed a new thrombotic event. A total of 77 women (9.4% of the female patients) had one or more pregnancies and 63 (81.8% of pregnant patients) had one or more live births. The most common fetal complications were early pregnancy loss (17.1% of pregnancies) and premature birth (35% of live births). 53 (5.3% of the total cohort) patients died. The most common causes of death were bacterial infection (21% of deaths), myocardial infarction (19%) and stroke (13%). No clinical or immunological predictor of thrombotic events, pregnancy morbidity or mortality was detected. Conclusion: Patients with APS still develop significant morbidity and mortality despite current treatment (oral anticoagulants or antiaggregants, or both).
TL;DR: This paper reviews the main issues to be addressed for estimating F from RS observations and applications of the measured F signal at the three scales of observation are presented and discussed to provide the state of the art in F estimation.