MicroRNA expression profiling in Imatinib-resistant Chronic Myeloid Leukemia patients without clinically significant ABL1-mutations

The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TK inhibitors, which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML. In this study, we have identified a group of 19 miRNAs that may predict clinical resistance to IM in patients with newly diagnosed CML

Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia

Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-29-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p,0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p = 0.006) and overall survival (OS) (p = 0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Quantum state preparation and macroscopic entanglement in gravitational-wave detectors

Long-baseline laser-interferometer gravitational-wave detectors are operating at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within a broad frequency band. Such a low classical noise budget has already allowed the creation of a controlled 2.7 kg macroscopic oscillator with an effective eigenfrequency of 150 Hz and an occupation number of 200. This result, along with the prospect for further improvements, heralds the new possibility of experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical behavior of objects in the realm of everyday experience - using gravitational-wave detectors. In this paper, we provide the mathematical foundation for the first step of a MQM experiment: the preparation of a macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum state, which is possible if the interferometer's classical noise beats the SQL in a broad frequency band. Our formalism, based on Wiener filtering, allows a straightforward conversion from the classical noise budget of a laser interferometer, in terms of noise spectra, into the strategy for quantum state preparation, and the quality of the prepared state. Using this formalism, we consider how Gaussian entanglement can be built among two macroscopic test masses, and the performance of the planned Advanced LIGO interferometers in quantum-state preparation

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286

Mediation of coffee-induced improvements in human vascular function by chlorogenic acids and its metabolites: two randomized, controlled, crossover intervention trials

Background & aims Polyphenol intake has been linked to improvements in human vascular function, although data on hydroxycinnamates, such as chlorogenic acid (CGA) have not yet been studied. We aimed to investigate the impact of coffee intake rich in chlorogenic acid on human vascular function and whether CGAs are involved in potential effects. Methods Two acute randomized, controlled, cross-over human intervention trials were conducted. The impact of coffee intake, matched for caffeine but differing in CGA content (89, and 310 mg) on flow-mediated dilation (FMD) was assessed in 15 healthy male subjects. In a second intervention trial conducted with 24 healthy male subjects, the impact of pure 5-caffeoylquinic acid (5-CQA), the main CGA in coffee (5-CQA; 450 mg and 900 mg) on FMD was also investigated. Results We observed a bi-phasic FMD response after low and high polyphenol, (89 mg and 310 mg CGA) intake, with increases at 1 (1.10 ± 0.43% and 1.34 ± 0.62%, respectively) and 5 (0.79% ± 0.32 and 1.52% ± 0.40, respectively) hours post coffee consumption. FMD responses to coffee intake was closely paralleled by the appearance of CGA metabolites in plasma, notably 3-, 4- and 5-CQA and ferulic-4′-O-sulfate at 1 h and isoferulic-4′-O-glucuronide and ferulic-4′-O-sulfate at 5 h. Intervention with purified 5-CQA (450 mg) also led to an improvement in FMD response relative to control (0.75 ± 1.31% at 1 h post intervention, p = 0.06) and concomitant appearance of plasma metabolites. Conclusions Coffee intake acutely improves human vascular function, an effect, in part, mediated by 5-CQA and its physiological metabolites

Proteomic profiling of stallion spermatozoa suggests changes in sperm metabolism and compromised redox regulation after cryopreservation

Proteomic technologies allow the detection of thousands of proteins at the same time, being a powerful technique to reveal molecular regulatory mechanisms in spermatozoa and also sperm damage linked to low fertility or specific biotechnologies. Modifications induced by the cryopreservation in the stallion sperm proteome were studied using UHPLC/MS/MS. Ejaculates from fertile stallions were collected and split in two subsamples, one was investigated as fresh (control) samples, and the other aliquot frozen and thawed using standard procedures and investigated as frozen thawed subsamples. UHPLC/MS/MS was used to study the sperm proteome under these two distinct conditions and bioinformatic enrichment analysis conducted. Gene Ontology (GO) and pathway enrichment analysis were performed revealing dramatic changes as consequence of cryopreservation. The terms oxidative phosphorylation, mitochondrial ATP synthesis coupled electron transport and electron transport chain were significantly enriched in fresh samples (P = 5.50 × 10−12, 4.26 × 10−8 and 7.26 × 10–8, respectively), while were not significantly enriched in frozen thawed samples (P = 1). The GO terms oxidation reduction process and oxidoreductase activity were enriched in fresh samples and the enrichment was reduced in frozen thawed samples (1.40 × 10−8, 1.69 × 10−6 versus 1.13 × 10−2 and 2-86 × 10−2 respectively). Reactome pathways (using human orthologs) significantly enriched in fresh sperm were TCA cycle and respiratory electron transport (P = 1.867 × 10−8), Respiratory electron transport ATP synthesis by chemiosmosis coupling (P = 2.124 × 10−5), Citric acid cycle (TCA cycle)(P = 8.395 × 10−4) Pyruvate metabolism and TCA cycle (P = 3.380 × 10−3), Respiratory electron transport (P = 2.764 × 10−2) and Beta oxidation of laurolyl-CoA to decanoyl CoA-CoA (P = 1.854 × 10−2) none of these pathways were enriched in thawed samples (P = 1). We have provided the first detailed study on how the cryopreservation process impacts the stallion sperm proteome. Our findings identify the metabolic proteome and redoxome as the two key groups of proteins affected by the procedure. Significance: In the present manuscript we investigated how the cryopreservation of stallion spermatozoa impacts the proteome of these cells. This procedure is routinely used in horse breeding and has a major impact in the industry, facilitating the trade of genetic material. This is still a suboptimal biotechnology, with numerous unresolved problems. The limited knowledge of the molecular insults occurring during cryopreservation is behind these problems. The application and development of proteomics to the spermatozoa, allow to obtain valuable information of the specific mechanisms affected by the procedure. In this paper, we report that cryopreservation impacts numerous proteins involved in metabolism regulation (mainly mitochondrial proteins involved in the TCA cycle, and oxidative phosphorylation) and also affects proteins with oxidoreductase activity. Moreover, specific proteins involved in the sperm-oocyte interaction are also affected by the procedure. The information gathered in this study, opens interesting questions and offer new lines of research for the improvement of the technology focusing the targets here identified, and the specific steps in the procedure (cooling, toxicity of antioxidants etc.) to be modified to reduce the damage

Measurement of charm production at central rapidity in proton-proton collisions at s=2.76\sqrt{s} = 2.76 TeV

The $p_{\rm T}$-differential production cross sections of the prompt (B feed-down subtracted) charmed mesons D$^0$, D$^+$, and D$^{*+}$ in the rapidity range $|y|<0.5$, and for transverse momentum $1< p_{\rm T} <12$ GeV/$c$, were measured in proton-proton collisions at $\sqrt{s} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. The analysis exploited the hadronic decays D$^0 \rightarrow$K$\pi$, D$^+ \rightarrow$K$\pi\pi$, D$^{*+} \rightarrow$D$^0\pi$, and their charge conjugates, and was performed on a $L_{\rm int} = 1.1$ nb$^{-1}$ event sample collected in 2011 with a minimum-bias trigger. The total charm production cross section at $\sqrt{s} = 2.76$ TeV and at 7 TeV was evaluated by extrapolating to the full phase space the $p_{\rm T}$-differential production cross sections at $\sqrt{s} = 2.76$ TeV and our previous measurements at $\sqrt{s} = 7$ TeV. The results were compared to existing measurements and to perturbative-QCD calculations. The fraction of cdbar D mesons produced in a vector state was also determined.Comment: 20 pages, 5 captioned figures, 4 tables, authors from page 15, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/307

Transverse sphericity of primary charged particles in minimum bias proton-proton collisions at s=0.9\sqrt{s}=0.9, 2.76 and 7 TeV

Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at $\sqrt{s}=0.9$, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with $p_{\rm T}\geq0.5$ GeV/c in $|\eta|\leq0.8$. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity ($N_{\rm ch}$) is reported for events with different $p_{\rm T}$ scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low $N_{\rm ch}$, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean $p_{\rm T}$ with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.Comment: 21 pages, 9 captioned figures, 3 tables, authors from page 16, published version, figures from http://aliceinfo.cern.ch/ArtSubmission/node/308