Severe Aortic Stenosis and Myocardial Function: Diagnostic and Prognostic Usefulness of Ultrasonic Integrated Backscatter Analysis

Background— The aim of this study was to assess the myocardial reflectivity pattern in severe aortic valve stenosis through the use of integrated backscatter (IBS) analysis. Patients with aortic stenosis (AS) were carefully selected in the Department of Cardiology. Methods and Results— Thirty-five subjects (AS: valve orifice ≤1 cm2; 12 female; mean age, 71.8±6.2 years) and 25 healthy subjects were studied. All subjects of the study had conventional 2D-Doppler echocardiography and IBS. Backscatter signal was sampled at the septum and posterior wall levels. Patients with AS were divided into 2 groups: 16 patients with initial signs of congestive heart failure and a depressed left ventricular systolic function (DSF) (ejection fraction [EF] range, 35% to 50%) and 19 asymptomatic patients with normal left ventricular systolic function (NSF) (EF >50%). Myocardial echo intensity (pericardium related) was significantly higher at the septum and posterior wall levels in DSF than in NSF and in control subjects. IBS variation, as an expression of variation of the signal, appeared to be significantly lower in AS with DSF than in NSF and in control subjects, at both the septum and posterior wall levels. Patients with DSF underwent aortic valve replacement, and, during surgical intervention, a septal myocardial biopsy was made for evaluation of myocardium/fibrosis ratio. Abnormally increased echo intensity was detected in left ventricular pressure overload by severe aortic stenosis and correlated with increase of myocardial collagen content (operating biopsy). Conclusions— One year after aortic valve replacement, we observed a significant reduction of left ventricular mass, and, only if pericardial indexed IBS value (reduction of interstitial fibrosis) decreased, it was possible to observe an improvement of EF and of IBS variation

The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma

Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0–2.5 μM) of OCA were added to culture media and, after 3–10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 μM. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients

Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS

A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2)31 repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2)31 repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS

Novel analgesic/anti-inflammatory agents: 1,5-diarylpyrrole nitrooxyalkyl ethers and related compounds as cyclooxygenase-2 inhibiting nitric oxide donors

A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed

Photographic detection of Cadmium(II) and Zinc(II) ions

The binding properties of two 2,8-dithia-5-aza-2,6-pyridinophane-based ligands, bearing respectively coumarin (HNCum) and naphthol-benzoxaazole (HNBO) optically active units as pendant arms, were studied with the aim of transition metal cations selective detection. The novel all-solid-state optodes were obtained by inclusion of fluorophores inside PVC-based polymeric films. The influence of lipophilic sites incorporation and plasticizer nature on pyridinophane-based optodes response was investigated. An enhanced selectivity of the ligands towards Cadmium(II) and Zinc(II) ions was detected. Light Emitting Diode, LED 380 nm, was used as light source, and a digital camera as a signal detector. The results obtained demonstrated the suitability of the developed optodes to perform fast and low cost simultaneous monitoring of Zn2+and Cd2+ ions by means of familiar devices and chemometrics. © 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license

Measurement of B(B-->X_s {\gamma}), the B-->X_s {\gamma} photon energy spectrum, and the direct CP asymmetry in B-->X_{s+d} {\gamma} decays

The photon spectrum in B --> X_s {\gamma} decay, where X_s is any strange hadronic state, is studied using a data sample of (382.8\pm 4.2) \times 10^6 e^+ e^- --> \Upsilon(4S) --> BBbar events collected by the BABAR experiment at the PEP-II collider. The spectrum is used to measure the branching fraction B(B --> X_s \gamma) = (3.21 \pm 0.15 \pm 0.29 \pm 0.08)\times 10^{-4} and the first, second, and third moments = 2.267 \pm 0.019 \pm 0.032 \pm 0.003 GeV,, )^2> = 0.0484 \pm 0.0053 \pm 0.0077 \pm 0.0005 GeV^2, and )^3> = -0.0048 \pm 0.0011 \pm 0.0011 \pm 0.0004 GeV^3, for the range E_\gamma > 1.8 GeV, where E_{\gamma} is the photon energy in the B-meson rest frame. Results are also presented for narrower E_{\gamma} ranges. In addition, the direct CP asymmetry A_{CP}(B --> X_{s+d} \gamma) is measured to be 0.057 \pm 0.063. The spectrum itself is also unfolded to the B-meson rest frame; that is the frame in which theoretical predictions for its shape are made.Comment: 37 pages, 19 postscript figures, submitted to Phys. Rev. D. No analysis or results have changed from previous version. Some changes to improve clarity based on interactions with Phys. Rev. D referees, including one new Figure (Fig. 13), and some minor wording/punctuation/spelling mistakes fixe

Measurement of the Time-Dependent CP Asymmetry of Partially Reconstructed B0->D*+D*- Decays

We present a new measurement of the time-dependent CP asymmetry of B0->D*+D*- decays using (471+-5) million BBbar pairs collected with the BaBar detector at the PEP-II B Factory at the SLAC National Accelerator Laboratory. Using the technique of partial reconstruction, we measure the time-dependent CP asymmetry parameters S=-0.34+-0.12+-0.05$ and C=+0.15+-0.09+-0.04. Using the value for the CP-odd fraction R_perp=0.158+-0.028+-0.006, previously measured by BaBar with fully reconstructed B0->D*+D*- events, we extract the CP-even components S+=-0.49+-0.18+-0.07+-0.04 and C+=+0.15+-0.09+-0.04. In each case, the first uncertainty is statistical and the second is systematic; the third uncertainty on S+ is the contribution from the uncertainty on R_perp. The measured value of the CP-even component S+ is consistent with the value of sin(2Beta) measured in b->(ccbar)s transitions, and with the Standard Model expectation of small penguin contributions.Comment: 17 pages, 7 figures, submitted to Physical Review

Search for lepton-number violating processes in B+ -> h- l+ l+ decays

We have searched for the lepton-number violating processes B+ -> h- l+ l+ with h- = K-/pi- and l+ = e+/mu+, using a sample of 471+/-3 million BBbar events collected with the BaBar detector at the PEP-II e+e- collider at the SLAC National Accelerator Laboratory. We find no evidence for these decays and place 90% confidence level upper limits on their branching fractions Br(B+ -> pi- e+ e+) K- e+ e+) pi- mu+ mu+) K- mu+ mu+) < 6.7 x 10^{-8}.Comment: 8 pages, 4 postscript figures, submitted to Phys. Rev. D. R

Measurement of CP Asymmetries and Branching Fractions in Charmless Two-Body B-Meson Decays to Pions and Kaons

We present improved measurements of CP-violation parameters in the decays $B^0 \to \pi^+ \pi^-$, $B^0 \to K^+ \pi^-$, and $B^0 \to \pi^0 \pi^0$, and of the branching fractions for $B^0 \to \pi^0 \pi^0$ and $B^0 \to K^0 \pi^0$. The results are obtained with the full data set collected at the $\Upsilon(4S)$ resonance by the BABAR experiment at the PEP-II asymmetric-energy $B$ factory at the SLAC National Accelerator Laboratory, corresponding to $467 \pm 5$ million $B\bar B$ pairs. We find the CP-violation parameter values and branching fractions $S_{\pi^+\pi^-} = -0.68 \pm 0.10 \pm 0.03, C_{\pi^+\pi^-} = -0.25 \pm 0.08 \pm 0.02, A_{K^-\pi^+} = -0.107 \pm 0.016 ^{+0.006}_{-0.004}, C_{\pi^0\pi^0} = -0.43 \pm 0.26 \pm 0.05, Br(B^0 \to \pi^0 \pi^0) = (1.83 \pm 0.21 \pm 0.13) \times 10^{-6}, Br(B^0 \to K^0 \pi^0) = (10.1 \pm 0.6 \pm 0.4) \times 10^{-6},$ where in each case, the first uncertainties are statistical and the second are systematic. We observe CP violation with a significance of 6.7 standard deviations for $B^0 \to\pi^+\pi^-$ and 6.1 standard deviations for $B^0 \to K^+ \pi^-$, including systematic uncertainties. Constraints on the Unitarity Triangle angle $\alpha$ are determined from the isospin relations among the $B \to \pi\pi$ rates and asymmetries. Considering only the solution preferred by the Standard Model, we find $\alpha$ to be in the range $[71^\circ,109^\circ]$ at the 68% confidence level.Comment: 18 pages, 11 postscript figures, submitted to Phys. Rev.

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde