Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB-VCAM-1 axis

Vascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months' storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis

A bile-based microRNA signature for differentiating malignant from benign pancreaticobiliary disease

Differentiating between pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) is crucial for the appropriate course of treatment, especially with advancements in the role of neoadjuvant chemotherapies for PDAC, compared to CCA. Furthermore, benign pancreaticobiliary diseases can mimic malignant disease, and indeterminate lesions may require repeated investigations to achieve a diagnosis. As bile flows in close proximity to these lesions, we aimed to establish a bile-based microRNA (miRNA) signature to discriminate between malignant and benign pancreaticobiliary diseases. We performed miRNA discovery by global profiling of 800 miRNAs using the NanoString nCounter platform in prospectively collected bile samples from malignant (n = 43) and benign (n = 14) pancreaticobiliary disease. Differentially expressed miRNAs were validated by RT-qPCR and further assessed in an independent validation cohort of bile from malignant (n = 37) and benign (n = 38) pancreaticobiliary disease. MiR-148a-3p was identified as a discriminatory marker that effectively distinguished malignant from benign pancreaticobiliary disease in the discovery cohort (AUC = 0.797 [95% CI 0.68–0.92]), the validation cohort (AUC = 0.772 [95% CI 0.66–0.88]), and in the combined cohorts (AUC = 0.752 [95% CI 0.67–0.84]). We also established a two-miRNA signature (miR-125b-5p and miR-194-5p) that distinguished PDAC from CCA (validation: AUC = 0.815 [95% CI 0.67–0.96]; and combined cohorts: AUC = 0.814 [95% CI 0.70–0.93]). Our research stands as the largest, multicentric, global profiling study of miRNAs in the bile from patients with pancreaticobiliary disease. We demonstrated their potential as clinically useful diagnostic tools for the detection and differentiation of malignant pancreaticobiliary disease. These bile miRNA biomarkers could be developed to complement current approaches for diagnosing pancreaticobiliary cancers. Graphical Abstract: [Figure not available: see fulltext.

Search for R-parity violating supersymmetry via the LLE couplings lambda_{121}, lambda_{122} or lambda_{133} in ppbar collisions at sqrt(s)=1.96 TeV

A search for gaugino pair production with a trilepton signature in the framework of R-parity violating supersymmetry via the couplings lambda_121, lambda_122, or lambda_133 is presented. The data, corresponding to an integrated luminosity of L~360/pb, were collected from April 2002 to August 2004 with the D0 detector at the Fermilab Tevatron Collider, at a center-of-mass energy of sqrt(s)=1.96 TeV. This analysis considers final states with three charged leptons with the flavor combinations eel, mumul, and eetau (l=e or mu). No evidence for supersymmetry is found and limits at the 95% confidence level are set on the gaugino pair production cross section and lower bounds on the masses of the lightest neutralino and chargino are derived in two supersymmetric models.Comment: 9 pages, 4 figures (fig2 includes 3 subfigures

Measurement of the Bs0B^{0}_{s} Lifetime Using Semileptonic Decays

We report a measurement of the $B^0_{s}$ lifetime in the semileptonic decay channel $B^0_{s}\to D^-_s \mu^{+}\nu X$ (and its charge conjugate), using approximately 0.4 fb$^{-1}$ of data collected with the D0 detector during 2002 -- 2004. We have reconstructed 5176 $D^-_s \mu^{+}$ signal events, where the $D_s^-$ is identified via the decay $D_s^-\to \phi\pi^-$, followed by $\phi\to K^+ K^-$. Using these events, we have measured the $B^0_s$ lifetime to be $\tau(B^0_{s}) = 1.398 \pm 0.044$ $({stat}) ^{+0.028}_{-0.025}$ $({syst}) {ps}$. This is the most precise measurement of the $B_s^0$ lifetime to date.Comment: To appear in Phys. Rev. Lett., 7 pages, 2 figure

Measurement of the Lifetime Difference in the B_s^0 System

We present a study of the decay B_s^0 -> J/psi phi We obtain the CP-odd fraction in the final state at time zero, R_perp = 0.16 +/- 0.10 (stat) +/- 0.02 (syst), the average lifetime of the (B_s, B_sbar) system, tau (B_s^0) =1.39^{+0.13}_{-0.16} (stat) ^{+0.01}_{-0.02} (syst) ps, and the relative width difference between the heavy and light mass eigenstates, Delta Gamma/Gamma = (Gamma_L - Gamma_H)/Gamma =0.24^{+0.28}_{-0.38} (stat) ^{+0.03}_{-0.04} (syst). With the additional constraint from the world average of the B_s^0$lifetime measurements using semileptonic decays, we find tau (B_s^0)= 1.39 +/- 0.06 ~ps and Delta Gamma/\Gamma = 0.25^{+0.14}_{-0.15}. For the ratio of the B_s^0 and B^0 lifetimes we obtain tau(B_s^0)/tau(B^0)} = 0.91 +/- 0.09 (stat) +/- 0.003 (syst).Comment: submitted to Phys. Rev. Lett. FERMILAB-PUB-05-324-

Measurement of Semileptonic Branching Fractions of B Mesons to Narrow D** States

Using the data accumulated in 2002-2004 with the DO detector in proton-antiproton collisions at the Fermilab Tevatron collider with centre-of-mass energy 1.96 TeV, the branching fractions of the decays B -> \bar{D}_1^0(2420) \mu^+ \nu_\mu X and B -> \bar{D}_2^{*0}(2460) \mu^+ \nu_\mu X and their ratio have been measured: BR(\bar{b}->B) \cdot BR(B-> \bar{D}_1^0 \mu^+ \nu_\mu X) \cdot BR(\bar{D}_1^0 -> D*- pi+) = (0.087+-0.007(stat)+-0.014(syst))%; BR(\bar{b}->B)\cdot BR(B->D_2^{*0} \mu^+ \nu_\mu X) \cdot BR(\bar{D}_2^{*0} -> D*- \pi^+) = (0.035+-0.007(stat)+-0.008(syst))%; and (BR(B -> \bar{D}_2^{*0} \mu^+ \nu_\mu X)BR(D2*0->D*- pi+)) / (BR(B -> \bar{D}_1^{0} \mu^+ \nu_\mu X)\cdot BR(\bar{D}_1^{0}->D*- \pi^+)) = 0.39+-0.09(stat)+-0.12(syst), where the charge conjugated states are always implied.Comment: submitted to Phys. Rev. Let

A search for W bb and W Higgs production in ppbar collisions at sqrt(s)=1.96 TeV

We present a search for W b \bar{b} production in p \bar{p} collisions at sqrt{s}=1.96 TeV in events containing one electron, an imbalance in transverse momentum, and two b-tagged jets. Using 174 pb-1 of integrated luminosity accumulated by the D0 experiment at the Fermilab Tevatron collider, and the standard-model description of such events, we set a 95% C.L. upper limit on W b \bar{b}$production of 6.6 pb for b quarks with transverse momenta p_T^b > 20 GeV and b \bar{b} separation in pseudorapidity-azimuth space Delta R_bb > 0.75. Restricting the search to optimized b \bar{b} mass intervals provides upper limits on$WH$production of 9.0$-$12.2 pb, for Higgs-boson masses of 105$-$135 GeV.Comment: 7 pages, 4 figures, 1 table, submitted to Physical Review Letter

Measurement of the ppbar to ttbar production cross section at sqrt(s)=1.96 TeV in the fully hadronic decay channel

A measurement of the top quark pair production cross section in proton anti-proton collisions at an interaction energy of sqrt(s)=1.96 TeV is presented. This analysis uses 405 pb-1 of data collected with the D0 detector at the Fermilab Tevatron Collider. Fully hadronic ttbar decays with final states of six or more jets are separated from the multijet background using secondary vertex tagging and a neural network. The ttbar cross section is measured as sigma(ttbar)=4.5 -1.9 +2.0 (stat) -1.1 +1.4 (syst) +/- 0.3 (lumi) pb for a top quark mass of m(t) = 175 GeV/c^2.Comment: 10 pages, 10 figures, submitted to Phys. Rev.

Search for Neutral Higgs Bosons Decaying to Tau Pairs in p-pbar Collisions at sqrt(s) = 1.96 TeV

A search for the production of neutral Higgs bosons Phi decaying into tau^+tau^- final states in p-pbar collisions at a center-of-mass energy of 1.96 TeV is presented. The data, corresponding to an integrated luminosity of up to 348 pb^-1, were collected by the D0 experiment at the Fermilab Tevatron Collider. Since no excess compared to the expectation from standard model processes is found, limits on the production cross section times branching ratio are set. The results are combined with those obtained from the D0 search for Phi b(b) to b-bbar-b(bbar) and are interpreted in the minimal supersymmetric standard model.Comment: Version accpeted by Phys. Rev. Lett. (minor changes

Search for the Rare Decay B0_s -> phi mu^+ mu- with the D0 Detector

We present a search for the flavor-changing neutral current decay B0_s -> phi mu+ mu- using about 0.45 fb^-1 of data collected in p \bar p collisions at sqrt{s} =1.96 TeV with the D{\O}detector at the Fermilab Tevatron Collider. We find an upper limit on the branching ratio of this decay normalized to B0_s -> J/psi phi of B(B0_s -> phi mu+ mu-)/B(B0_s -> J/psi phi) < 4.4\times 10^{-3} at the 95% C.L. Using the central value of the world average branching fraction of B0_s -> J/psi phi, the limit corresponds to B(B0_s -> phi mu+ mu-) < 4.1 \times 10^{-6} at the 95% C.L., the most stringent upper bound to date.Comment: 7 pages, 2 figures, LaTeX, to be submitted to Physical Review Letter