Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment

Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation

A search for charged massive long-lived particles

We report on a search for charged massive long-lived particles (CMLLPs), based on 5.2 fb$^{-1}$ of integrated luminosity collected with the D0 detector at the Fermilab Tevatron $p\bar{p}$ collider. We search for events in which one or more particles are reconstructed as muons but have speed and ionization energy loss $(dE/dx)$ inconsistent with muons produced in beam collisions. CMLLPs are predicted in several theories of physics beyond the standard model. We exclude pair-produced long-lived gaugino-like charginos below 267 GeV and higgsino-like charginos below 217 GeV at 95% C.L., as well as long-lived scalar top quarks with mass below 285 GeV.Comment: submitted to Phys. Rev. Letter

Zgamma production and limits on anomalous ZZgamma and Zgammagamma couplings in ppbar collisions at sqrt(s)=1.96 TeV

We present a measurement of ppbar->Zgamma->ll+gamma (l = e, mu) production with a data sample corresponding to an integrated luminosity of 6.2 fb^{-1} collected by the D0 detector at the Fermilab Tevatron ppbar Collider. The results of the electron and muon channels are combined, and we measure the total production cross section and the differential cross section dsigma/dp_T^gamma, where p_T^gamma is the momentum of the photon in the plane transverse to the beamline. The results obtained are consistent with the standard model predictions from next-to-leading order calculations. We use the transverse momentum spectrum of the photon to place limits on anomalous ZZgamma and Zgammagamma couplings

Search for a Narrow ttbar Resonance in ppbar Collisions at sqrt{s}=1.96 TeV

We report a search for a narrow ttbar resonance that decays into a lepton+jets final state based on an integrated luminosity of 5.3/fb of proton-antiproton collisions at sqrt{s}=1.96 TeV collected by the D0 Collaboration at the Fermilab Tevatron Collider. We set upper limits on the production cross section of such a resonance multiplied by its branching fraction to ttbar which we compare to predictions for a leptophobic topcolor Z' boson. We exclude such a resonance at the 95% confidence level for masses below 835 GeV.Comment: 7 pages, 3 figures, submitted to Physical Review Letter

Search for B0→π0π0B^{0}\to \pi^{0}\pi^{0} Decay

We have searched for the charmless hadronic decay of B0 mesons into two neutral pions. Using 9.13fb^-1 taken at the Upsilon(4S) with the CLEO detector, we obtain an improved upper limit for the branching fraction BR(B0-->pi0pi0) < 5.7*10^-6 at the 90% confidence level.Comment: pages postscript, also available through http://w4.lns.cornell.edu/public/CLN

Search for Zgamma events with large missing transverse energy in ppbar collisions at sqrt(s)=1.96 TeV

We present the first search for supersymmetry (SUSY) in Zgamma final states with large missing transverse energy using data corresponding to an integrated luminosity of 6.2 fb-1 collected with the D0 experiment in ppbar collisions at sqrt(s)=1.96 TeV. This signature is predicted in gauge-mediated SUSY-breaking models, where the lightest neutralino is the next-to-lightest supersymmetric particle (NLSP) and is produced in pairs, possibly through decay from heavier supersymmetric particles. The NLSP can decay either to a Z boson or a photon and an associated gravitino that escapes detection. We exclude this model at the 95% C.L. for SUSY breaking scales of Lambda < 87 TeV, corresponding to neutralino masses of < 151 GeV.Comment: submitted to Phys. Rev. Let

Search for WHWH associated production in ppˉp \bar{p} collisions at s=1.96 TeV\sqrt{s}=1.96\,{\rm TeV}

This report describes a search for associated production of $W$ and Higgs bosons based on data corresponding to an integrated luminosity of $\cal{L}$$\approx 5.3 \rm fb^{-1}$ collected with the D0 detector at the Fermilab Tevatron $p\bar{p}$ Collider. Events containing a $W\rightarrow \ell \nu$ candidate (with $\ell$ corresponding to $e$ or $\mu$) are selected in association with two or three reconstructed jets. One or two of the jets are required to be consistent with having evolved from a $b$ quark. A multivariate discriminant technique is used to improve the separation of signal and backgrounds. Expected and observed upper limits are obtained for the product of the $WH$ production cross section and branching ratios and reported in terms of ratios relative to the prediction of the standard model as a function of the mass of the Higgs boson ($M_{H}$). The observed and expected 95% C.L. upper limits obtained for an assumed $M_{H}=115 \rm GeV$ are, respectively, factors of 4.5 and 4.8 larger than the value predicted by the standard model.Comment: 25 pages, 14 figure

Measurements of single top quark production cross sections and |Vtb| in ppbar collisions at sqrt{s}=1.96 TeV

We present measurements of production cross sections of single top quarks in \ppbar collisions at $\sqrt{s}=1.96\;\rm TeV$ in a data sample corresponding to an integrated luminosity of $5.4\;\rm fb^{-1}$ collected by the D0 detector at the Fermilab Tevatron Collider. We select events with an isolated electron or muon, an imbalance in transverse energy, and two, three, or four jets, with one or two of them containing a bottom hadron. We obtain an inclusive cross section of \sigma({\ppbar}{\rargap}tb+X, tqb+X) = 3.43\pm^{0.73}_{0.74}\;\rm pb and use it to extract the CKM matrix element $0.79 < |V_{tb}| \leq 1$ at the 95% C.L. We also measure \sigma({\ppbar}{\rargap}tb+X) = 0.68\pm^{0.38}_{0.35}\;\rm pb and \sigma({\ppbar}{\rargap}tqb+X) = 2.86\pm^{0.69}_{0.63}\;\rm pb when assuming, respectively, $tqb$ and $tb$ production rates as predicted by the standard model.Comment: 11 pages, 8 figures, submitted to Phys. Rev.

Measurement of Leptonic Asymmetries and Top Quark Polarization in ttbar Production

We present measurements of lepton (l) angular distributions in ttbar -> W+ b W- b -> l+ nu b l- nubar bbar decays produced in ppbar collisions at a center-of-mass energy of sqrt(s)=1.96TeV, where l is an electron or muon. Using data corresponding to an integrated luminosity of 5.4fb^-1, collected with the D0 detector at the Fermilab Collider, we find that the angular distributions of l- relative to anti-protons and l+ relative to protons are in agreement with each other. Combining the two distributions and correcting for detector acceptance we obtain the forward-backward asymmetry A^l_FB = (5.8 +- 5.1(stat) +- 1.3(syst))%, compared to the standard model prediction of A^l_FB (predicted) = (4.7 +- 0.1)%. This result is further combined with the measurement based on the analysis of the l+jets final state to obtain A^l_FB = (11.8 +- 3.2)%. Furthermore, we present a first study of the top-quark polarization.Comment: submitted versio