Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma

<p>Abstract</p> <p>Background</p> <p>The etiology of hemangiosarcoma remains incompletely understood. Its common occurrence in dogs suggests predisposing factors favor its development in this species. These factors could represent a constellation of heritable characteristics that promote transformation events and/or facilitate the establishment of a microenvironment that is conducive for survival of malignant blood vessel-forming cells. The hypothesis for this study was that characteristic molecular features distinguish hemangiosarcoma from non-malignant endothelial cells, and that such features are informative for the etiology of this disease.</p> <p>Methods</p> <p>We first investigated mutations of VHL and Ras family genes that might drive hemangiosarcoma by sequencing tumor DNA and mRNA (cDNA). Protein expression was examined using immunostaining. Next, we evaluated genome-wide gene expression profiling using the Affymetrix Canine 2.0 platform as a global approach to test the hypothesis. Data were evaluated using routine bioinformatics and validation was done using quantitative real time RT-PCR.</p> <p>Results</p> <p>Each of 10 tumor and four non-tumor samples analyzed had wild type sequences for these genes. At the genome wide level, hemangiosarcoma cells clustered separately from non-malignant endothelial cells based on a robust signature that included genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning. This signature did not simply reflect a cancer-associated angiogenic phenotype, as it also distinguished hemangiosarcoma from non-endothelial, moderately to highly angiogenic bone marrow-derived tumors (lymphoma, leukemia, osteosarcoma).</p> <p>Conclusions</p> <p>The data show that inflammation and angiogenesis are important processes in the pathogenesis of vascular tumors, but a definitive ontogeny of the cells that give rise to these tumors remains to be established. The data do not yet distinguish whether functional or ontogenetic plasticity creates this phenotype, although they suggest that cells which give rise to hemangiosarcoma modulate their microenvironment to promote tumor growth and survival. We propose that the frequent occurrence of canine hemangiosarcoma in defined dog breeds, as well as its similarity to homologous tumors in humans, offers unique models to solve the dilemma of stem cell plasticity and whether angiogenic endothelial cells and hematopoietic cells originate from a single cell or from distinct progenitor cells.</p

Determination of sin2 θeff w using jet charge measurements in hadronic Z decays

The electroweak mixing angle is determined with high precision from measurements of the mean difference between forward and backward hemisphere charges in hadronic decays of the Z. A data sample of 2.5 million hadronic Z decays recorded over the period 1990 to 1994 in the ALEPH detector at LEP is used. The mean charge separation between event hemispheres containing the original quark and antiquark is measured for bb̄ and cc̄ events in subsamples selected by their long lifetimes or using fast D*'s. The corresponding average charge separation for light quarks is measured in an inclusive sample from the anticorrelation between charges of opposite hemispheres and agrees with predictions of hadronisation models with a precision of 2%. It is shown that differences between light quark charge separations and the measured average can be determined using hadronisation models, with systematic uncertainties constrained by measurements of inclusive production of kaons, protons and A's. The separations are used to measure the electroweak mixing angle precisely as sin2 θeff w = 0.2322 ± 0.0008(exp. stat.) ±0.0007(exp. syst.) ± 0.0008(sep.). The first two errors are due to purely experimental sources whereas the third stems from uncertainties in the quark charge separations

Measurement of the W mass by direct reconstruction in e+e−e^+ e^- collisions at 172 GeV

The mass of the W boson is obtained from reconstructed invariant mass distributions in W-pair events. The sample of W pairs is selected from 10.65~pb$^{-1}$ collected with the ALEPH detector at a mean centre-of-mass energy of 172.09 \GEV. The invariant mass distribution of simulated events are fitted to the experimental distributions and the following W masses are obtained: $WW \to q\overline{q}q\overline{q } m_W = 81.30 +- 0.47(stat.) +- 0.11(syst.) GeV/c^2$, $WW \to l\nu q\overline{q}(l=e,\mu) m_W = 80.54 +- 0.47(stat.) +- 0.11(syst.) GeV/c^2$, $WW \to \tau\nu q\overline{q} m_W = 79.56 +- 1.08(stat.) +- 0.23(syst.) GeV/C62$. The statistical errors are the expected errors for Monte Carlo samples of the same integrated luminosity as the data. The combination of these measurements gives: $m_W = 80.80 +- 0.11(syst.) +- 0.03(LEP energy) GeV/^2$

STUDY OF THE 4-FERMION FINAL-STATE AT THE Z-RESONANCE

The process e+e- --> llBARffBAR, where 1 is a charged or a neutral lepton and f any charged fermion, is analyzed. The study uses the ALEPH data collected at LEP from 1989 to 1993 at centre-of-mass energies between 88 and 95 GeV, corresponding to almost two million hadronic Z decays and to a total integrated luminosity of 79 pb-1. For all channels, the data agree well with the standard model expectation both in shape and normalization. The indication of an excess in the e+e- --> tau+ tau- ffBAR channel, reported by ALEPH in 1991, is not confirmed

STUDY OF THE 4-FERMION FINAL-STATE AT THE Z-RESONANCE

The process e+e- --&gt; llBARffBAR, where 1 is a charged or a neutral lepton and f any charged fermion, is analyzed. The study uses the ALEPH data collected at LEP from 1989 to 1993 at centre-of-mass energies between 88 and 95 GeV, corresponding to almost two million hadronic Z decays and to a total integrated luminosity of 79 pb-1. For all channels, the data agree well with the standard model expectation both in shape and normalization. The indication of an excess in the e+e- --&gt; tau+ tau- ffBAR channel, reported by ALEPH in 1991, is not confirmed

PRODUCTION OF CHARMED MESONS IN Z DECAYS

The production of charmed mesons D0(-), D+/-, and D*+/- is studied in a sample of 478,000 hadronic Z decays. The production rates are measured to be GAMMA(Z --> D*+/- X)/GAMMA(had) = 0.187 +/- 0.015 (exp.) +/- 0.013 (BR), GAMMA(Z --> D+/- X) = 0.251 +/- 0.026 (exp.) +/- 0.025 (BR), GAMMA(Z --> D0(-) X)/GAMMA(had) = 0.518 +/- 0.052 (exp.) +/- 0.035 (BR), where the errors from this analysis are separated from those coming from the D branching ratios (BR). The D *+/momentum distribution is extracted separately for Z --> cc and Z --> bbBAR events with the help of event shape variables. It is consistent with the prediction of the JETSET Monte Carlo program after adjustment of the charm fragmentation function. Constraining the shape of the Z --> bbBAR contribution, the average fraction of the beam energy taken by a D* meson produced in the fragmentation of a charm quark is extracted by a parametric fit to be [X(E)]c = 0.495 +/- 0.011 +/- 0.007. Evidence for D**0 (D1(2420)0 and/or D2*(2460)0) production is found in the D*+/-pi-/+ channel, accounting for a fraction (18 +/- 5 +/- 2)% of all D*+/- production. The relative production of vector and pseudoscalar mesons is dicussed, together with the possible effects of D** production. The c-quark forward-backward Z-pole asymmetry is determined from that of high momentum D*+/- to be A(FB)0,c = (7.7 +/- 4.4)%