Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis

Background: ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues. Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV. less thanbrgreater than less thanbrgreater thanMethods: Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS. Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA. Expression of pro/anti-apoptotic factors, transcription factors C/EBP-alpha, C/EBP-beta and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR. less thanbrgreater than less thanbrgreater thanResults: AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50 +/- 14% vs. HBD 64 +/- 11%, p andlt; 0.0001). In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1. AASV patients had normal levels of G-CSF, GM-CSF and IL-3. Both C/EBP-alpha, C/EBP-beta were significantly higher in neutrophils from AASV patients than HBD. Levels of sFAS were significantly higher in AASV compared to HBD. less thanbrgreater than less thanbrgreater thanConclusion: Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ. Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV. Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.Funding Agencies|Swedish Research Council|71X-15152|Crafoord Foundation||</p

Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival

<p>Abstract</p> <p>Background</p> <p>The JAK2^V617Fmutation plays a major role in the pathogenesis of myeloproliferative neoplasms and is found in the vast majority of patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia or from primary myelofibrosis. The V617F mutation is thought to provide hematopoietic stem cells and myeloid progenitors with a survival and proliferation advantage. It has previously been shown that activated JAK2 promotes cell survival by upregulating the anti-apoptotic STAT5 target gene Bcl-xL. In this study, we have investigated the role of additional apoptotic players, the pro-apoptotic protein Bim as well as the anti-apoptotic protein Mcl-1.</p> <p>Methods</p> <p>Pharmacological inhibition of JAK2/STAT5 signaling in JAK2^V617Fmutant SET-2 and MB-02 cells was used to study effects on signaling, cell proliferation and apoptosis by Western blot analysis, WST-1 proliferation assays and flow cytometry. Cells were transfected with siRNA oligos to deplete candidate pro- and anti-apoptotic proteins. Co-immunoprecipitation assays were performed to assess the impact of JAK2 inhibition on complexes of pro- and anti-apoptotic proteins.</p> <p>Results</p> <p>Treatment of JAK2^V617Fmutant cell lines with a JAK2 inhibitor was found to trigger Bim activation. Furthermore, Bim depletion by RNAi suppressed JAK2 inhibitor-induced cell death. Bim activation following JAK2 inhibition led to enhanced sequestration of Mcl-1, besides Bcl-xL. Importantly, Mcl-1 depletion by RNAi was sufficient to compromise JAK2^V617Fmutant cell viability and sensitized the cells to JAK2 inhibition.</p> <p>Conclusions</p> <p>We conclude that Bim and Mcl-1 have key opposing roles in regulating JAK2^V617Fcell survival and propose that inactivation of aberrant JAK2 signaling leads to changes in Bim complexes that trigger cell death. Thus, further preclinical evaluation of combinations of JAK2 inhibitors with Bcl-2 family antagonists that also tackle Mcl-1, besides Bcl-xL, is warranted to assess the therapeutic potential for the treatment of chronic myeloproliferative neoplasms.</p

Measurement of correlated μ−overlineb\mu - {overline b} jet cross sections in ppˉp {\bar p} collisions at s=1.8\sqrt{s}=1.8 TeV

We report on measurements of differential $\mu - {\bar b}$ cross sections, where the muon is from a semi-leptonic $b$ decay and the ${\bar b}$ is identified using precision track reconstruction in jets. The semi-differential correlated cross sections, d$\sigma$/d\Et^{{\bar b}}, d$\sigma$/d\pt^{{\bar b}}, and d$\sigma$/d$\delta\phi(\mu - {\bar b})$ for \pt^{\mu}>~9 GeV/c, $|\eta^{\mu}|$~10 GeV, $|\eta^{{\bar b}}|<$~1.5, are presented and compared to next-to-leading order QCD calculations.Comment: Uses Latex, Article 12 point, figures appended as uuencoded file The full PostScript available via WWW at http://www-cdf.fnal.gov/physics/pub95/cdf3164_mu_bbar_prd_final.p

Measurement of the BB Meson Differential Cross Section, dσ/dpTd\sigma/dp_T, in ppˉp\bar{p} Collisions at s=1.8\sqrt{s} = 1.8 TeV

This paper presents the first direct measurement of the $B$ meson differential cross section, $d\sigma/dp_T$, in $p\bar{p}$ collisions at $\sqrt{s}=1.8$ TeV using a sample of $19.3 \pm 0.7$ pb$^{-1}$ accumulated by the Collider Detector at Fermilab (CDF). The cross section is measured in the central rapidity region $|y| 6.0$ GeV/$c$ by fully reconstructing the $B$ meson decays $B^{+}\to J/\psi K^{+}$ and $B^{0}\to J/\psi K^{*0}(892)$, where $J/\psi \to \mu^+\mu^-$ and $K^{*0} \to K^+ \pi^-$. A comparison is made to the theoretical QCD prediction calculated at next-to-leading order.Comment: 14 pages. Submitted to Phys. Rev. Lett. The postscript file is at http://www-cdf.fnal.gov/physics/pub95/cdf2893_bexcl_xsection.p

Search for New Particles Decaying to Dijets in p-pbar Collisions at sqrt(s)=1.8 TeV

We have used 19 pb**-1 of data collected with the Collider Detector at Fermilab to search for new particles decaying to dijets. We exclude at 95% confidence level models containing the following new particles: axigluons with mass between 200 and 870 GeV, excited quarks with mass between 80 and 570 GeV, and color octet technirhos with mass between 320 and 480 GeV.Comment: Submitted to Physical Review Letters in December 199

Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype

Purpose Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach. Methods Whole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays. Results We identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70. Conclusion This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching

Measurement of σ⋅B(W→eν)\sigma \cdot B (W \to e \nu) and σ⋅B(Z0→e+e−)\sigma \cdot B(Z^0 \to e^+e^-) in ppˉp {\bar p} collisions at s=1.8\sqrt{s}=1.8 TeV

We present a measurement of $\sigma \cdot B(W \to e \nu)$ and $\sigma \cdot B(Z^0 \to e^+e^-)$ in proton - antiproton collisions at $\sqrt{s} =1.8$ TeV using a significantly improved understanding of the integrated luminosity. The data represent an integrated luminosity of 19.7 pb$^{-1}$ from the 1992-1993 run with the Collider Detector at Fermilab (CDF). We find $\sigma \cdot B(W \to e \nu) = 2.49 \pm 0.12$~nb and $\sigma \cdot B(Z^0 \to e^+e^-) = 0.231 \pm 0.012$~nb.Comment: Uses Latex, Article 12 point, figure appended as uuencoded file The full PostScript available via WWW at http://www-cdf.fnal.gov/physics/pub95/cdf3312_sigma_1a_prl_v3.p

Limits on WWZWWZ and WWγWW\gamma couplings from WWWW and WZWZ production in pp‾p\overline{p} collisions at s=1.8\sqrt{s} = 1.8 TeV

Direct limits are set on $WWZ$ and $WW\gamma$ three-boson couplings in a search for $WW$ and $WZ$ production with high transverse momentum in $p\overline{p}$ collisions at $\sqrt{s} = 1.8$ TeV, using the Collider Detector at Fermilab. The results are in agreement with the SU(2) $\times$ U(1) model of electroweak interactions. Assuming Standard Model $WW\gamma$ coupling, the the limits are interpreted as direct evidence for a non-zero $WWZ$ coupling at subprocess energies near 500 GeV. Alternatively, assumiong identical $WWZ$ and $WW\gamma$ couplings, bounds $-0.11 < \kappa < 2.27$ and $-0.81 < \lambda < 0.84$ are obtained at $95\%$ CL for a form factor scale 1000 GeV.Comment: 16 pages, submitted to PRL, URL: http://www-cdf.fnal.gov/physics/pub95/cdf2951_vvprl.p

The Charge Asymmetry in W-Boson Decays Produced in p-pbar Collisions at sqrt(s) = 1.8 TeV

The charge asymmetry has been measured using $19,039~W$ decays recorded by the CDF detector during the 1992-93 run of the Tevatron Collider. The asymmetry is sensitive to the ratio of $d$ and $u$ quark distributions to $x<0.01$ at $Q^2 \approx M_W^2$, where nonperturbative effects are minimal. It is found that of the two current sets of parton distributions, those of Martin, Roberts and Stirling (MRS) are favored over the sets most recently produced by the CTEQ collaboration. The $W$ asymmetry data provide a stronger constraints on $d/u$ ratio than the recent measurements of $F_2^{\mu n}/F_2^{\mu p}$ which are limited by uncertainties originating from deutron corrections.Comment: to be published in PR