Microarray and Proteomic Analyses of Myeloproliferative Neoplasms with a Highlight on the mTOR Signaling Pathway

The gene and protein expression profiles in myeloproliferative neoplasms (MPNs) may reveal gene and protein markers of a potential clinical relevance in diagnosis, treatment and prediction of response to therapy. Using cDNA microarray analysis of 25,100 unique genes, we studied the gene expression profile of CD34(+) cells and granulocytes obtained from peripheral blood of subjects with essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). The microarray analyses of the CD34(+) cells and granulocytes were performed from 20 de novo MPN subjects: JAK2 positive ET, PV, PMF subjects, and JAK2 negative ET/PMF subjects. The granulocytes for proteomic studies were pooled in 4 groups: PV with JAK2 mutant allele burden above 80%, ET with JAK2 mutation, PMF with JAK2 mutation and ET/PMF with no JAK2 mutation. The number of differentially regulated genes was about two fold larger in CD34(+) cells compared to granulocytes. Thirty-six genes (including RUNX1, TNFRSF19) were persistently highly expressed, while 42 genes (including FOXD4, PDE4A) were underexpressed both in CD34(+) cells and granulocytes. Using proteomic studies, significant up-regulation was observed for MAPK and PI3K/AKT signaling regulators that control myeloid cell apoptosis and proliferation: RAC2, MNDA, S100A8/9, CORO1A, and GNAI2. When the status of the mTOR signaling pathway related genes was analyzed, PI3K/AKT regulators were preferentially up-regulated in CD34(+) cells of MPNs, with down-regulated major components of the protein complex EIF4F. Molecular profiling of CD34(+) cells and granulocytes of MPN determined gene expression patterns beyond their recognized function in disease pathogenesis that included dominant up-regulation of PI3K/AKT signaling

Essential thrombocythemia

Essential thrombocythemia (ET) is an acquired myeloproliferative disorder (MPD) characterized by a sustained elevation of platelet number with a tendency for thrombosis and hemorrhage. The prevalence in the general population is approximately 30/100,000. The median age at diagnosis is 65 to 70 years, but the disease may occur at any age. The female to male ratio is about 2:1. The clinical picture is dominated by a predisposition to vascular occlusive events (involving the cerebrovascular, coronary and peripheral circulation) and hemorrhages. Some patients with ET are asymptomatic, others may experience vasomotor (headaches, visual disturbances, lightheadedness, atypical chest pain, distal paresthesias, erythromelalgia), thrombotic, or hemorrhagic disturbances. Arterial and venous thromboses, as well as platelet-mediated transient occlusions of the microcirculation and bleeding, represent the main risks for ET patients. Thromboses of large arteries represent a major cause of mortality associated with ET or can induce severe neurological, cardiac or peripheral artery manifestations. Acute leukemia or myelodysplasia represent only rare and frequently later-onset events. The molecular pathogenesis of ET, which leads to the overproduction of mature blood cells, is similar to that found in other clonal MPDs such as chronic myeloid leukemia, polycythemia vera and myelofibrosis with myeloid metaplasia of the spleen. Polycythemia vera, myelofibrosis with myeloid metaplasia of the spleen and ET are generally associated under the common denomination of Philadelphia (Ph)-negative MPDs. Despite the recent identification of the JAK2 V617F mutation in a subset of patients with Ph-negative MPDs, the detailed pathogenetic mechanism is still a matter of discussion. Therapeutic interventions in ET are limited to decisions concerning the introduction of anti-aggregation therapy and/or starting platelet cytoreduction. The therapeutic value of hydroxycarbamide and aspirin in high risk patients has been supported by controlled studies. Avoiding thromboreduction or opting for anagrelide to postpone the long-term side effects of hydrocarbamide in young or low risk patients represent alternative options. Life expectancy is almost normal and similar to that of a healthy population matched by age and sex

The NOMAD Experiment at the CERN SPS

The NOMAD experiment is a short base-line search for ν<sub>μ</sub> − ν<sub>τ</sub> oscillations in the CERN neutrino beam. The ν<sub>τ</sub>'s are searched for through their charged current interactions followed by the observation of the resulting τ− through its electronic, muonic or hadronic decays. These decays are recognized using kinematical criteria necessitating the use of a light target which enables the reconstruction of individual particles produced in the neutrino interactions. This paper describes the various components of the NOMAD detector: the target and muon drift chambers, the electromagnetic and hadronic calorimeters, the preshower and transition radiation detectors and the veto and trigger scintillation counters. The beam and data acquisition system are also described. The quality of the reconstruction and individual particles is demonstrated through the ability of NOMAD to observe K<sub>s</sub><sup>0</sup>'s, Λ<sup>0</sup>'s and π<sup>0</sup>'s. Finally, the observation of τ− through its electronic decay being one of the most promising channels in the search, the identification of electrons in NOMAD is discussed

The NOMAD experiment at the CERN SPS

The NOMAD experiment is a short base-line search for $\nu_{\mu}\rightarrow \nu_{\tau}$ oscillations in the CERN neutrino beam. The $\nu_{\tau}$'s are searched for through their charged-current interactions followed by the observation of the resulting $\tau^{-}$ through its electronic, muonic or hadronic decays. These decays are recognized using kinematical criteria necessitating the use of a light target which enables the reconstruction of individual particles produced in the neutrino interactions. This paper describes the various components of the NOMAD detector: the target and muon drift chambers, the electromagnetic and hadronic calorimeters, the preshower and transition radiation detectors, and the veto and trigger scintillation counters. The beam and data acquisition system are also described. The quality of the reconstruction of individual particles is demonstrated through the ability of NOMAD to observe K$^0_{\rm s}$'s, $\Lambda^0$'s and $\pi^0$'s. Finally, the observation of $\tau^{-}$ through its electronic decay being one of the most promising channels in the search, the identification of electrons in NOMAD is discussed

Search for a new gauge boson in π0\pi^{0} decays

A search was made for a new light gauge boson $X$ which might be produced in $\pi^{0}\to\gamma + X$ decay from neutral pions generated by 450-GeV protons in the CERN SPS neutrino target. The X's would penetrate the downstream shielding and be observed in the NOMAD detector via the Primakoff effect, in the process of $X \to\pi^{0}$ conversion in the external Coulomb field of a nucleus. With $1.45\times10^{18}$ protons on target, 20 candidate events with energy between 8 and 140 GeV were found from the analysis of neutrino data. This number is in agreement with the expectation of 18.1$\pm$2.8 background events from standard neutrino processes. A new 90% C.L. upper limit on the branching ratio $Br(\pi^{0}\to\gamma + X)< (3.3 to 1.9) \times10^{-5}$ for $X$ masses ranging from 0 to 120 MeV/c^2 is obtained.Comment: 15 pages, LaTex, 6 eps figures included, submitted to Physics Letters