Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas.

Background. Cushing\u2019s disease presents gender disparities in prevalence and clinical course. Little is known, however, about sexual dimorphism at the level of the corticotrope adenoma itself. The aim of the present study was to evaluate molecular features of ACTH-secreting pituitary adenomas collected from female and male patients with Cushing\u2019s disease. (2) Methods. We analyzed 153 ACTH-secreting adenomas collected from 31 men and 122 women. Adenomas were established in culture and ACTH synthesis and secretion assessed in basal conditions as well as during incubation with CRH or dexamethasone. Concurrently, microarray analysis was performed on formalin-fixed specimens and differences in the expression profiles between specimens from male and female patients identified. (3) Results. ACTH medium concentrations in adenomas obtained from male patients were significantly lower than those observed in adenomas from female patients. This could be observed for baseline as well as modulated secretion. Analysis of corticotrope transcriptomes revealed considerable similarities with few, selected differences in functional annotations. Differentially expressed genes comprised genes with known sexual dimorphism, genes involved in tumour development and genes relevant to pituitary pathophysiology. (4) Conclusions. Our study shows for the first time that human corticotrope adenomas present sexual dimorphism and underlines the need for a gender-dependent analysis of these tumours. Differentially expressed genes may represent the basis for gender-tailored target therapy

Malignancy course of pituitary adenoma in MEN1 syndrome: Clinical-Neuroradiological signs

Pituitary carcinomas (PCa) are extremely rare, indistinguishable from pituitary adenomas on histopathological grounds and have a poor prognosis. Most PCa start as PRL or ACTH secreting tumors in males, with relapsing invasive behaviour, refractoriness to medical and radiotherapy and increasing hormonal levels. The presence of distant metastases is still required for the diagnosis of PCa. The association with genetic endocrine diseases must be taken into account, since it adds further risk of evolution towards malignancy. Intradural spinal metastases have also been reported, so a complete craniospinal MR evaluation is recommended, when clinically indicated. We report a case of PCa, associated with MEN1 syndrome, with evidence of meningeal spread to the tentorium cerebelli, clival dura and spinal drop metastases mimicking spinal nerves schwannomas

Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more "typical" corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas

E835 at FNAL: Charmonium Spectroscopy in pˉp\bar p p Annihilations

I present preliminary results on the search for $h_c$ in its $\eta_c\gamma$ and $J/\psi\pi^0$ decay modes. We observe an excess of \eta_c\gamma$events near 3526 MeV that has a probability${\cal P} \sim 0.001$to arise from background fluctations. The resonance parameters are$M=3525.8 \pm 0.2 \pm 0.2 $MeV,$\Gamma\leq$1 MeV, and$10.6\pm 3.7\pm3.4(br) < \Gamma_{\bar{p}p}B_{\eta_c\gamma} < 12.8\pm 4.8\pm4.5(br) $eV. We find no event excess within the search region in the$J/\psi\pi^0$ mode.Comment: Presented at the 6th International Conference on Hyperons, Charm and Beauty Hadrons (BEACH 2004), Chicago(Il), June 27-July 3,200

Interference Study of the chi_c0 (1^3P_0) in the Reaction Proton-Antiproton -> pi^0 pi^0

Fermilab experiment E835 has observed proton-antiproton annihilation production of the charmonium state chi_c0 and its subsequent decay into pi^0 pi^0. Although the resonant amplitude is an order of magnitude smaller than that of the non-resonant continuum production of pi^0 pi^0, an enhanced interference signal is evident. A partial wave expansion is used to extract physics parameters. The amplitudes J=0 and 2, of comparable strength, dominate the expansion. Both are accessed by L=1 in the entrance proton-antiproton channel. The product of the input and output branching fractions is determined to be B(pbar p -> chi_c0) x B(chi_c0 -> pi^0 pi^0)= (5.09 +- 0.81 +- 0.25) x 10^-7.Comment: 4 pages, 4 figures, Accepted by PRL (July 2003

Precision measurements of the total and partial widths of the psi(2S) charmonium meson with a new complementary-scan technique in antiproton-proton annihilations

We present new precision measurements of the psi(2S) total and partial widths from excitation curves obtained in antiproton-proton annihilations by Fermilab experiment E835 at the Antiproton Accumulator in the year 2000. A new technique of complementary scans was developed to study narrow resonances with stochastically cooled antiproton beams. The technique relies on precise revolution-frequency and orbit-length measurements, while making the analysis of the excitation curve almost independent of machine lattice parameters. We study the psi(2S) meson through the processes pbar p -> e+ e- and pbar p -> J/psi + X -> e+ e- + X. We measure the width to be Gamma = 290 +- 25(sta) +- 4(sys) keV and the combination of partial widths Gamma_e+e- * Gamma_pbarp / Gamma = 579 +- 38(sta) +- 36(sys) meV, which represent the most precise measurements to date.Comment: 17 pages, 3 figures, 3 tables. Final manuscript accepted for publication in Phys. Lett. B. Parts of the text slightly expanded or rearranged; results are unchange

Measurement of the two photon decay of the χc0(13P0) state of charmonium

AbstractWe report on the decay to two photons of the χc0(13P0) charmonium resonance formed in p̄p interactions at Fermilab experiment E835. We have measured the product of branching ratios BR(χc0→p̄p)×BR(χc0→γγ)=(6.52±1.18(stat)+0.48−0.72(sys))×10−8. Using values from the 2002 PDG, this measurement leads to the partial width Γ(χc0→γγ)=2.9±0.9 keV

Measurement of the branching ratios ψ′→e+e−\psi^\prime \to e^+ e^-, ψ′→J/ψππ\psi^\prime \to J/\psi \pi \pi and ψ′→J/ψη\psi^\prime \to J/\psi \eta

We have measured several branching ratios for $\psi^\prime$ decay using the data collected by FNAL E835 experiment during year 2000, obtaining ${\cal B}(\psi^\prime \to e^+ e^-) = 0.0068\pm0.0001\pm0.0004$, ${\cal B}(\psi^\prime \to J/\psi \pi^+ \pi^-) = 0.292\pm0.005\pm0.018$, ${\cal B}(\psi^\prime \to J/\psi \pi^0 \pi^0) = 0.167\pm0.005\pm0.014$ and ${\cal B}(\psi^\prime \to J/\psi \eta) = 0.028\pm0.002\pm0.002$. We also present a measurement of the dipion mass distribution in the decays $\psi^\prime \to J/\psi \pi \pi$

A Study of \bar{p}p -> Two Neutral Pseudoscalar Mesons at the chi_c0(1^3P_0) Formation Energy

Fermilab experiment E835 has studied reactions \bar{p}p -> pi0 pi0, pi0 eta, eta eta, pi0 eta' and eta eta' in the energy region of the chi_c0(1^3P_0) from 3340 MeV to 3470 MeV. Interference between resonant and continuum production is observed in the pi0 pi0 and eta eta channels, and the product of the input and output branching fractions is measured. Limits on resonant production are set for the pi0 eta and pi0 eta' channels. An indication of interference is observed in the eta eta' channel. The technique for extracting resonance parameters in an environment dominated by continuum production is described.Comment: 15 pages, 21 figures, submitted Phys. Rev.

Measurement of the Resonance Parameters of the χ1(13P1)\chi_{1}(1^3P_1) and χ2(13P2)\chi_{2}(1^3P_2) States of Charmonium formed in Antiproton-Proton Annihilations

We have studied the $^3P_J$ ($\chi_c)$ states of charmonium in formation by antiproton-proton annihilations in experiment E835 at the Fermilab Antiproton Source. We report new measurements of the mass, width, and $B(\chi_{cJ} \to \bar{p} p) \times \Gamma(\chi_{cJ} \to J/\psi + anything)$ for the $\chi_{c1}$ and $\chi_{c2}$ by means of the inclusive reaction $\bar{p}p \to \chi_{cJ} \to J/\psi + anything \to (e^{+}e^{-}) +anything$. Using the subsample of events where $\chi_{cJ} \to \gamma + J/\psi \to \gamma + (e^{+}e^{-})$ is fully reconstructed, we derive $B(\chi_{cJ} \to \bar p p)\times \Gamma(\chi_{cJ} \to J/\psi + \gamma)$. We summarize the results of the E760 (updated) and E835 measurements of mass, width and $B(\chi_{cJ} \to \bar{p}p) \Gamma(\chi_{cJ} \to J/\psi+\gamma)$ (J=0,1,2) and discuss the significance of these measurements