Immunohistochemical evidence of a cytokine and chemokine network in three patients with Erdheim-Chester disease: Implications for pathogenesis.

OBJECTIVE: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis (LCH) of unknown etiology, characterized by diffuse histiocyte infiltration of bones and soft tissue. The purpose of this study was to assess cell proliferation and expression of cytokines, chemokines, and chemokine receptors that may potentially be important in histiocyte accumulation in ECD lesions. METHODS: Biopsies were performed on 3 patients with ECD. The diagnosis of the disease was based on clinical signs including typical radiologic osteosclerosis, and on the detection of foamy CD68+,CD1a- non-Langerhans' cell histiocytes on histologic examination. The expression of the proliferation marker Ki-67 as well as of selected chemokine/chemokine receptor pairs and cytokines was analyzed by immunohistochemistry. RESULTS: In all samples, Ki-67 was undetectable in CD68+ histiocytes. Conversely, these cells expressed the chemokines CCL2 (monocyte chemotactic protein 1), CCL4/macrophage inflammatory protein 1beta (MIP-1beta), CCL5/RANTES, CCL20/MIP-3alpha, and CCL19/MIP-3beta, and their counter-receptors CCR1, CCR2, CCR3, CCR5, CCR6, and CCR7. Moreover, ECD histiocytes expressed interferon-gamma-inducible 10-kd protein (CXCL10), which is specifically induced by interferon-gamma, and interleukin-6 and RANKL, which are both implicated in bone remodeling. Finally, all cases showed a Th1-type lymphocyte infiltrate. CONCLUSION: Our data indicate that, similar to LCH, ECD lesions are characterized by a complex cytokine and chemokine network, which may orchestrate histiocyte activation and accumulation through an autocrine loop and contribute to the pathogenesis of the disease

High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

The aim of the present study was to evaluate the role of a weekly preoperative chemotherapy in locally advanced, unresectable gastric cancer. In all, 82 patients with an Eastern Oncology Cooperative Group PS less than or equal to2 and normal cardiac function were enrolled onto the study. Surgical unresectability was confirmed in 52 patients (63%) at laparotomy, and in 30 (27%) cases by CT scan of the abdomen and endoscopic ultrasonography. Chemotherapy treatment was: cisplatin 40 mg m(-2); 5- fluorouracil 500 mg m(-2); epidoxorubicin 35 mg m(-2); 6S-leucovorin 250 mg m(-2) and glutathione 1.5 gm(-2) (PELF). One cycle consisted of 8 weekly treatments. Response to chemotherapy was observed in 40 of 82 patients (49%): six (7%) complete and 34 (41%) partial responses, and in four (5%) cases a complete pathological response was confirmed. Of the 40 responding patients, 37 (45%) had potentially curative surgery. Grade 3/4 leucopenia and thrombocytopenia occurred in three and two patients. At a median follow-up of 48 months, 25 of the 37 resected patients (68%) were alive and 24 (65%) were disease free. The median and 4-year survival for the whole group was 17 months and 31%, respectively. The median survival was 12 months for inoperable patients and it was not reached in resected patients

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss

Mutations in PINK1 and PARK2 cause autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons. To discover potential therapeutic pathways, we identified factors that genetically interact with Drosophila park and Pink1. We found that overexpression of the translation inhibitor Thor (4E-BP) can suppress all of the pathologic phenotypes, including degeneration of dopaminergic neurons in Drosophila. 4E-BP is activated in vivo by the TOR inhibitor rapamycin, which could potently suppress pathology in Pink1 and park mutants. Rapamycin also ameliorated mitochondrial defects in cells from individuals with PARK2 mutations. Recently, 4E-BP was shown to be inhibited by the most common cause of parkinsonism, dominant mutations in LRRK2. We also found that loss of the Drosophila LRRK2 homolog activated 4E-BP and was also able to suppress Pink1 and park pathology. Thus, in conjunction with recent findings, our results suggest that pharmacologic stimulation of 4E-BP activity may represent a viable therapeutic approach for multiple forms of parkinsonism

Activation of Host Translational Control Pathways by a Viral Developmental Switch

In response to numerous signals, latent herpesvirus genomes abruptly switch their developmental program, aborting stable host–cell colonization in favor of productive viral replication that ultimately destroys the cell. To achieve a rapid gene expression transition, newly minted capped, polyadenylated viral mRNAs must engage and reprogram the cellular translational apparatus. While transcriptional responses of viral genomes undergoing lytic reactivation have been amply documented, roles for cellular translational control pathways in enabling the latent-lytic switch have not been described. Using PEL-derived B-cells naturally infected with KSHV as a model, we define efficient reactivation conditions and demonstrate that reactivation substantially changes the protein synthesis profile. New polypeptide synthesis correlates with 4E-BP1 translational repressor inactivation, nuclear PABP accumulation, eIF4F assembly, and phosphorylation of the cap-binding protein eIF4E by Mnk1. Significantly, inhibiting Mnk1 reduces accumulation of the critical viral transactivator RTA through a post-transcriptional mechanism, limiting downstream lytic protein production, and impairs reactivation efficiency. Thus, herpesvirus reactivation from latency activates the host cap-dependent translation machinery, illustrating the importance of translational regulation in implementing new developmental instructions that drastically alter cell fate

Geographical heterogeneity of clinical and serological phenotypes of systemic sclerosis observed at tertiary referral centres. The experience of the Italian SIR-SPRING registry and review of the world literature

Introduction: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature.Materials and methods: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 +/- 26.9 yrs.; mean disease duration 8.9 +/- 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas.Results: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches.Conclusion: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities

The role of sex in the pathophysiology of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II). Female susceptibility to PAH has been known for some time, and most recent figures show a female-to-male ratio of 4:1. Variations in the female sex hormone estrogen and estrogen metabolism modify FPAH risk, and penetrance of the disease in BMPR-II mutation carriers is increased in females. Several lines of evidence point towards estrogen being pathogenic in the pulmonary circulation, and thus increasing the risk of females developing PAH. Recent studies have also suggested that estrogen metabolism may be crucial in the development and progression of PAH with studies indicating that downstream metabolites such as 16α-hydroxyestrone are upregulated in several forms of experimental pulmonary hypertension (PH) and can cause pulmonary artery smooth muscle cell proliferation and subsequent vascular remodelling. Conversely, other estrogen metabolites such as 2-methoxyestradiol have been shown to be protective in the context of PAH. Estrogen may also upregulate the signalling pathways of other key mediators of PAH such as serotonin

Measurement of W+W− production in association with one jet in proton–proton collisions at sqrt(s) = 8TeV with the ATLAS detector

The production of W boson pairs in association with one jet in pp collisions at View the MathML sources=8 TeV is studied using data corresponding to an integrated luminosity of 20.3 fb−1 collected by the ATLAS detector during 2012 at the CERN Large Hadron Collider. The cross section is measured in a fiducial phase-space region defined by the presence of exactly one electron and one muon, missing transverse momentum and exactly one jet with a transverse momentum above 25 GeV and a pseudorapidity of |η|<4.5|η|<4.5. The leptons are required to have opposite electric charge and to pass transverse momentum and pseudorapidity requirements. The fiducial cross section is found to be View the MathML sourceσWWfid,1-jet=136±6(stat)±14(syst)±3(lumi) fb. In combination with a previous measurement restricted to leptonic final states with no associated jets, the fiducial cross section of WW production with zero or one jet is measured to be View the MathML sourceσWWfid,≤1-jet=511±9(stat)±26(syst)±10(lumi) fb. The ratio of fiducial cross sections in final states with one and zero jets is determined to be 0.36±0.050.36±0.05. Finally, a total cross section extrapolated from the fiducial measurement of WW production with zero or one associated jet is reported. The measurements are compared to theoretical predictions and found in good agreement