p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape

The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B Cell Receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We have analyzed the impact of p66Shc ablation on disease severity and progression in the mouse model of chronic lymphocytic leukemia Eμ-TCL1. We show that Eμ-TCL1/p66Shc-/- mice develop an aggressive disease that has an earlier onset, a higher incidence and leads to earlier death compared to Eμ-TCL1 mice. Eμ-TCL1/p66Shc-/- mice display substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlates with an upregulation of chemokine receptors whose ligands are expressed therein. This also applies to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to inversely correlate with their p66Shc expression levels. p66Shc expression declined with disease progression in Eμ-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor Ibrutinib. Our results highlight p66Shc deficiency as an important factor in chronic lymphocytic leukemia progression and severity and underscore p66Shc expression as a relevant therapeutic target

The Impact of Crystal Light Yield Non-Proportionality on a Typical Calorimetric Space Experiment: Beam Test Measurements and Monte Carlo Simulations

Calorimetric space experiments were employed for the direct measurements of cosmic-ray spectra above the TeV region. According to several theoretical models and recent measurements, relevant features in both electron and nucleus fluxes are expected. Unfortunately, sizable disagreements among the current results of different space calorimeters exist. In order to improve the accuracy of future experiments, it is fundamental to understand the reasons of these discrepancies, especially since they are not compatible with the quoted experimental errors. A few articles of different collaborations suggest that a systematic error of a few percentage points related to the energy-scale calibration could explain these differences. In this work, we analyze the impact of the nonproportionality of the light yield of scintillating crystals on the energy scale of typical calorimeters. Space calorimeters are usually calibrated by employing minimal ionizing particles (MIPs), e.g., nonshowering proton or helium nuclei, which feature different ionization density distributions with respect to particles included in showers. By using the experimental data obtained by the CaloCube collaboration and a minimalist model of the light yield as a function of the ionization density, several scintillating crystals (BGO, CsI(Tl), LYSO, YAP, YAG and BaF2) are characterized. Then, the response of a few crystals is implemented inside the Monte Carlo simulation of a space calorimeter to check the energy deposited by electromagnetic and hadronic showers. The results of this work show that the energy scale obtained by MIP calibration could be affected by sizable systematic errors if the nonproportionality of scintillation light is not properly taken into account

Photodiode Read-Out System for the Calorimeter of the Herd Experiment

HERD is a future experiment for the direct detection of high energy cosmic rays. The instrument is based on a calorimeter optimized not only for a good energy resolution but also for a large acceptance. Each crystal composing the calorimeter is equipped with two read-out systems: one based on wavelength-shifting fibers and the other based on two photodiodes with different active areas assembled in a monolithic package. In this paper, we describe the photodiode read-out system, focusing on experimental requirements, design and estimated performances. Finally, we show how these features lead to the flight model project of the photodiode read-out system

p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their dephosphorylation-dependent release from \u3b2-arrestin at early endosomes

Neoplastic cell traffic abnormalities are central to the pathogenesis of chronic lymphocytic leukemia (CLL). Enhanced CXC chemokine receptor-4 (CXCR4) and chemokine receptor-7 (CCR7) recycling contributes to the elevated surface levels of these receptors on CLL cells. Here we have addressed the role of p66Shc, a member of the Shc family of protein adaptors the expression of which is defective in CLL cells, in CXCR4/CCR7 recycling. p66Shc reconstitution in CLL cells reduced CXCR4/CCR7 recycling, lowering their surface levels and attenuating B-cell chemotaxis, due to their accumulation in Rab5+ endosomes as serine-phosphoproteins bound to \u3b2-arrestin. This results from the ability of p66Shc to inhibit Ca2+ and PP2B-dependent CXCR4/CCR7 dephosphorylation and \u3b2-arrestin release. We also show that ibrutinib, a Btk inhibitor that promotes leukemic cell mobilization from lymphoid organs, reverses the CXCR4/CCR7 recycling abnormalities in CLL cells by increasing p66Shc expression. These results, identifying p66Shc as a regulator of CXCR4/CCR7 recycling in B cells, underscore the relevance of its deficiency to CLL pathogenesis and provide new clues to the mechanisms underlying the therapeutic effects of ibrutinib