Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53

Inotuzumab ozogamicin (IO) is an anti-CD22 calicheamicin immunoconjugate that has been recently approved for the treatment of relapsed or refractory B-Acute Lymphoblastic Leukemia (r/r B-ALL). We employed both immortalized and primary cells derived from CD22-positive lymphoproliferative disorders to investigate the signaling pathways contributing to IO sensitivity or resistance. We found that the drug reduced the proliferation rate of CD22-positive cell lines expressing wild-type p53, but was remarkably less effective on cells exhibiting mutant p53. In addition, CD22-positive cells surviving IO were mostly blocked in the G2/M phase of the cell cycle because of Chk1 activation that, in the presence of a wild-type p53 background, led to p21 induction. When we combined IO with the Chk1 inhibitor UCN-01, we successfully abrogated IO-induced G2/M arrest regardless of the underlying p53 status, indicating that the DNA damage response triggered by IO is also modulated by p53-independent mechanisms. To establish a predictive value for p53 in determining IO responsiveness, we expressed mutant p53 in cell lines displaying the wild-type gene and observed an increase in IO IC50 values. Likewise, overexpression of an inducible wild-type p53 in cells natively presenting a mutant protein decreased their IC50 for IO. These results were also confirmed in primary CD22-positive cells derived from B-ALL patients at diagnosis and from patients with r/r B-ALL. Furthermore, co-treatment with IO and UCN-01 significantly increased cell death in primary cells expressing mutant p53. In summary, our findings suggest that p53 status may represent a biomarker predictive of IO efficacy in patients diagnosed with CD22-positive malignancies

Reduction of volumetric bone mineral density in postmenopausal women with hepatitis C virus-correlated chronic liver disease: a peripheral quantitative computed tomography (pQCT) study

BACKGROUND: The prevalence of osteoporosis in chronic liver disease (CLD) varies considerably among the studies, depending on patient selection and diagnostic criteria. We aimed to measure bone turnover markers and volumetric bone mineral density (BMD) in a group of postmenopausal women with CLD using both dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), in comparison with age-matched healthy subjects. METHODS: Thirty-five postmenopausal patients with HCV-correlated CLD and 35 healthy postmenopausal women, as controls, underwent a DXA scan at lumbar and femoral level and a pQCT measurement of the nondominant forearm. Serum concentrations of biochemical markers relevant to bone turnover were also measured. RESULTS: Patients showed no differences in DXA values either at lumbar or femoral level compared to controls. On the contrary, pQCT geometrical (cortical cross-sectional area) and volumetric (total and trabecular volumetric BMD) parameters were significantly reduced in the CLD women. Also the Strength-Strain Index (SSI), an estimate of diaphyseal bone resistance to bending and torsion, was significantly lower in patients than in controls. Patients with CLD presented an unbalanced bone turnover, with increased bone resorption markers. CONCLUSIONS: The bone geometrical and volumetric parameters measured in our CLD postmenopausal women, by pQCT, show a reduced bone mineral quality and stiffness. Conversely, DXA-measurements seem unable to appreciate the bone alterations in these patients. This would encourage further studies to validate pQCT analysis as a diagnostic tool for a correct estimate of bone involvement in CLD

Il linguaggio e le lingue: tra teoria e storia Atti del I Convegno Cispels, Roma 17–19 Settembre 2018

Il volume raccoglie gli atti del I convegno Cispels tenutosi presso il Dipartimento di filosofia della Sapienza nel settembre 2018

A Novel Approach to β-Decay : PANDORA, a New Experimental Setup for Future In-Plasma Measurements

Theoretical predictions as well as experiments performed at storage rings have shown that the lifetimes of β-radionuclides can change significantly as a function of the ionization state. In this paper we describe an innovative approach, based on the use of a compact plasma trap to emulate selected stellar-like conditions. It has been proposed within the PANDORA project (Plasmas for Astrophysics, Nuclear Decay Observation and Radiation for Archaeometry) with the aim to measure, for the first time in plasma, nuclear β-decay rates of radionuclides involved in nuclear-astrophysics processes. To achieve this task, a compact magnetic plasma trap has been designed to reach the needed plasma densities, temperatures, and charge-states distributions. A multi-diagnostic setup will monitor, on-line, the plasma parameters, which will be correlated with the decay rate of the radionuclides. The latter will be measured through the detection of the γ-rays emitted by the excited daughter nuclei following the β-decay. An array of 14 HPGe detectors placed around the trap will be used to detect the emitted γ-rays. For the first experimental campaign three isotopes, 176Lu, 134Cs, and 94Nb, were selected as possible physics cases. The newly designed plasma trap will also represent a tool of choice to measure the plasma opacities in a broad spectrum of plasma conditions, experimentally poorly known but that have a great impact on the energy transport and spectroscopic observations of many astrophysical objects. Status and perspectives of the project will be highlighted in the paper.peerReviewe