The cell cycle checkpoint inhibitors in the treatment of leukemias

open3noThe study was funded by the University of Bologna and by the Italian Association for Cancer Research (AIRC).The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias.openGhelli Luserna di Rora', A; Iacobucci, I; Martinelli, GGhelli Luserna di Rora', A; Iacobucci, I; Martinelli,

Characterisation of AMS H35 HV-CMOS monolithic active pixel sensor prototypes for HEP applications

Monolithic active pixel sensors produced in High Voltage CMOS (HV-CMOS) technology are being considered for High Energy Physics applications due to the ease of production and the reduced costs. Such technology is especially appealing when large areas to be covered and material budget are concerned. This is the case of the outermost pixel layers of the future ATLAS tracking detector for the HL-LHC. For experiments at hadron colliders, radiation hardness is a key requirement which is not fulfilled by standard CMOS sensor designs that collect charge by diffusion. This issue has been addressed by depleted active pixel sensors in which electronics are embedded into a large deep implantation ensuring uniform charge collection by drift. Very first small prototypes of hybrid depleted active pixel sensors have already shown a radiation hardness compatible with the ATLAS requirements. Nevertheless, to compete with the present hybrid solutions a further reduction in costs achievable by a fully monolithic design is desirable. The H35DEMO is a large electrode full reticle demonstrator chip produced in AMS 350 nm HV-CMOS technology by the collaboration of Karlsruher Institut f\"ur Technologie (KIT), Institut de F\'isica d'Altes Energies (IFAE), University of Liverpool and University of Geneva. It includes two large monolithic pixel matrices which can be operated standalone. One of these two matrices has been characterised at beam test before and after irradiation with protons and neutrons. Results demonstrated the feasibility of producing radiation hard large area fully monolithic pixel sensors in HV-CMOS technology. H35DEMO chips with a substrate resistivity of 200$\Omega$ cm irradiated with neutrons showed a radiation hardness up to a fluence of $10^{15}$n$_{eq}$cm$^{-2}$ with a hit efficiency of about 99% and a noise occupancy lower than $10^{-6}$ hits in a LHC bunch crossing of 25ns at 150V

Modulation of amyloidogenic peptide aggregation by photoactivatable co-releasing ruthenium(II) complexes

Three Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives as ligands were investigated for their ability to modulate the aggregation process of the second helix of the C-terminal domain of nucleophosmin 1, namely nucleophosmin 1 (NPM1)264–277, a model amyloidogenic system, before and after irradiation at 365 nm. Thioflavin T (ThT) binding assays and UV/Vis absorption spectra indicate that binding of the compounds to the peptide inhibits its aggregation and that the inhibitory effect increases upon irradiation (half maximal effective concentration (EC50) values in the high micromolar range). Electrospray ionization mass spectrometry data of the peptide in the presence of one of these compounds confirm that the modulation of amyloid aggregation relies on the formation of adducts obtained when the Ru compounds react with the peptide upon releasing of labile ligands, like chloride and carbon monoxide. This mechanism of action explains the subtle different behavior of the three compounds observed in ThT experiments. Overall, data support the hypothesis that metal-based CO releasing molecules can be used to develop metal-based drugs with potential application as anti-amyloidogenic agents

Persistence of Nonceliac Wheat Sensitivity, Based on Long-term Follow-up

We investigated how many patients with a diagnosis of nonceliac wheat sensitivity (NCWS) still experienced wheat sensitivity after a median follow-up time of 99 months. We collected data from 200 participants from a previous study of NCWS, performed between July and December 2016 in Italy; 148 of these individuals were still on a strict wheat- free diet. In total, 175 patients (88%) improved (had fewer symptoms) after a diagnosis of NCWS; 145 of 148 patients who adhered strictly to a gluten-free diet (98%) had reduced symptoms, compared with 30 of 52 patients who did not adhere to a gluten-free diet (58%) (P < .0001). Of the 22 patients who repeated the double-blind, placebo- controlled challenge, 20 reacted to wheat. We conclude that NCWS is a persistent condition. Clinicaltrials.gov registration number: NCT02823522

Test beam measurement of the first prototype of the fast silicon pixel monolithic detector for the TT-PET project

The TT-PET collaboration is developing a PET scanner for small animals with 30 ps time-of-flight resolution and sub-millimetre 3D detection granularity. The sensitive element of the scanner is a monolithic silicon pixel detector based on state-of-the-art SiGe BiCMOS technology. The first ASIC prototype for the TT-PET was produced and tested in the laboratory and with minimum ionizing particles. The electronics exhibit an equivalent noise charge below 600 e- RMS and a pulse rise time of less than 2 ns, in accordance with the simulations. The pixels with a capacitance of 0.8 pF were measured to have a detection efficiency greater than 99% and, although in the absence of the post-processing, a time resolution of approximately 200 ps

Unexpectedly large electron correlation measured in Auger spectra of ferromagnetic iron thin films: orbital-selected Coulomb and exchange contributions

A set of electron-correlation energies as large as 10 eV have been measured for a magnetic 2ML Fefilm deposited on Ag(001). By exploiting the spin selectivity in angle-resolved Auger-photoelectroncoincidence spectroscopy and the Cini-Sawatzky theory, the core-valence-valence Auger spectrumof a spin-polarized system have been resolved: correlation energies have been determined for eachindividual combination of the two holes created in the four sub-bands involved in the decay: majorityand minority spin, as well asegandt2g. The energy difference between final states with paralleland antiparallel spin of the two emitted electrons is ascribed to the spin-flip energy for the final ionstate, thus disentangling the contributions of Coulomb and exchange interactions.Comment: 5 pages, 2 figures, 1 tabl

Thermal conductivity of the Toda lattice with conservative noise

We study the thermal conductivity of the one dimensional Toda lattice perturbed by a stochastic dynamics preserving energy and momentum. The strength of the stochastic noise is controlled by a parameter $\gamma$. We show that heat transport is anomalous, and that the thermal conductivity diverges with the length $n$ of the chain according to $\kappa(n) \sim n^\alpha$, with $0 < \alpha \leq 1/2$. In particular, the ballistic heat conduction of the unperturbed Toda chain is destroyed. Besides, the exponent $\alpha$ of the divergence depends on $\gamma$

Novel high-speed monolithic silicon detector for particle physics

This contribution presents simulation results, implementation, and first tests of a monolithic detector developed at KIT. It consists of a sensor diode tightly integrated with an analogue front-end based on SiGe (Silicon-Germanium) SG13G2 130 nm BiCMOS technology produced at the Leibniz Institute for High Performance Microelectronics (IHP). The pixel size is 100 μm × 100 μm, and the nwell charge collection node dimensions were reduced to 10 μm × 10 μm. We investigate the influence of this approach on sensor performance, spatial resolution via charge sharing and timing behaviour