Concordance of copy number abnormality detection using SNP arrays and Multiplex Ligation-dependent Probe Amplification (MLPA) in acute lymphoblastic leukaemia

In acute lymphoblastic leukaemia, MLPA has been used in research studies to identify clinically relevant copy number abnormality (CNA) profiles. However, in diagnostic settings other techniques are often employed. We assess whether equivalent CNA profiles are called using SNP arrays, ensuring platform independence. We demonstrate concordance between SNP6.0 and MLPA CNA calling on 143 leukaemia samples from two UK trials; comparing 1,287 calls within eight genes and a region. The techniques are 99% concordant using manually augmented calling, and 98% concordant using an automated pipeline. We classify these discordant calls and examine reasons for discordance. In nine cases the circular binary segmentation (CBS) algorithm failed to detect focal abnormalities or those flanking gaps in IKZF1 probe coverage. Eight cases were discordant due to probe design differences, with focal abnormalities detectable using one technique not observable by the other. Risk classification using manually augmented array calling resulted in four out of 143 patients being assigned to a different CNA risk group and eight patients using the automated pipeline. We conclude that MLPA defined CNA profiles can be accurately mirrored by SNP6.0 or similar array platforms. Automated calling using the CBS algorithm proved successful, except for IKZF1 which should be manually inspected

The use ultrasound guided for refilling intrathecal baclofene pump in complicated clinical cases: A practical approach

Muscular spasticity due to neurological disorders is a heavy cause of severe pain and disability for many patients, compromising the independence and quality life. Baclofene is a good tool to guarantee patients independence and pain control. Anyway in chronic therapy oral treatment become unsatisfactory. In all these cases, intrathecal baclofen therapy (ITB), after sub fascial implantation of intrathecal pumps is used as an important long term treatment to reduce spasticity. After pump implantation the drug reservoir must be refilled periodically in order to maintain the reduction of spasticity and avoid the symptoms and signs of withdrawal. ITB refilling, which involves the insertion of a needle through the skin until the access port of the pump, is often hard, mainly due to the layer of abdominal fat, spasticity, suboptimal pump positioning, pump rotation or inversion, and scar formation over the implantation site. To avoid the difficulties of ITB refilling radiography or other invasive supportive examinations are sometimes needed. We reported here our experience and we suggest a simple method to use the ultrasound in refilling with particular attention to some cases with complications after implantation with a difficult approach in refilling. We used the ultrasound examination to identify the access port of her pump so as to avoid multiple needle punctures and infections and radiation exposition. Ultrasound-guided technique may facilitate ITB refill in technically challenging cases. With ultrasound ITB was easily detectable and was quite simple to identify the exact point of needle injection. In the last years different new applications for ultrasounds are emerging. In our opinion the use of Doppler ultrasounds in the study of muscles and nerves represent an emerging tool for the physician's neurological rehabilitation

Energy and time resolution for a LYSO matrix prototype of the Mu2e experiment

We have measured the performances of a LYSO crystal matrix prototype tested with electron and photon beams in the energy range 60$-$450 MeV. This study has been carried out to determine the achievable energy and time resolutions for the calorimeter of the Mu2e experiment.Comment: 2 pages, 3 figures, 13th Pisa Meeting on Advanced Detector

SNAr-Based, facile synthesis of a library of Benzothiaoxazepine-1,1’-dioxides

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Combinatorial Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/cc1001023.The construction of a library of benzothiaoxazepine-1,1’-dioxides utilizing a one-pot, SNAr diversification – ODCT50 scavenging protocol is reported. This protocol combines microwave irradiation to facilitate the reaction, in conjunction with a soluble ROMP-derived scavenger (ODCT) to afford the desired products in good overall purity. Utilizing this protocol, a 78-member library was successfully synthesized and submitted for biological evaluation

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions

The Mu2e undoped CsI crystal calorimeter

The Mu2e experiment at Fermilab will search for Charged Lepton Flavor Violating conversion of a muon to an electron in an atomic field. The Mu2e detector is composed of a tracker, an electromagnetic calorimeter and an external system, surrounding the solenoid, to veto cosmic rays. The calorimeter plays an important role to provide: a) excellent particle identification capabilities; b) a fast trigger filter; c) an easier tracker track reconstruction. Two disks, located downstream of the tracker, contain 674 pure CsI crystals each. Each crystal is read out by two arrays of UV-extended SiPMs. The choice of the crystals and SiPMs has been finalized after a thorough test campaign. A first small scale prototype consisting of 51 crystals and 102 SiPM arrays has been exposed to an electron beam at the BTF (Beam Test Facility) in Frascati. Although the readout electronics were not the final, results show that the current design is able to meet the timing and energy resolution required by the Mu2e experiment.Comment: 6 pages, 8 figures, proceedings of the "Calorimetry for the high energy frontier (CHEF17)" conference, 2-6 October 2017, Lyon, Franc

Quality Assurance on a custom SiPMs array for the Mu2e experiment

The Mu2e experiment at Fermilab will search for the coherent $\mu \to e$ conversion on aluminum atoms. The detector system consists of a straw tube tracker and a crystal calorimeter. A pre-production of 150 Silicon Photomultiplier arrays for the Mu2e calorimeter has been procured. A detailed quality assur- ance has been carried out on each SiPM for the determination of its own operation voltage, gain, dark current and PDE. The measurement of the mean-time-to-failure for a small random sample of the pro-production group has been also completed as well as the determination of the dark current increase as a function of the ioninizing and non-ioninizing dose.Comment: 4 pages, 10 figures, conference proceeding for NSS-MIC 201

Design, status and perspective of the Mu2e crystal calorimeter

The Mu2e experiment at Fermilab will search for the charged lepton flavor violating process of neutrino-less $\mu \to e$ coherent conversion in the field of an aluminum nucleus. Mu2e will reach a single event sensitivity of about $2.5\cdot 10^{-17}$ that corresponds to four orders of magnitude improvements with respect to the current best limit. The detector system consists of a straw tube tracker and a crystal calorimeter made of undoped CsI coupled with Silicon Photomultipliers. The calorimeter was designed to be operable in a harsh environment where about 10 krad/year will be delivered in the hottest region and work in presence of 1 T magnetic field. The calorimeter role is to perform $\mu$/e separation to suppress cosmic muons mimiking the signal, while providing a high level trigger and a seeding the track search in the tracker. In this paper we present the calorimeter design and the latest R$\&$D results.Comment: 4 pages, conference proceeding for a presentation held at TIPP'2017. To be published on Springer Proceedings in Physic