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Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q− and 17p−). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P <0.01; n =52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels ( P <0.0001; n =9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy.

Analysis of X-chromosome inactivation patterns in females has been used to assess clonality of various tumours and for prenatal diagnosis of X-linked disorders. Studies with these methods in acute myeloid leukaemia suggest that a significant proportion of cases have clonal remissions (ie, persistence of the malignant clone), which may represent return to a preleukaemic state. We therefore analysed X-chromosome inactivation patterns with differential methylation patterns of heterozygotes for three DNA probes, HPRT, PGK, and M27β, in leukaemic patients and normal controls. As expected, blast cells from 67 of 68 analysable samples (99%) were monoclonal or had a skewed X-inactivation pattern. A skewed pattern in remission was also found in 26 of 77 patients (34%), proportion only slightly greater than control (16/75, 21%). In 7 of 10 patients with a skewed pattern in myeloid cells there was similar skewing in the T cells, which is compatible with the concept of a constitutively skewed X-chromosome inactivation pattern of haemopoietic cells in these patients. Our study illustrates the difficulty of interpreting clonality in individual tumour samples and emphasises the importance of comparisons with non-malignant tissue of the same cell type from that individual and from normal control populations.

Having noticed an article in your issue of November 18, on Chrysanthemum Rust, I have taken the liberty of forwarding you copy of a paper on that subject, read before the Guernsey Growers' Association, by a large Chrysanthemum grower, who has this season put in practice the recommendations given; and the results have been highly satisfactory.

Triple-GEM detectors are a well known technology in high energy physics. In order to have a complete understanding of their behavior, in parallel with on beam testing, a Monte Carlo code has to be developed to simulate their response to the passage of particles. The software must take into account all the physical processes involved from the primary ionization up to the signal formation, e.g. the avalanche multiplication and the effect of the diffusion on the electrons. In the case of gas detectors, existing software such as Garfield already perform a very detailed simulation but are CPU time consuming. A description of a reliable but faster simulation is presented here: it uses a parametric description of the variables of interest obtained by suitable preliminary Garfield simulations and tuned to the test beam data. It can reproduce the real values of the charge measured by the strip, needed to reconstruct the position with the Charge Centroid method. In addition, particular attention was put to the simulation of the timing information, which permits to apply also the micro-Time Projection Chamber position reconstruction, for the first time on a triple-GEM. A comparison between simulation and experimental values of some sentinel variables in different conditions of magnetic field, high voltage settings and incident angle will be shown.

Gas detector development is one of the pillars of the research in fundamental physics. Since several years, a new concept of detectors, called Micro Pattern Gas Detector (MPGD), allowed to overcome several problems related to other types of commonly used detectors, like drift chamber and micro strips detectors, reducing the rate of discharges and providing better radiation tolerance. Among the most used MPGDs are the Gas Electron Multipliers (GEMs). Invented by Sauli in 1997, nowadays GEMs have become an important reality for particle detectors in high energy physics. Commonly deployed as fast timing detectors and triggers, their fast response, high rate capability and high radiation hardness make them also suitable as tracking detectors. The readout scheme is one of the most important features in tracking technology. Analog readout based on the calculation of the center of gravity technique allows to overcome the limit imposed by digital pads, whose spatial resolution is limited by the pitch dimensions. However, the presence of high external magnetic fields can distort the electronic cloud and affect the performance. The development of the micro-TPC reconstruction method brings GEM detectors into a new prospective, improving significantly the spatial resolutionin presence of high magnetic fields. This innovative technique allows to reconstruct the 3-dimensional particle position, as Time Projection Chamber, but within a drift gap of a few millimeters. In these report, the charge centroid and micro-TPC methods are described in details. We discuss the results of several test beams performed with planar chambers in magnetic field. These results are one of the first developments of micro-TPC technique for GEM detectors, which allows to reach unprecedented performance in a high magnetic field of 1 T.

Neutrinoless double beta decay (0vββ) is considered the best potential resource to access the absolute neutrino mass scale. Moreover, if observed, it will signal that neutrinos are their own anti-particles (Majorana particles). Presently, this physics case is one of the most important research \"beyond Standard Model\" and might guide the way towards a Grand Unified Theory of fundamental interactions. Since the 0vββ decay process involves nuclei, its analysis necessarily implies nuclear structure issues. In the NURE project, supported by a Starting Grant of the European Research Council (ERC), nuclear reactions of double charge-exchange (DCE) are used as a tool to extract information on the 0vββ Nuclear Matrix Elements. In DCE reactions and ββ decay indeed the initial and final nuclear states are the same and the transition operators have similar structure. Thus the measurement of the DCE absolute cross-sections can give crucial information on ββ matrix elements. In a wider view, the NUMEN international collaboration plans a major upgrade of the INFN-LNS facilities in the next years in order to increase the experimental production of nuclei of at least two orders of magnitude, thus making feasible a systematic study of all the cases of interest as candidates for 0vββ.

Micro Pattern Gas Detectors (MPGD) are the new frontier in gas trackers. Among this kind of devices, the Gas Electron Multiplier (GEM) chambers are widely used. The experimental signals acquired with the detector must obviously be reconstructed and analysed. In this contribution, a new offline software to perform reconstruction, alignment and analysis on the data collected with APV-25 and TIGER ASICs will be presented. GRAAL (Gem Reconstruction And Analysis Library) is able to measure the performance of a MPGD detector with a strip segmented anode (presently). The code is divided in three parts: reconstruction, where the hits are digitized and clusterized; tracking, where a procedure fits the points from the tracking system and uses that information to align the chamber with rotations and shifts; analysis, where the performance is evaluated (e.g. efficiency, spatial resolution,etc.). The user must set the geometry of the setup and then the program returns automatically the analysis results, taking care of different conditions of gas mixture, electric field, magnetic field, geometries, strip orientation, dead strip, misalignment and many others.

The experiment BESIII, running at the accelerator BEPCII in Beijing (P.R.C.), is going to be updated with the replacement of the Inner Drift Chamber with a Cylindrical triple-GEM Inner Tracker (CGEM-IT). In the R&D stage, two standalone C++ codes were implemented: GTS (Garfield-based Triple-GEM Simulator), for digitization and tuning of simulated data to the experimental ones, and GRAAL (GEM Reconstruction And Analysis Library), for the reconstruction and analysis of the experimental events collected in testbeams. GTS simulates the triple-GEM response to the particle passage, treating each stage separately: ionization, GEM properties, gas mixture, magnetic field and finally the induction of the signal on the anode. The necessary information was extracted by GARFIELD++ simulations, parametrized and used as input in GTS. This speeds up the simulation, since GTS performs only samplings instead of the full digitization chain. The simulated events were reconstructed with the same procedure used for experimental data and tuning factors were evaluated to obtain a satisfactory match. GRAAL is used in the analysis of the testbeam experimental data. It provides several levels of reconstruction: from the cluster formation, gathering contiguous firing strips, to the spatial position and the signal time reconstruciton. Two algorithms are used: the charge centroid and the micro-TPC, which exploit the charge deposition on the strips and the time information. Also a merging of the two algorithms is available to efficiently weight the two outcomes and obtain the best estimate of the spatial coordinate. Moreover, GRAAL performs tracking and alignment. Both codes are going to be made available also for other MPGDs simulation and reconstruction.