Need for an accurate molecular diagnosis to assess the donor origin of leukemia relapse after allogeneic stem cell transplantation

Background and Objectives. Leukemia relapse occurring in donor cells after allogeneic hematopoietic stem cell transplantation has been reported in rare cases. Cytogenetic analysis and molecular probing of variable number of tandem repeats (VNTRs) have been used to confirm this unusual event in the few cases so far reported in the literature. The aim of this study was to demonstrate that extensive molecular characterization of leukemic cells at diagnosis and relapse may be necessary to avoid many technical pitfalls possibly leading to an erroneous diagnosis of leukemia relapse in donor cells after allogeneic transplantation. Design and Methods. We report the case of a 49-year old man who received an allogeneic transplantation from his HLA-identical sister because of BCR-ABI+ acute lymphoblastic leukemia (ALL). After having achieved complete hematologic and molecular remission, two years later an overt leukemia relapse occurred with cytogenetic findings suggesting a leukemia relapse in donor cells. The donor or patient origin of leukemic cells at relapse was further investigated by fluorescence in situ hybridization (FISH) karyotyping, reverse transcription (RT) polymerase chain reaction (PCR) analysis of BCR-ABL chimeric transcripts, PCR amplification of several VNTRs and the Y chromosome-specific DYS14 sequence and finally by amplification, cloning and sequencing of the CDRIII region of the immunoglobulin heavy chain (IgH) gene. Results. At the time of relapse, conventional and FISH karyotyping revealed the presence of a Phl+ chromosome and a female karyotype in all the 25 metaphases analyzed and PCR amplification of the Y chromosome-specific DYS14 sequence was negative. Moreover, the molecular evaluation of hematopoietic chimerism performed by the NZ-22 VNTR allowed us to demonstrate that at the time of relapse, a consistent proportion of hematopoietic cells was of donor origin. However, the molecular cloning and sequencing of the CDRIII region of the immunoglobuin heavy chain (IgH) gene rearrangement in leukemic blasts at diagnosis and relapse demonstrated their identity thus formally proving the patient origin of both leukemic clones. Interpretation and Conclusions. While the simplest interpretation of the apparent female karyotype at relapse is the consequence of a loss of the Y chromosome which in leukemic blasts took place along with duplication of an X-chromosome, this case strongly emphasizes the need for accurate and extensive molecular characterization to prove the donor origin of a leukemia relapse after allogeneic transplantation

Two-pass two-way acceleration in a superconducting continuous wave linac to drive low jitter x-ray free electron lasers

We present a design study of an innovative scheme to generate high rep rate (MHz-class) GeV electron beams by adopting a two-pass two-way acceleration in a Superconducting (SC) linac operated in Continuous Wave (CW) mode. The electron beam is accelerated twice by being re-injected in opposite direction of propagation into the linac after the first passage. Acceleration in opposite directions is accomplished thanks to standing waves supported in RF cavities. The task of recirculating the electron beam when it leaves the linac after first pass is performed by a Bubble-shaped Arc Compressor composed by a sequence of Double Bend Achromat. In this paper we address the main issues inherent to the two-pass acceleration process and the preservation of the electron beam quality parameters (emittance, energy spread, peak current) required to operate X-ray Free Electron Lasers with low jitters in the amplitude, spectral and temporal domain, as achieved by operating in seeding and/or oscillator mode a CW FEL up to 1 MHz rep rate. Detailed start-to-end simulations are shown to assess the capability of this new scheme to double the electron beam energy as well as to compress the electron bunch length from picoseconds down to tens of femtoseconds. The advantage of such a scheme is to halve the requested linac length for the same final electron beam energy, which is typically in the few GeV range, as needed to drive an X-ray FEL. The AC power to supply the cryogenic plant is also significantly reduced with respect to a conventional single-pass SC linac for the same final energy. We are reporting also X-ray FEL simulations for typical values of wavelengths of interest (in the 200 eV \u2013 8 keV photon energy range) to better illustrate the potentiality of this new scheme

Monitoring the FLASH Cryomodule Transportation from DESY Hamburg to CEA Saclay: Coupler Contact, Vacuum, Acceleration and Vibration Analysis

With a view to the series production of one hundred, 12 m long XFEL 1.3 GHz cryomodules and their transportation from the assembly site at CEA Saclay (F) to the installation site at DESY Hamburg (D) a test transportation of a FLASH cryomodule has been performed, in the condition foreseen for the mass transportation. The present study examines the stresses induced on the module and verifies the damping capabilities of the transport frame in order to minimize risk of damage to the most critical components. During the transportation, acceleration and vibration have been monitored as well as coupler antenna contacts and vacuum performances. This paper describes the analysis performed and compares those results to the data of a similar transportation study at Fermilab for the CM1 cryomodule

First Observation of Self-Amplified Spontaneous Emission in a Free-Electron Laser at 109 nm Wavelength

We present the first observation of Self-Amplified Spontaneous Emission (SASE) in a free-electron laser (FEL) in the Vacuum Ultraviolet regime at 109 nm wavelength (11 eV). The observed free-electron laser gain (approx. 3000) and the radiation characteristics, such as dependency on bunch charge, angular distribution, spectral width and intensity fluctuations all corroborate the existing models for SASE FELs.Comment: 6 pages including 6 figures; e-mail: [email protected]

Brixsino High-Flux Dual X-Ray and THz Radiation Source Based on Energy Recovery Linacs

We present the conceptual design of a compact light source named BriXSinO. BriXSinO was born as demonstrator of the Marix project, but it is also a dual high flux radiation source Inverse Compton Source (ICS) of X-ray and Free-Electron Laser of THz spectral range radiation conceived for medical applications and general applied research. The accelerator is a push-pull CW-SC Energy Recovery Linac (ERL) based on superconducting cavities technology and allows to sustain MW-class beam power with almost just one hundred kW active power dissipation/consumption. ICS line produces 33 keV monochromatic X-Rays via Compton scattering of the electron beam with a laser system in Fabry-Pérot cavity at a repetition rate of 100 MHz. The THz FEL oscillator is based on an undulator imbedded in optical cavity and generates THz wavelengths from 15 to 50 micron

MariX, an advanced MHz-class repetition rate X-ray source for linear regime time-resolved spectroscopy and photon scattering

The need of a fs-scale pulsed, high repetition rate, X-ray source for time-resolved fine analysis of matter (spectroscopy and photon scattering) in the linear response regime is addressed by the conceptual design of a facility called MariX (Multi-disciplinary Advanced Research Infrastructure for the generation and application of X-rays) outperforming current X-ray sources for the declared scope. MariX is based on the original design of a two-pass two-way superconducting linear electron accelerator, equipped with an arc compressor, to be operated in CW mode (1 MHz). MariX provides FEL emission in the range 0.2–8 keV with 108 photons per pulse ideally suited for photoelectric effect and inelastic X-ray scattering experiments. The accelerator complex includes an early stage that supports an advanced inverse Compton source of very high-flux hard X-rays of energies up to 180 keV that is well adapted for large area radiological imaging, realizing a broad science programme and serving a multidisciplinary user community, covering fundamental science of matter and application to life sciences, including health at preclinical and clinical level

Glial Cell Line-Derived Neurotrophic Factor (GDNF) as a Novel Candidate Gene of Anxiety.

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor for dopaminergic neurons with promising therapeutic potential in Parkinson's disease. A few association analyses between GDNF gene polymorphisms and psychiatric disorders such as schizophrenia, attention deficit hyperactivity disorder and drug abuse have also been published but little is known about any effects of these polymorphisms on mood characteristics such as anxiety and depression. Here we present an association study between eight (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111) GDNF single nucleotide polymorphisms (SNPs) and anxiety and depression scores measured by the Hospital Anxiety and Depression Scale (HADS) on 708 Caucasian young adults with no psychiatric history. Results of the allele-wise single marker association analyses provided significant effects of two single nucleotide polymorphisms on anxiety scores following the Bonferroni correction for multiple testing (p = 0.00070 and p = 0.00138 for rs3812047 and rs3096140, respectively), while no such result was obtained on depression scores. Haplotype analysis confirmed the role of these SNPs; mean anxiety scores raised according to the number of risk alleles present in the haplotypes (p = 0.00029). A significant sex-gene interaction was also observed since the effect of the rs3812047 A allele as a risk factor of anxiety was more pronounced in males. In conclusion, this is the first demonstration of a significant association between the GDNF gene and mood characteristics demonstrated by the association of two SNPs of the GDNF gene (rs3812047 and rs3096140) and individual variability of anxiety using self-report data from a non-clinical sample