151 research outputs found
Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever
Published: 20 April 2021PURPOSE: Conditioning therapy with high-dose melphalan (HDM) is associated with a high risk of gut toxicity, fever and infections in haematopoietic stem cell transplant (HSCT) recipients. However, validated preclinical models that adequately reflect clinical features of melphalan-induced toxicity are not available. We therefore aimed to develop a novel preclinical model of melphalan-induced toxicity that reflected well-defined clinical dynamics, as well as to identify targetable mechanisms that drive intestinal injury. METHODS: Male Wistar rats were treated with 4-8 mg/kg melphalan intravenously. The primary endpoint was plasma citrulline. Secondary endpoints included survival, weight loss, diarrhea, food/water intake, histopathology, body temperature, microbiota composition (16S sequencing) and bacterial translocation. RESULTS: Melphalan 5 mg/kg caused self-limiting intestinal injury, severe neutropenia and fever while impairing the microbial metabolome, prompting expansion of enteric pathogens. Intestinal inflammation was characterized by infiltration of polymorphic nuclear cells in the acute phases of mucosal injury, driving derangement of intestinal architecture. Ileal atrophy prevented bile acid reabsorption, exacerbating colonic injury via microbiota-dependent mechanisms. CONCLUSION: We developed a novel translational model of melphalan-induced toxicity, which has excellent homology with the well-known clinical features of HDM transplantation. Application of this model will accelerate fundamental and translational study of melphalan-induced toxicity, with the clinical parallels of this model ensuring a greater likelihood of clinical success.H. R. Wardill, C. E. M. de Mooij, A. R. da Silva Ferreira, I. P. van de Peppel, R. Havinga, H. J. M. Harmsen ... et al
Differential (2+1) Jet Event Rates and Determination of alpha_s in Deep Inelastic Scattering at HERA
Events with a (2+1) jet topology in deep-inelastic scattering at HERA are
studied in the kinematic range 200 < Q^2< 10,000 GeV^2. The rate of (2+1) jet
events has been determined with the modified JADE jet algorithm as a function
of the jet resolution parameter and is compared with the predictions of Monte
Carlo models. In addition, the event rate is corrected for both hadronization
and detector effects and is compared with next-to-leading order QCD
calculations. A value of the strong coupling constant of alpha_s(M_Z^2)=
0.118+- 0.002 (stat.)^(+0.007)_(-0.008) (syst.)^(+0.007)_(-0.006) (theory) is
extracted. The systematic error includes uncertainties in the calorimeter
energy calibration, in the description of the data by current Monte Carlo
models, and in the knowledge of the parton densities. The theoretical error is
dominated by the renormalization scale ambiguity.Comment: 25 pages, 6 figures, 3 tables, submitted to Eur. Phys.
Multiplicity Structure of the Hadronic Final State in Diffractive Deep-Inelastic Scattering at HERA
The multiplicity structure of the hadronic system X produced in
deep-inelastic processes at HERA of the type ep -> eXY, where Y is a hadronic
system with mass M_Y< 1.6 GeV and where the squared momentum transfer at the pY
vertex, t, is limited to |t|<1 GeV^2, is studied as a function of the invariant
mass M_X of the system X. Results are presented on multiplicity distributions
and multiplicity moments, rapidity spectra and forward-backward correlations in
the centre-of-mass system of X. The data are compared to results in e+e-
annihilation, fixed-target lepton-nucleon collisions, hadro-produced
diffractive final states and to non-diffractive hadron-hadron collisions. The
comparison suggests a production mechanism of virtual photon dissociation which
involves a mixture of partonic states and a significant gluon content. The data
are well described by a model, based on a QCD-Regge analysis of the diffractive
structure function, which assumes a large hard gluonic component of the
colourless exchange at low Q^2. A model with soft colour interactions is also
successful.Comment: 22 pages, 4 figures, submitted to Eur. Phys. J., error in first
submission - omitted bibliograph
Low Q^2 Jet Production at HERA and Virtual Photon Structure
The transition between photoproduction and deep-inelastic scattering is
investigated in jet production at the HERA ep collider, using data collected by
the H1 experiment. Measurements of the differential inclusive jet
cross-sections dsigep/dEt* and dsigmep/deta*, where Et* and eta* are the
transverse energy and the pseudorapidity of the jets in the virtual
photon-proton centre of mass frame, are presented for 0 < Q2 < 49 GeV2 and 0.3
< y < 0.6. The interpretation of the results in terms of the structure of the
virtual photon is discussed. The data are best described by QCD calculations
which include a partonic structure of the virtual photon that evolves with Q2.Comment: 20 pages, 5 Figure
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