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High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.
Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT
Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.
Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission
Holographic Anyons in the ABJM Theory
We consider the holographic anyons in the ABJM theory from three different
aspects of AdS/CFT correspondence. First, we identify the holographic anyons by
using the field equations of supergravity, including the Chern-Simons terms of
the probe branes. We find that the composite of Dp-branes wrapped over CP3 with
the worldvolume magnetic fields can be the anyons. Next, we discuss the
possible candidates of the dual anyonic operators on the CFT side, and find the
agreement of their anyonic phases with the supergravity analysis. Finally, we
try to construct the brane profile for the holographic anyons by solving the
equations of motion and Killing spinor equations for the embedding profile of
the wrapped branes. As a by product, we find a BPS spiky brane for the dual
baryons in the ABJM theory.Comment: 1+33 pages, 3 figures; v2 discussion for D4-D6 case added, references
added; v3 comments adde
Decays of metastable vacua in SQCD
The decay rates of metastable SQCD vacua in ISS-type models, both towards
supersymmetric vacua as well as towards other nonsupersymmetric configurations
arising in theories with elementary spectators, are estimated numerically in
the semiclassical approximation by computing the corresponding multifield
bounce configurations. The scaling of the bounce action with respect to the
most relevant dimensionless couplings and ratios of scales is analyzed. In the
case of the decays towards the susy vacua generated by nonperturbative effects,
the results confirm previous analytical estimations of this scaling, obtained
by assuming a triangular potential barrier. The decay rates towards susy vacua
generated by R-symmetry breaking interactions turn out to be more than
sufficiently suppressed for the phenomenologically relevant parameter range,
and their behavior in this regime differs from analytic estimations valid for
parametrically small scale ratios. It is also shown that in models with
spectator fields, even though the decays towards vacua involving nonzero
spectator VEVs don't have a strong parametric dependence on the scale ratios,
the ISS vacuum can still be made long-lived in the presence of R-symmetry
breaking interactions.Comment: 22 pages, 7 figure
Geometry of open strings ending on backreacting D3-branes
We investigate open string theory on backreacting D3-branes using a spacetime
approach. We study in detail the half-BPS supergravity solutions describing
open strings ending on D3-branes, in the near horizon of the D3-branes. We
recover quantitatively several non-trivial features of open string physics
including the appearance of D3-brane spikes, the polarization of fundamental
strings into D5-branes, and the Hanany-Witten effect. Finally we detail the
computation of the gravitational potential between two open strings, and
contrast it with the holographic computation of Wilson lines. We argue that the
D-brane backreaction has a large influence on the low-energy gravity, which may
lead to experimental tests for string theory brane-world scenarios.Comment: 64 pages, 20 figure
Chiral Generations on Intersecting 5-branes in Heterotic String Theory
We show that there exist two 27 and one 27 bar of E6, net one D=4, N=1 chiral
matter supermultiplet as zero modes localized on the intersection of two
5-branes in the E8 x E8 heterotic string theory. The smeared intersecting
5-brane solution is used via the standard embedding to construct a heterotic
background, which provides, after a compactification of some of the transverse
dimensions, a five-dimensional Randall-Sundrum II like brane-world set-up in
heterotic string theory. As a by-product, we present a new proof of anomaly
cancellation between those from the chiral matter and the anomaly inflow onto
the brane without small instanton.Comment: 26 pages, 5 figures; references added, typo correcte
Moving Branes with Background Massless and Tachyon Fields in the Compact Spacetime
In this article we shall obtain the boundary state associated with a moving
-brane in the presence of the Kalb-Ramond field , an internal
U(1) gauge field and a tachyon field, in the compact spacetime.
According to this state, properties of the brane and a closed string, with
mixed boundary conditions emitted from it, will be obtained. Using this
boundary state we calculate the interaction amplitude of two moving
and -branes with above background fields in a partially compact
spacetime. They are parallel or perpendicular to each other. Properties of the
interaction amplitude will be analyzed and contribution of the massless states
to the interaction will be extracted.Comment: 13 pages, Latex, no figur
P19-23. Putative prefusion mechanism of HIV-1 Env revealed by ligand-induced quaternary alterations in o-gp140 trimers
International audienc
The -theorem and the Asymptotics of 4D Quantum Field Theory
We study the possible IR and UV asymptotics of 4D Lorentz invariant unitary
quantum field theory. Our main tool is a generalization of the
Komargodski-Schwimmer proof for the -theorem. We use this to rule out a
large class of renormalization group flows that do not asymptote to conformal
field theories in the UV and IR. We show that if the IR (UV) asymptotics is
described by perturbation theory, all beta functions must vanish faster than
as (). This implies that the
only possible asymptotics within perturbation theory is conformal field theory.
In particular, it rules out perturbative theories with scale but not conformal
invariance, which are equivalent to theories with renormalization group
pseudocycles. Our arguments hold even for theories with gravitational
anomalies. We also give a non-perturbative argument that excludes theories with
scale but not conformal invariance. This argument holds for theories in which
the stress-energy tensor is sufficiently nontrivial in a technical sense that
we make precise.Comment: 41 pages, 2 figures. v2: Arguments clarified, some side comments
corrected, connection to previous work by Jack and Osborn described,
conclusions unaffecte
Quantum AdS_5 x S^5 superstring in the AdS light-cone gauge
We consider the AdS_5 x S^5 superstring in the light-cone gauge adapted to a
massless geodesic in AdS5 in the Poincare patch. The resulting action has a
relatively simple structure which makes it a natural starting point for various
perturbative quantum computations. We illustrate the utility of this AdS
light-cone gauge action by computing the 1-loop and 2-loop corrections to the
null cusp anomalous dimension reproducing in a much simpler and efficient way
earlier results obtained in conformal gauge. This leads to a further insight
into the structure of the superstring partition function in non-trivial
background.Comment: 21pages, Late
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