1,129 research outputs found
Abundant and equipotent founder cells establish and maintain acute lymphoblastic leukaemia
High frequencies of blasts in primary acute lymphoblastic leukaemia (ALL) samples have the potential to induce leukaemia and to engraft mice. However, it is unclear how individual ALL cells each contribute to drive leukaemic development in a bulk transplant and the extent to which these blasts vary functionally. We used cellular barcoding as a fate mapping tool to track primograft ALL blasts in vivo. Our results show that high numbers of ALL founder cells contribute at similar frequencies to leukaemic propagation over serial transplants, without any clear evidence of clonal succession. These founder cells also exhibit equal capacity to home and engraft to different organs, although stochastic processes may alter the composition in restrictive niches. Our findings enhance the stochastic stem cell model of ALL by demonstrating equal functional abilities of singular ALL blasts and show that successful treatment strategies must eradicate the entire leukaemic cell population
The MLL-Menin Interaction is a Therapeutic Vulnerability in <em>NUP98</em>-rearranged AML
\ua9 2023 Wolters Kluwer Health. All rights reserved. Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors
Measurement of the electron electric dipole moment using GdIG
A new method for the detection of the electron edm using a solid is
described. The method involves the measurement of a voltage induced across the
solid by the alignment of the samples magnetic dipoles in an applied magnetic
field, H. A first application of the method to GdIG has resulted in a limit on
the electron edm of 5E-24 e-cm, which is a factor of 40 below the limit
obtained from the only previous solid-state edm experiment. The result is
limited by the imperfect discrimination of an unexpectedly large voltage that
is even upon the reversal of the sample magnetization.Comment: 10 pages, 5 figures, v2:references corrected, submitted to PRL,
v3:added labels to figure
RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML
Acute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors. RUNX1-EVI1 directs a stem cell-like transcriptional network reliant on GATA2, whereas that of RUNX1-ETO-expressing cells is more mature and depends on RUNX1. However, both types of AML are dependent on the continuous expression of the fusion proteins. Our data provide a molecular explanation for the differences in clinical prognosis for these types of AML
Long-lasting XUV activation of helium nanodroplets for avalanche ionization
We study the dynamics of avalanche ionization of pure helium nanodroplets
activated by a weak extreme-ultraviolet (XUV) pulse and driven by an intense
near-infrared (NIR) pulse. In addition to a transient enhancement of ignition
of a nanoplasma at short delay times ~fs, long-term activation of the
nanodroplets lasting up to a few nanoseconds is observed. Molecular dynamics
simulations suggest that the short-term activation is caused by the injection
of seed electrons into the droplets by XUV photoemission. Long-term activation
appears due to electrons remaining loosely bound to photoions which form stable
`snowball' structures in the droplets. Thus, we show that XUV irradiation can
induce long-lasting changes of the strong-field optical properties of
nanoparticles, potentially opening new routes to controlling
avalanche-ionization phenomena in nanostructures and condensed-phase systems
Self-similar solution of a nonsteady problem of nonisothermal vapour condensation on a droplet growing in diffusion regime
This paper presents a mathematically exact self-similar solution to the joint
nonsteady problems of vapour diffusion towards a droplet growing in a
vapour-gas medium and of removal of heat released by a droplet into a
vapour-gas medium during vapour condensation. An equation for the temperature
of the droplet is obtained; and it is only at that temperature that the
self-similar solution exists. This equation requires the constancy of the
droplet temperature and even defines it unambiguously throughout the whole
period of the droplet growth. In the case of strong display of heat effects,
when the droplet growth rate decreases significantly, the equation for the
temperature of the droplet is solved analytically. It is shown that the
obtained temperature fully coincides with the one that settles in the droplet
simultaneously with the settlement of its diffusion regime of growth. At the
obtained temperature of the droplet the interrelated nonsteady vapour
concentration and temperature profiles of the vapour-gas medium around the
droplet are expressed in terms of initial (prior to the nucleation of the
droplet) parameters of the vapour-gas medium. The same parameters are used to
formulate the law in accordance with which the droplet is growing in diffusion
regime, and also to define the time that passes after the nucleation of the
droplet till the settlement of diffusion regime of droplet growth, when the
squared radius of the droplet becomes proportionate to time. For the sake of
completeness the case of weak display of heat effects is been studied.Comment: 12 pages, 4 figure
Cost and value in contemporary heart failure clinical guidance documents
OBJECTIVES: This study sought to evaluate the frequency and nature of cost/value statements in contemporary heart failure (HF) clinical guidance documents (CGDs).
BACKGROUND: In an era of rising health care costs and expanding therapeutic options, there is an increasing need for formal consideration of cost and value in the development of HF CGDs.
METHODS: HF CGDs published by major professional cardiovascular organizations between January 2010 and February 2021 were reviewed for the inclusion of cost/value statements.
RESULTS: Overall, 33 documents were identified, including 5 (15%) appropriate use criteria, 7 (21%) clinical practice guidelines, and 21 (64%) expert consensus documents. Most CGDs (27 of 33; 82%) included at least 1 cost/value statement, and 20 (61%) CGDs included at least 1 cost/value-related citation. Most of these statements were found in expert consensus documents (77.7%). Three (9%) documents reported estimated costs of recommended interventions, but only 1 estimated out-of-pocket cost. Of 179 cost/value-related statements observed, 116 (64.8%) highlighted the economic impact of HF or HF-related care, 6 (3.4%) advocated for cost/value issues, 15 (8.4%) reported gaps in cost/value evidence, and 42 (23.5%) supported clinical guidance recommendations. Over time, patterns of inclusion of statements and citations of cost/value have been largely stable.
CONCLUSIONS: Although most contemporary HF CGDs contain at least 1 cost/value statement, most CGDs focus on the high economic impact of HF and its related care; explicit inclusion of cost/value to support clinical guidance recommendations remains infrequent. These results highlight key opportunities for the integration of formalized cost/value considerations in future HF-focused CGDs
Spectrum of Chiral Operators in Strongly Coupled Gauge Theories
We analyze the large spectrum of chiral primary operators of three
dimensional fixed points of the renormalization group. Using the space-time
picture of the fixed points and the correspondence between anti-de Sitter
compactifications and conformal field theories we are able to extract the
dimensions of operators in short superconformal multiplets. We write down some
of these operators in terms of short distance theories flowing to these
non-trivial fixed points in the infrared.Comment: harvmac, 16 pages, one acknowledgement adde
Soft branes in supersymmetry-breaking backgrounds
We revisit the analysis of effective field theories resulting from
non-supersymmetric perturbations to supersymmetric flux compactifications of
the type-IIB superstring with an eye towards those resulting from the
backreaction of a small number of anti-D3-branes. Independently of the
background, we show that the low-energy Lagrangian describing the fluctuations
of a stack of probe D3-branes exhibits soft supersymmetry breaking, despite
perturbations to marginal operators that were not fully considered in some
previous treatments. We take this as an indication that the breaking of
supersymmetry by anti-D3-branes or other sources may be spontaneous rather than
explicit. In support of this, we consider the action of an anti-D3-brane
probing an otherwise supersymmetric configuration and identify a candidate for
the corresponding goldstino.Comment: 36+5 pages. References added, minor typos correcte
Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1
\ua9 2024 The Author(s). AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier
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