151 research outputs found
Repurposing anthelmintic agents to eradicate resistant leukemia
Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia
High immunoproteasome activity and sXBP1 in pediatric precursor B-ALL predicts sensitivity towards proteasome inhibitors
Proteasome inhibitors (PIs) are approved backbone treatments in multiple myeloma. More recently, inhibition of proteasome activity with the PI bortezomib has been clinically evaluated as a novel treatment strategy in pediatric acute lymphoblastic leukemia (ALL). However, we lack a marker that could identify ALL patients responding to PI-based therapy. By using a set of activity-based proteasome probes in conjunction with cytotoxicity assays, we show that B-cell precursor ALL (BCP-ALL), in contrast to T-ALL, demonstrates an increased activity of immunoproteasome over constitutive proteasome, which correlates with high ex vivo sensitivity to the PIs bortezomib and ixazomib. The novel selective PI LU015i-targeting immunoproteasome beta 5i induces cytotoxicity in BCP-ALL containing high beta 5i activity, confirming immunoproteasome activity as a novel therapeutic target in BCP-ALL. At the same time, cotreatment with beta 2-selective proteasome inhibitors can sensitize T-ALL to currently available PIs, as well as to beta 5i selective PI. In addition, levels of total and spliced forms of XBP1 differ between BCP-ALL and T-ALL, and only in BCP-ALL does high-spliced XBP1 correlate with sensitivity to bortezomib. Thus, in BCP-ALL, high immunoproteasome activity may serve as a predictive marker for PI-based treatment options, potentially combined with XBP1 analyses.Bio-organic Synthesi
Momentum asymmetries as CP violating observables
Three body decays can exhibit CP violation that arises from interfering
diagrams with different orderings of the final state particles. We construct
several momentum asymmetry observables that are accessible in a hadron collider
environment where some of the final state particles are not reconstructed and
not all the kinematic information can be extracted. We discuss the
complications that arise from the different possible production mechanisms of
the decaying particle. Examples involving heavy neutralino decays in
supersymmetric theories and heavy Majorana neutrino decays in Type-I seesaw
models are examined.Comment: 20 pages, 9 figures. Clarifying comments and one reference added,
matches published versio
Constraints on supersymmetry with light third family from LHC data
We present a re-interpretation of the recent ATLAS limits on supersymmetry in
channels with jets (with and without b-tags) and missing energy, in the context
of light third family squarks, while the first two squark families are
inaccessible at the 7 TeV run of the Large Hadron Collider (LHC). In contrast
to interpretations in terms of the high-scale based constrained minimal
supersymmetric standard model (CMSSM), we primarily use the low-scale
parametrisation of the phenomenological MSSM (pMSSM), and translate the limits
in terms of physical masses of the third family squarks. Side by side, we also
investigate the limits in terms of high-scale scalar non-universality, both
with and without low-mass sleptons. Our conclusion is that the limits based on
0-lepton channels are not altered by the mass-scale of sleptons, and can be
considered more or less model-independent.Comment: 20 pages, 8 figures, 2 tables. Version published in JHE
Stop the Top Background of the Stop Search
The main background for the supersymmetric stop direct production search
comes from Standard Model ttbar events. For the single-lepton search channel,
we introduce a few kinematic variables to further suppress this background by
focusing on its dileptonic and semileptonic topologies. All are defined to have
end points in the background, but not signal distributions. They can
substantially improve the stop signal significance and mass reach when combined
with traditional kinematic variables such as the total missing transverse
energy. Among them, our variable M^W_T2 has the best overall performance
because it uses all available kinematic information, including the on-shell
mass of both W's. We see 20%-30% improvement on the discovery significance and
estimate that the 8 TeV LHC run with 20 fb-1 of data would be able to reach an
exclusion limit of 650-700 GeV for direct stop production, as long as the stop
decays dominantly to the top quark and a light stable neutralino. Most of the
mass range required for the supersymmetric solution of the naturalness problem
in the standard scenario can be covered.Comment: 16 pages, 5 figure
Light Stop Decay in the MSSM with Minimal Flavour Violation
In supersymmetric scenarios with a light stop particle and a
small mass difference to the lightest supersymmetric particle (LSP) assumed to
be the lightest neutralino, the flavour changing neutral current decay
can be the dominant decay channel and can
exceed the four-body stop decay for certain parameter values. In the framework
of Minimal Flavour Violation (MFV) this decay is CKM-suppressed, thus inducing
long stop lifetimes. Stop decay length measurements at the LHC can then be
exploited to test models with minimal flavour breaking through Standard Model
Yukawa couplings. The decay width has been given some time ago by an
approximate formula, which takes into account the leading logarithms of the MFV
scale. In this paper we calculate the exact one-loop decay width in the
framework of MFV. The comparison with the approximate result exhibits
deviations of the order of 10% for large MFV scales due to the neglected
non-logarithmic terms in the approximate decay formula. The difference in the
branching ratios is negligible. The large logarithms have to be resummed. The
resummation is performed by the solution of the renormalization group
equations. The comparison of the exact one-loop result and the tree level
flavour changing neutral current decay, which incorporates the resummed
logarithms, demonstrates that the resummation effects are important and should
be taken into account.Comment: 29 page
Many faces of low mass neutralino dark matter in the unconstrained MSSM, LHC data and new signals
If all strongly interacting sparticles (the squarks and the gluinos) in an
unconstrained minimal supersymmetric standard model (MSSM) are heavier than the
corresponding mass lower limits in the minimal supergravity (mSUGRA) model,
obtained by the current LHC experiments, then the existing data allow a variety
of electroweak (EW) sectors with light sparticles yielding dark matter (DM)
relic density allowed by the WMAP data. Some of the sparticles may lie just
above the existing lower bounds from LEP and lead to many novel DM producing
mechanisms not common in mSUGRA. This is illustrated by revisiting the above
squark-gluino mass limits obtained by the ATLAS Collaboration, with an
unconstrained EW sector with masses not correlated with the strong sector.
Using their selection criteria and the corresponding cross section limits, we
find at the generator level using Pythia, that the changes in the mass limits,
if any, are by at most 10-12% in most scenarios. In some cases, however, the
relaxation of the gluino mass limits are larger (). If a subset of
the strongly interacting sparticles in an unconstrained MSSM are within the
reach of the LHC, then signals sensitive to the EW sector may be obtained. This
is illustrated by simulating the \etslash, , and \etslash signals in i) the light stop scenario and ii) the light
stop-gluino scenario with various light EW sectors allowed by the WMAP data.
Some of the more general models may be realized with non-universal scalar and
gaugino masses.Comment: 27 pages, 1 figure, references added, minor changes in text, to
appear in JHE
CP asymmetries in the supersymmetric trilepton signal at the LHC
In the CP-violating Minimal Supersymmetric Standard Model, we study the
production of a neutralino-chargino pair at the LHC. For their decays into
three leptons, we analyze CP asymmetries which are sensitive to the CP phases
of the neutralino and chargino sector. We present analytical formulas for the
entire production and decay process, and identify the CP-violating
contributions in the spin correlation terms. This allows us to define the
optimal CP asymmetries. We present a detailed numerical analysis of the cross
sections, branching ratios, and the CP observables. For light neutralinos,
charginos, and squarks, the asymmetries can reach several 10%. We estimate the
discovery potential for the LHC to observe CP violation in the trilepton
channel.Comment: 39 pages, 8 figures, version to appear in EPJC, discussion(s) added,
typo in (D.79), (D.118) corrected, new Fig. 7; The European Physical Journal
C, Volume 72, Issue 3, 201
Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.
TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease
Divergent evolution of terrestrial locomotor abilities in extant Crocodylia
Extant Crocodylia are exceptional because they employ almost the full range of quadrupedal footfall patterns (“gaits”) used by mammals; including asymmetrical gaits such as galloping and bounding. Perhaps this capacity evolved in stem Crocodylomorpha, during the Triassic when taxa were smaller, terrestrial, and long-legged. However, confusion about which Crocodylia use asymmetrical gaits and why persists, impeding reconstructions of locomotor evolution. Our experimental gait analysis of locomotor kinematics across 42 individuals from 15 species of Crocodylia obtained 184 data points for a wide velocity range (0.15–4.35 ms−1). Our results suggest either that asymmetrical gaits are ancestral for Crocodylia and lost in the alligator lineage, or that asymmetrical gaits evolved within Crocodylia at the base of the crocodile line. Regardless, we recorded usage of asymmetrical gaits in 7 species of Crocodyloidea (crocodiles); including novel documentation of these behaviours in 5 species (3 critically endangered). Larger Crocodylia use relatively less extreme gait kinematics consistent with steeply decreasing athletic ability with size. We found differences between asymmetrical and symmetrical gaits in Crocodylia: asymmetrical gaits involved greater size-normalized stride frequencies and smaller duty factors (relative ground contact times), consistent with increased mechanical demands. Remarkably, these gaits did not differ in maximal velocities obtained: whether in Alligatoroidea or Crocodyloidea, trotting or bounding achieved similar velocities, revealing that the alligator lineage is capable of hitherto unappreciated extreme locomotor performance despite a lack of asymmetrical gait usage. Hence asymmetrical gaits have benefits other than velocity capacity that explain their prevalence in Crocodyloidea and absence in Alligatoroidea—and their broader evolution
- …