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 $\tilde{t}_1$ and a small mass difference to the lightest supersymmetric particle (LSP) assumed to be the lightest neutralino, the flavour changing neutral current decay $\tilde{t}_1 \to c \tilde{\chi}_1^0$ 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 ($\approx 20$). 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 $blj$\etslash, $l= e and \mu$, and $b\tau j$\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