Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL

New Gauged Linear Sigma Models for 8D HyperKahler Manifolds and Calabi-Yau Crystals

We propose two kinds of gauged linear sigma models whose moduli spaces are real eight-dimensional hyperKahler and Calabi-Yau manifolds, respectively. Here, hyperKahler manifolds have sp(2) holonomy in general and are dual to Type IIB (p,q)5-brane configurations. On the other hand, Calabi-Yau fourfolds are toric varieties expressed as quotient spaces. Our model involving fourfolds is different from the usual one which is directly related to a symplectic quotient procedure. Remarkable features in newly-found three-dimensional Chern-Simons-matter theories appear here as well, such as dynamical Fayet-Iliopoulos parameters, one dualized photon and its residual discrete gauge symmetry.Comment: 20 pages, 1 figure; v2: minor changes and references added; v3: statements improved, newer than JHEP versio

TWAM: A Certifying Abstract Machine for Logic Programs

Type-preserving (or typed) compilation uses typing derivations to certify correctness properties of compilation. We have designed and implemented a type-preserving compiler for a simply-typed dialect of Prolog we call T-Prolog. The crux of our approach is a new certifying abstract machine which we call the Typed Warren Abstract Machine (TWAM). The TWAM has a dependent type system strong enough to specify the semantics of a logic program in the logical framework LF. We present a soundness metatheorem which constitutes a partial correctness guarantee: well-typed programs implement the logic program specified by their type. This metatheorem justifies our design and implementation of a certifying compiler from T-Prolog to TWAM.Comment: 41 pages, under submission to ACM Transactions on Computational Logi

Three-dimensional geometric morphometrics of thorax-pelvis covariation and its potential for predicting the thorax morphology: A case study on Kebara 2 Neandertal

The skeletal torso is a complex structure of outstanding importance in understanding human body shape evolution, but reconstruction usually entails an element of subjectivity as researchers apply their own anatomical expertise to the process. Among different fossil reconstruction methods, 3D geometric morphometric techniques have been increasingly used in the last decades. Two-block partial least squares analysis has shown great potential for predicting missing elements by exploiting the covariation between two structures (blocks) in a reference sample: one block can be predicted from the other one based on the strength of covariation between blocks. The first aim of this study is to test whether this predictive approach can be used for predicting thorax morphologies from pelvis morphologies within adult Homo sapiens reference samples with known covariation between the thorax and the pelvis. The second aim is to apply this method to Kebara 2 Neandertal (Israel, ∼60 ka) to predict its thorax morphology using two different pelvis reconstructions as predictors. We measured 134 true landmarks, 720 curve semilandmarks, and 160 surface semilandmarks on 60 3D virtual torso models segmented from CT scans. We conducted three two-block partial least squares analyses between the thorax (block 1) and the pelvis (block 2) based on the H. sapiens reference samples after performing generalized Procrustes superimposition on each block separately. Comparisons of these predictions in full shape space by means of Procrustes distances show that the male-only predictive model yields the most reliable predictions within modern humans. In addition, Kebara 2 thorax predictions based on this model concur with the thorax morphology proposed for Neandertals. The method presented here does not aim to replace other techniques, but to rather complement them through quantitative prediction of a virtual 'scaffold' to articulate the thoracic fossil elements, thus extending the potential of missing data estimation beyond the methods proposed in previous works

Therapeutic targeting of CK2 in acute and chronic leukemias

CK2 is a ubiquitously expressed, constitutively active Ser/Thr protein kinase, which is considered the most pleiotropic protein kinase in the human kinome. Such a pleiotropy explains the involvement of CK2 in many cellular events. However, its predominant roles are stimulation of cell growth and prevention of apoptosis. High levels of CK2 messenger RNA and protein are associated with CK2 pathological functions in human cancers. Over the last decade, basic and translational studies have provided evidence of CK2 as a pivotal molecule driving the growth of different blood malignancies. CK2 overexpression has been demonstrated in nearly all the types of hematological cancers, including acute and chronic leukemias, where CK2 is a key regulator of signaling networks critical for cell proliferation, survival and drug resistance. The findings that emerged from these studies suggest that CK2 could be a valuable therapeutic target in leukemias and supported the initiation of clinical trials using CK2 antagonists. In this review, we summarize the recent advances on the understanding of the signaling pathways involved in CK2 inhibition-mediated effects with a particular emphasis on the combinatorial use of CK2 inhibitors as novel therapeutic strategies for treating both acute and chronic leukemia patients

Supersymmetric Extension of GCA in 2d

We derive the infinite dimensional Supersymmetric Galilean Conformal Algebra (SGCA) in the case of two spacetime dimensions by performing group contraction on 2d superconformal algebra. We also obtain the representations of the generators in terms of superspace coordinates. Here we find realisations of the SGCA by considering scaling limits of certain 2d SCFTs which are non-unitary and have their left and right central charges become large in magnitude and opposite in sign. We focus on the Neveu-Schwarz sector of the parent SCFTs and develop, in parallel to the GCA studies recently in (arXiv:0912.1090), the representation theory based on SGCA primaries, Ward identities for their correlation functions and their descendants which are null states.Comment: La TeX file, 32 pages; v2: typos corrected, journal versio

Four-Dimensional SCFTs from M5-Branes

We engineer a large new set of four-dimensional N=1 superconformal field theories by wrapping M5-branes on complex curves. We present new supersymmetric AdS_5 M-theory backgrounds which describe these fixed points at large N, and then directly construct the dual four-dimensional CFTs for a certain subset of these solutions. Additionally, we provide a direct check of the central charges of these theories by using the M5-brane anomaly polynomial. This is a companion paper which elaborates upon results reported in arXiv:1112:5487.Comment: 45 pages, 11 figure