Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34<sup>+</sup>38<sup>lo</sup>) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells <i>in vitro</i>. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34<sup>+</sup> cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease

Ramond-Ramond Cohomology and O(D,D) T-duality

In the name of supersymmetric double field theory, superstring effective actions can be reformulated into simple forms. They feature a pair of vielbeins corresponding to the same spacetime metric, and hence enjoy double local Lorentz symmetries. In a manifestly covariant manner --with regard to O(D,D) T-duality, diffeomorphism, B-field gauge symmetry and the pair of local Lorentz symmetries-- we incorporate R-R potentials into double field theory. We take them as a single object which is in a bi-fundamental spinorial representation of the double Lorentz groups. We identify cohomological structure relevant to the field strength. A priori, the R-R sector as well as all the fermions are O(D,D) singlet. Yet, gauge fixing the two vielbeins equal to each other modifies the O(D,D) transformation rule to call for a compensating local Lorentz rotation, such that the R-R potential may turn into an O(D,D) spinor and T-duality can flip the chirality exchanging type IIA and IIB supergravities.Comment: 1+37 pages, no figure; Structure reorganized, References added, To appear in JHEP. cf. Gong Show of Strings 2012 (http://wwwth.mpp.mpg.de/members/strings/strings2012/strings_files/program/Talks/Thursday/Gongshow/Lee.pdf

On the Riemann Tensor in Double Field Theory

Double field theory provides T-duality covariant generalized tensors that are natural extensions of the scalar and Ricci curvatures of Riemannian geometry. We search for a similar extension of the Riemann curvature tensor by developing a geometry based on the generalized metric and the dilaton. We find a duality covariant Riemann tensor whose contractions give the Ricci and scalar curvatures, but that is not fully determined in terms of the physical fields. This suggests that \alpha' corrections to the effective action require \alpha' corrections to T-duality transformations and/or generalized diffeomorphisms. Further evidence to this effect is found by an additional computation that shows that there is no T-duality invariant four-derivative object built from the generalized metric and the dilaton that reduces to the square of the Riemann tensor.Comment: 36 pages, v2: minor changes, ref. added, v3: appendix on frame formalism added, version to appear in JHE

A Double Sigma Model for Double Field Theory

We define a sigma model with doubled target space and calculate its background field equations. These coincide with generalised metric equation of motion of double field theory, thus the double field theory is the effective field theory for the sigma model.Comment: 26 pages, v1: 37 pages, v2: references added, v3: updated to match published version - background and detail of calculations substantially condensed, motivation expanded, refs added, results unchange

Massive Type II in Double Field Theory

We provide an extension of the recently constructed double field theory formulation of the low-energy limits of type II strings, in which the RR fields can depend simultaneously on the 10-dimensional space-time coordinates and linearly on the dual winding coordinates. For the special case that only the RR one-form of type IIA carries such a dependence, we obtain the massive deformation of type IIA supergravity due to Romans. For T-dual configurations we obtain a `massive' but non-covariant formulation of type IIB, in which the 10-dimensional diffeomorphism symmetry is deformed by the mass parameter.Comment: 21 page

Large Gauge Transformations in Double Field Theory

Finite gauge transformations in double field theory can be defined by the exponential of generalized Lie derivatives. We interpret these transformations as `generalized coordinate transformations' in the doubled space by proposing and testing a formula that writes large transformations in terms of derivatives of the coordinate maps. Successive generalized coordinate transformations give a generalized coordinate transformation that differs from the direct composition of the original two. Instead, it is constructed using the Courant bracket. These transformations form a group when acting on fields but, intriguingly, do not associate when acting on coordinates.Comment: 40 pages, v2: discussion of dilaton added, to appear in JHE

N=1 Supersymmetric Double Field Theory

We construct the N=1 supersymmetric extension of double field theory for D=10, including the coupling to an arbitrary number n of abelian vector multiplets. This theory features a local O(1,9+n) x O(1,9) tangent space symmetry under which the fermions transform. It is shown that the supersymmetry transformations close into the generalized diffeomorphisms of double field theory.Comment: 22 pages, v2: minor corrections, ref. added, to appear in JHE

Gauged Double Field Theory

We find necessary and sufficient conditions for gauge invariance of the action of Double Field Theory (DFT) as well as closure of the algebra of gauge symmetries. The so-called weak and strong constraints are sufficient to satisfy them, but not necessary. We then analyze compactifications of DFT on twisted double tori satisfying the consistency conditions. The effective theory is a Gauged DFT where the gaugings come from the duality twists. The action, bracket, global symmetries, gauge symmetries and their closure are computed by twisting their analogs in the higher dimensional DFT. The non-Abelian heterotic string and lower dimensional gauged supergravities are particular examples of Gauged DFT.Comment: Minor changes, references adde