Are tyrosine kinase inhibitors promising for the treatment of systemic sclerosis and other fibrotic diseases?

Tissue fibrosis causes organ failure and death in patients with systemic sclerosis (SSc), but clearly effective anti-fibrotic therapies are not available. The tyrosine kinase inhibitor (TKI) imatinib, which blocks the pro-fibrotic c-Abl kinase and PDGF receptor, is currently evaluated in clinical proof-of-concept trials for the treatment of patients with SSc. In experimental models, imatinib efficiently prevented and reduced tissue fibrosis. First clinical case studies demonstrated anti-fibrotic effects of imatinib in selected patients with SSc and other fibrotic diseases, and observational studies in sclerotic chronic graft-versus-host disease showed promising results. Besides imatinib, the two novel TKIs of c-Abl and PDGF receptor nilotinib and dasatinib have recently proven efficacy in experimental models of SSc. The potential of TKIs of the VEGF receptor (e.g., semaxinib, vatalanib, sutent, and sorafenib) and the EGF receptor (e.g., erlotinib, gefitinib, lapatinib, and canertinib) as anti-fibrotic treatments are also discussed in this review. Prior to clinical use, however, controlled trials need to address efficacy as well as tolerability of TKIs in patients with different fibrotic diseases

Finite nilpotent semigroups of small coclass

The parameter coclass has been used successfully in the study of nilpotent algebraic objects of different kinds. In this paper a definition of coclass for nilpotent semigroups is introduced and semigroups of coclass 0, 1, and 2 are classified. Presentations for all such semigroups and formulae for their numbers are obtained. The classification is provided up to isomorphism as well as up to isomorphism or anti-isomorphism. Commutative and self-dual semigroups are identified within the classification.Comment: 11 page

Deformed Quantum Cohomology and (0,2) Mirror Symmetry

We compute instanton corrections to correlators in the genus-zero topological subsector of a (0,2) supersymmetric gauged linear sigma model with target space P1xP1, whose left-moving fermions couple to a deformation of the tangent bundle. We then deduce the theory's chiral ring from these correlators, which reduces in the limit of zero deformation to the (2,2) ring. Finally, we compare our results with the computations carried out by Adams et al.[ABS04] and Katz and Sharpe[KS06]. We find immediate agreement with the latter and an interesting puzzle in completely matching the chiral ring of the former.Comment: AMSLatex, 30 pages, one eps figure. V4: typos corrected, final version appearing in JHE

Frontiers of antifibrotic therapy in systemic sclerosis

Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in modern societies, targeted anti-fibrotic therapies are still not approved for most fibrotic disorders. However, intense research over the last decade has improved our understanding of the underlying pathogenesis of fibrotic diseases. We now appreciate fibrosis as the consequence of a persistent tissue repair responses, which, in contrast to normal wound healing, fails to be effectively terminated. Profibrotic mediators released from infiltrating leukocytes, activated endothelial cells and degranulated platelets may predominantly drive fibroblast activation and collagen release in early stages, whereas endogenous activation of fibroblasts due epigenetic modifications and biomechanical or physical factors such as stiffening of the extracellular matrix and hypoxia may play pivotal role for disease progression in later stages. In the present review, we discuss novel insights into the pathogenesis of fibrotic diseases using systemic sclerosis (SSc) as example for an idiopathic, multisystem disorder. We set a strong translational focus and predominantly discuss approaches with very high potential for rapid transfer from bench-to-bedside. We highlight the molecular basis for ongoing clinical trials in SSc and also provide an outlook on upcoming trials. This article is protected by copyright. All rights reserved

N=2 S-duality via Outer-automorphism Twists

Compactification of 6d N=(2,0) theory of type G on a punctured Riemann surface has been effectively used to understand S-dualities of 4d N=2 theories. We can further introduce branch cuts on the Riemann surface across which the worldvolume fields are transformed by the discrete symmetries associated to those of the Dynkin diagram of type G. This allows us to generate more S-dualities, and in particular to reproduce a couple of S-dual pairs found previously by Argyres and Wittig.Comment: 8 pages, 6 figure

On the Heterotic World-sheet Instanton Superpotential and its individual Contributions

For supersymmetric heterotic string compactifications on a Calabi-Yau threefold $X$ endowed with a vector bundle $V$ the world-sheet superpotential $W$ is a sum of contributions from isolated rational curves \C in $X$; the individual contribution is given by an exponential in the K\"ahler class of the curve times a prefactor given essentially by the Pfaffian which depends on the moduli of $V$ and the complex structure moduli of $X$. Solutions of $DW=0$ (or even of $DW=W=0$) can arise either by nontrivial cancellations between the individual terms in the summation over all contributing curves or because each of these terms is zero already individually. Concerning the latter case conditions on the moduli making a single Pfaffian vanish (for special moduli values) have been investigated. However, even if corresponding moduli - fulfilling these constraints - for the individual contribution of one curve are known it is not at all clear whether {\em one} choice of moduli exists which fulfills the corresponding constraints {\em for all contributing curves simultaneously}. Clearly this will in general happen only if the conditions on the 'individual zeroes' had already a conceptual origin which allows them to fit together consistently. We show that this happens for a class of cases. In the special case of spectral cover bundles we show that a relevant solution set has an interesting location in moduli space and is related to transitions which change the generation number.Comment: 47 page

An Exact Solution to O(26) Sigma Model coupled to 2-D Gravity

By a mapping to the bosonic string theory, we present an exact solution to the O(26) sigma model coupled to 2-D quantum gravity. In particular, we obtain the exact gravitational dressing to the various matter operators classified by the irreducible representations of O(26). We also derive the exact form of the gravitationally modified beta function for the original coupling constant $e^2$. The relation between our exact solution and the asymptotic solution given in ref[3] is discussed in various aspects.Comment: 10 pages, pupt-144

Hermitian Matrix Model with Plaquette Interaction

We study a hermitian $(n+1)$-matrix model with plaquette interaction, $\sum_{i=1}^n MA_iMA_i$. By means of a conformal transformation we rewrite the model as an $O(n)$ model on a random lattice with a non polynomial potential. This allows us to solve the model exactly. We investigate the critical properties of the plaquette model and find that for $n\in]-2,2]$ the model belongs to the same universality class as the $O(n)$ model on a random lattice.Comment: 15 pages, no figures, two references adde

A heterotic sigma model with novel target geometry

We construct a (1,2) heterotic sigma model whose target space geometry consists of a transitive Lie algebroid with complex structure on a Kaehler manifold. We show that, under certain geometrical and topological conditions, there are two distinguished topological half--twists of the heterotic sigma model leading to A and B type half--topological models. Each of these models is characterized by the usual topological BRST operator, stemming from the heterotic (0,2) supersymmetry, and a second BRST operator anticommuting with the former, originating from the (1,0) supersymmetry. These BRST operators combined in a certain way provide each half--topological model with two inequivalent BRST structures and, correspondingly, two distinct perturbative chiral algebras and chiral rings. The latter are studied in detail and characterized geometrically in terms of Lie algebroid cohomology in the quasiclassical limit.Comment: 83 pages, no figures, 2 references adde