Heterotic compactifications with principal bundles for general groups and general levels

We examine to what extent heterotic string worldsheets can describe arbitrary E8xE8 gauge fields. The traditional construction of heterotic strings builds each E8 via a Spin(16)/Z2 subgroup, typically realized as a current algebra by left-moving fermions, and as a result, only E8 gauge fields reducible to Spin(16)/Z2 gauge fields are directly realizable in standard constructions. However, there exist perturbatively consistent E8 gauge fields which can not be reduced to Spin(16)/Z2, and so cannot be described within standard heterotic worldsheet constructions. A natural question to then ask is whether there exists any (0,2) SCFT that can describe such E8 gauge fields. To answer this question, we first show how each ten-dimensional E8 partition function can be built up using other subgroups than Spin(16)/Z2, then construct ``fibered WZW models'' which allow us to explicitly couple current algebras for general groups and general levels to heterotic strings. This technology gives us a very general approach to handling heterotic compactifications with arbitrary principal bundles. It also gives us a physical realization of some elliptic genera constructed recently by Ando and Liu.Comment: 48 pages, LaTeX; v2: references added; v3: typos fixe

Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosis

Tissue fibrosis is a major cause of death in SSc, but therapies that target selectively fibrosis are not yet available for routine clinical use. Recent pre-clinical studies suggest that selective tyrosine kinase inhibitors that target c-Abl, PDGF receptor or Src kinases might be promising targets for anti-fibrotic approaches. Dual inhibition of c-Abl and PDGF receptor by imatinib and nilotinib, and inhibition of Src kinases either selectively by SU6656 or in combination with c-Abl and PDGF by dasatinib exerted potent anti-fibrotic effects. Imatinib, nilotinib, dasatinib and SU6656 reduced dose-dependently the synthesis of extracellular matrix protein in human dermal fibroblasts in vitro and prevented fibrosis in the mouse model of bleomycin-induced skin fibrosis. Clinical data from patients with chronic myelogenous leukaemia suggest that imatinib, nilotinib and dasatinib are well tolerated. Based on the promising pre-clinical data, imatinib is currently evaluated in clinical trials for the treatment of fibrosis in SSc and trials with other tyrosine kinase inhibitors are in preparatio

Criteria to select molecular targets for anti-fibrotic therapy

Tissue fibrosis is a major cause of morbidity and mortality in SSc. An increasing number of promising molecular targets for anti-fibrotic therapies have been described recently. However, the number of patients eligible for clinical trials is limited in SSc. The present article discusses criteria to select the most promising molecular targets for clinical trials in SSc. Based on consensus among experts, important criteria for the selection of molecular-based therapies were as follows: First, there should be strong experimental evidence that targeting the molecule of interest inhibits fibrosis. Optimally, the anti-fibrotic effects should be confirmed in at least two complementary animal models of SSc. Second, inhibitors of the molecule of interest should be clinically available. Third, clinical experience with the drug of interest in other diseases hastens the initiation of clinical trials and reduces the risk of unexpected side-effects. Finally, funding for clinical trials with the drug of interest in SSc should be available. We propose that the priority of novel targets for evaluation in clinical trials in SSc might be selected based on these consensus criteri

World-sheet Stability of (0,2) Linear Sigma Models

We argue that two-dimensional (0,2) gauged linear sigma models are not destabilized by instanton generated world-sheet superpotentials. We construct several examples where we show this to be true. The general proof is based on the Konishi anomaly for (0,2) theories.Comment: 18 pages, LaTe

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

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

Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis

Activation of the immune system and increased synthesis of extracellular matrix proteins by fibroblasts are hallmarks in the pathogenesis of SSc. The molecular mechanisms underlying the infiltration of inflammatory cells into the skin and the subsequent activation of fibroblasts are still largely unknown. Chemokines are a family of small molecules that are classified according to the position of the NH2-terminal cysteine motif. Recent data indicate that chemokines and in particular two members of the subfamily of monocyte chemoattractant proteins, MCP-1 (CCL-2) and MCP-3 (CCL-7), might be involved in the pathogenesis of SSc. MCP-1 and -3 are overexpressed by SSc fibroblasts and in skin lesions from SSc patients compared to healthy controls. MCP-1 and -3 are chemotactic for inflammatory cells and stimulate their migration into the skin. In addition to their pro-inflammatory effects, MCP-1 and -3 contribute to tissue fibrosis by activating the synthesis of extracellular matrix proteins in SSc fibroblasts. Therapeutic strategies targeting MCP-1 have revealed promising results in several animal models of SSc. Antagonists against the receptor CCR2 are currently tested in clinical trials of a variety of diseases and also represent interesting candidates for target-directed therapy in SS