ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a KrasG12D/p53R172H mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three‐dimensional collagen matrices by increasing matrix remodeling activities. RNA sequencing revealed a coordinated program of ROCK‐induced genes that facilitate extracellular matrix remodeling, with greatest fold‐changes for matrix metalloproteinases (MMPs) Mmp10 and Mmp13. MMP inhibition not only decreased collagen degradation and invasion, but also reduced proliferation in three‐dimensional contexts. Treatment of KrasG12D/p53R172H PDAC mice with a ROCK inhibitor prolonged survival, which was associated with increased tumor‐associated collagen. These findings reveal an ancillary role for increased ROCK signaling in pancreatic cancer progression to promote extracellular matrix remodeling that facilitates proliferation and invasive tumor growth

The lightcone of G\"odel-like spacetimes

A study of the lightcone of the G\"odel universe is extended to the so-called G\"odel-like spacetimes. This family of highly symmetric 4-D Lorentzian spaces is defined by metrics of the form $ds^2=-(dt+H(x)dy)^2+D^2(x)dy^2+dx^2+dz^2$, together with the requirement of spacetime homogeneity, and includes the G\"odel metric. The quasi-periodic refocussing of cone generators with startling lens properties, discovered by Ozsv\'{a}th and Sch\"ucking for the lightcone of a plane gravitational wave and also found in the G\"odel universe, is a feature of the whole G\"odel family. We discuss geometrical properties of caustics and show that (a) the focal surfaces are two-dimensional null surfaces generated by non-geodesic null curves and (b) intrinsic differential invariants of the cone attain finite values at caustic subsets.Comment: 19 pages, 1 figur

Clinical and molecular characterization of HER2 amplified-pancreatic cancer

<p>Background: Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.</p> <p>Methods: HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).</p> <p>Results: An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.</p> <p>Conclusions: HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.</p&gt

Classical Integrability of the Squashed Three-sphere, Warped AdS3 and Schroedinger Spacetime via T-Duality

We discuss the integrability of 2d non-linear sigma models with target space being the squashed three-sphere, warped anti-de Sitter space and the Schroedinger spacetime. These models can be obtained via T-duality from integrable models. We construct an infinite family of non-local conserved charges from the T-dual Lax currents, enhancing the symmetry of warped anti-de Sitter space and the Schroedinger spacetime to sl2(R)+sl2(R).Comment: 29 Pages, 3 appendices. Minor changes: added references, footnot

Potentials of Mean Force for Protein Structure Prediction Vindicated, Formalized and Generalized

Understanding protein structure is of crucial importance in science, medicine and biotechnology. For about two decades, knowledge based potentials based on pairwise distances -- so-called "potentials of mean force" (PMFs) -- have been center stage in the prediction and design of protein structure and the simulation of protein folding. However, the validity, scope and limitations of these potentials are still vigorously debated and disputed, and the optimal choice of the reference state -- a necessary component of these potentials -- is an unsolved problem. PMFs are loosely justified by analogy to the reversible work theorem in statistical physics, or by a statistical argument based on a likelihood function. Both justifications are insightful but leave many questions unanswered. Here, we show for the first time that PMFs can be seen as approximations to quantities that do have a rigorous probabilistic justification: they naturally arise when probability distributions over different features of proteins need to be combined. We call these quantities reference ratio distributions deriving from the application of the reference ratio method. This new view is not only of theoretical relevance, but leads to many insights that are of direct practical use: the reference state is uniquely defined and does not require external physical insights; the approach can be generalized beyond pairwise distances to arbitrary features of protein structure; and it becomes clear for which purposes the use of these quantities is justified. We illustrate these insights with two applications, involving the radius of gyration and hydrogen bonding. In the latter case, we also show how the reference ratio method can be iteratively applied to sculpt an energy funnel. Our results considerably increase the understanding and scope of energy functions derived from known biomolecular structures

The Seven-sphere and its Kac-Moody Algebra

We investigate the seven-sphere as a group-like manifold and its extension to a Kac-Moody-like algebra. Covariance properties and tensorial composition of spinors under $S^7$ are defined. The relation to Malcev algebras is established. The consequences for octonionic projective spaces are examined. Current algebras are formulated and their anomalies are derived, and shown to be unique (even regarding numerical coefficients) up to redefinitions of the currents. Nilpotency of the BRST operator is consistent with one particular expression in the class of (field-dependent) anomalies. A Sugawara construction is given.Comment: 22 pages. Macropackages used: phyzzx, epsf. Three epsf figure files appende

Goedel, Penrose, anti-Mach: extra supersymmetries of time-dependent plane waves

We prove that M-theory plane waves with extra supersymmetries are necessarily homogeneous (but possibly time-dependent), and we show by explicit construction that such time-dependent plane waves can admit extra supersymmetries. To that end we study the Penrose limits of Goedel-like metrics, show that the Penrose limit of the M-theory Goedel metric (with 20 supercharges) is generically a time-dependent homogeneous plane wave of the anti-Mach type, and display the four extra Killings spinors in that case. We conclude with some general remarks on the Killing spinor equations for homogeneous plane waves.Comment: 20 pages, LaTeX2

Holography and the Polyakov action

In two dimensional conformal field theory the generating functional for correlators of the stress-energy tensor is given by the non-local Polyakov action associated with the background geometry. We study this functional holographically by calculating the regularized on-shell action of asymptotically AdS gravity in three dimensions, associated with a specified (but arbitrary) boundary metric. This procedure is simplified by making use of the Chern-Simons formulation, and a corresponding first-order expansion of the bulk dreibein, rather than the metric expansion of Fefferman and Graham. The dependence of the resulting functional on local moduli of the boundary metric agrees precisely with the Polyakov action, in accord with the AdS/CFT correspondence. We also verify the consistency of this result with regard to the nontrivial transformation properties of bulk solutions under Brown-Henneaux diffeomorphisms.Comment: 20 pages, RevTeX, v2: minor typos corrected and references adde

TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.

The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas

Equivalence of three-dimensional spacetimes

A solution to the equivalence problem in three-dimensional gravity is given and a practically useful method to obtain a coordinate invariant description of local geometry is presented. The method is a nontrivial adaptation of Karlhede invariant classification of spacetimes of general relativity. The local geometry is completely determined by the curvature tensor and a finite number of its covariant derivatives in a frame where the components of the metric are constants. The results are presented in the framework of real two-component spinors in three-dimensional spacetimes, where the algebraic classifications of the Ricci and Cotton-York spinors are given and their isotropy groups and canonical forms are determined. As an application we discuss Goedel-type spacetimes in three-dimensional General Relativity. The conditions for local space and time homogeneity are derived and the equivalence of three-dimensional Goedel-type spacetimes is studied and the results are compared with previous works on four-dimensional Goedel-type spacetimes.Comment: 13 pages - content changes and corrected typo