Identification of epidermal Pdx1 expression discloses different roles of Notch1 and Notch2 in murine KrasG12D-induced skin carcinogenesis in vivo

Background The Ras and Notch signaling pathways are frequently activated during development to control many diverse cellular processes and are often dysregulated during tumorigenesis. To study the role of Notch and oncogenic Kras signaling in a progenitor cell population, Pdx1-Cre mice were utilized to generate conditional oncogenic KrasG12D mice with ablation of Notch1 and/or Notch2. Methodology/Principal Findings Surprisingly, mice with activated KrasG12D and Notch1 but not Notch2 ablation developed skin papillomas progressing to squamous cell carcinoma providing evidence for Pdx1 expression in the skin. Immunostaining and lineage tracing experiments indicate that PDX1 is present predominantly in the suprabasal layers of the epidermis and rarely in the basal layer. Further analysis of keratinocytes in vitro revealed differentiation-dependent expression of PDX1 in terminally differentiated keratinocytes. PDX1 expression was also increased during wound healing. Further analysis revealed that loss of Notch1 but not Notch2 is critical for skin tumor development. Reasons for this include distinct Notch expression with Notch1 in all layers and Notch2 in the suprabasal layer as well as distinctive p21 and β-catenin signaling inhibition capabilities. Conclusions/Significance Our results provide strong evidence for epidermal expression of Pdx1 as of yet not identified function. In addition, this finding may be relevant for research using Pdx1-Cre transgenic strains. Additionally, our study confirms distinctive expression and functions of Notch1 and Notch2 in the skin supporting the importance of careful dissection of the contribution of individual Notch receptors

Quantum Diffeomorphisms and Conformal Symmetry

We analyze the constraints of general coordinate invariance for quantum theories possessing conformal symmetry in four dimensions. The character of these constraints simplifies enormously on the Einstein universe $R \times S^3$. The $SO(4,2)$ global conformal symmetry algebra of this space determines uniquely a finite shift in the Hamiltonian constraint from its classical value. In other words, the global Wheeler-De Witt equation is {\it modified} at the quantum level in a well-defined way in this case. We argue that the higher moments of $T^{00}$ should not be imposed on the physical states {\it a priori} either, but only the weaker condition $\langle \dot T^{00} \rangle = 0$. We present an explicit example of the quantization and diffeomorphism constraints on $R \times S^3$ for a free conformal scalar field.Comment: PlainTeX File, 37 page

An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers

Conformal Invariance and Cosmic Background Radiation

The spectrum and statistics of the cosmic microwave background radiation (CMBR) are investigated under the hypothesis that scale invariance of the primordial density fluctuations should be promoted to full conformal invariance. As in the theory of critical phenomena, this hypothesis leads in general to deviations from naive scaling. The spectral index of the two-point function of density fluctuations is given in terms of the quantum trace anomaly and is greater than one, leading to less power at large distance scales than a strict Harrison-Zel'dovich spectrum. Conformal invariance also implies non-gaussian statistics for the higher point correlations and in particular, it completely determines the large angular dependence of the three-point correlations of the CMBR.Comment: 4 pages, Revtex file, uuencoded with one figur

Kaluza-Klein Induced Gravity Inflation

A D-dimensional induced gravity theory is studied carefully in a $4 + (D-4)$ dimensional Friedmann-Robertson-Walker space-time. We try to extract information of the symmetry breaking potential in search of an inflationary solution with non-expanding internal-space. We find that the induced gravity model imposes strong constraints on the form of symmetry breaking potential in order to generate an acceptable inflationary universe. These constraints are analyzed carefully in this paper.Comment: 10 pages, title changed, corrected some typos, two additional comments adde

Inflationary Universe in Higher Derivative Induced Gravity

In an induced-gravity model, the stability condition of an inflationary slow-rollover solution is shown to be $\phi_0 \partial_{\phi_0}V(\phi_0)=4V(\phi_0)$. The presence of higher derivative terms will, however, act against the stability of this expanding solution unless further constraints on the field parameters are imposed. We find that these models will acquire a non-vanishing cosmological constant at the end of inflation. Some models are analyzed for their implication to the early universe.Comment: 6 pages, two typos correcte

Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9–based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy–induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors

Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway

Mice lacking all three Rb genes in the liver develop tumors resembling specific subgroups of human hepatocellular carcinomas, and Notch activity appears to suppress the growth and progression of these tumors

Weyl Cohomology and the Effective Action for Conformal Anomalies

We present a general method of deriving the effective action for conformal anomalies in any even dimension, which satisfies the Wess-Zumino consistency condition by construction. The method relies on defining the coboundary operator of the local Weyl group, and giving a cohomological interpretation to counterterms in the effective action in dimensional regularization with respect to this group. Non-trivial cocycles of the Weyl group arise from local functionals that are Weyl invariant in and only in the physical even integer dimension. In the physical dimension the non-trivial cocycles generate covariant non-local action functionals characterized by sensitivity to global Weyl rescalings. The non-local action so obtained is unique up to the addition of trivial cocycles and Weyl invariant terms, both of which are insensitive to global Weyl rescalings. These distinct behaviors under rigid dilations can be used to distinguish between infrared relevant and irrelevant operators in a generally covariant manner. Variation of the $d=4$ non-local effective action yields two new conserved geometric stress tensors with local traces. The method may be extended to any even dimension by making use of the general construction of conformal invariants given by Fefferman and Graham. As a corollary, conformal field theory behavior of correlators at the asymptotic infinity of either anti-de Sitter or de Sitter spacetimes follows, i.e. AdS$_{d+1}$ or deS$_{d+1}$/CFT$_d$ correspondence. The same construction naturally selects all infrared relevant terms (and only those terms) in the low energy effective action of gravity in any even integer dimension. The infrared relevant terms arising from the known anomalies in d=4 imply that the classical Einstein theory is modified at large distances.Comment: 32 pages. LateX file. LateX twic