Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli

PURPOSE: Recent in vitro studies suggested that the autocrine leptin loop might contribute to breast cancer development by enhancing cell growth and survival. To evaluate whether the leptin system could become a target in breast cancer therapy, we examined the expression of leptin and its receptor (ObR) in primary and metastatic breast cancer and noncancer mammary epithelium. We also studied whether the expression of leptin/ObR in breast cancer can be induced by obesity-related stimuli, such as elevated levels of insulin, insulin-like growth factor-I (IGF-I), estradiol, or hypoxic conditions. EXPERIMENTAL DESIGN: The expression of leptin and ObR was examined by immunohistochemistry in 148 primary breast cancers and 66 breast cancer metastases as well as in 90 benign mammary lesions. The effects of insulin, IGF-I, estradiol, and hypoxia on leptin and ObR mRNA expression were assessed by reverse transcription-PCR in MCF-7 and MDA-MB-231 breast cancer cell lines. RESULTS: Leptin and ObR were significantly overexpressed in primary and metastatic breast cancer relative to noncancer tissues. In primary tumors, leptin positively correlated with ObR, and both biomarkers were most abundant in G3 tumors. The expression of leptin mRNA was enhanced by insulin and hypoxia in MCF-7 and MDA-MB-231 cells, whereas IGF-I and estradiol stimulated leptin mRNA only in MCF-7 cells. ObR mRNA was induced by insulin, IGF-I, and estradiol in MCF-7 cells and by insulin and hypoxia in MDA-MB-231 cells. CONCLUSIONS: Leptin and ObR are overexpressed in breast cancer, possibly due to hypoxia and/or overexposure of cells to insulin, IGF-I, and/or estradiol

Instantons on ALE spaces and orbifold partitions

We consider N=4 theories on ALE spaces of $A_{k-1}$ type. As is well known, their partition functions coincide with $A_{k-1}$ affine characters. We show that these partition functions are equal to the generating functions of some peculiar classes of partitions which we introduce under the name 'orbifold partitions'. These orbifold partitions turn out to be related to the generalized Frobenius partitions introduced by G. E. Andrews some years ago. We relate the orbifold partitions to the blended partitions and interpret explicitly in terms of a free fermion system.Comment: 28 pages, 10 figures; reference adde

Multiple D4-D2-D0 on the Conifold and Wall-crossing with the Flop

We study the wall-crossing phenomena of D4-D2-D0 bound states with two units of D4-brane charge on the resolved conifold. We identify the walls of marginal stability and evaluate the discrete changes of the BPS indices by using the Kontsevich-Soibelman wall-crossing formula. In particular, we find that the field theories on D4-branes in two large radius limits are properly connected by the wall-crossings involving the flop transition of the conifold. We also find that in one of the large radius limits there are stable bound states of two D4-D2-D0 fragments.Comment: 24 pages, 4 figures; v2: typos corrected, minor changes, a reference adde

ABJM theory as a Fermi gas

The partition function on the three-sphere of many supersymmetric Chern-Simons-matter theories reduces, by localization, to a matrix model. We develop a new method to study these models in the M-theory limit, but at all orders in the 1/N expansion. The method is based on reformulating the matrix model as the partition function of an ideal Fermi gas with a non-trivial, one-particle quantum Hamiltonian. This new approach leads to a completely elementary derivation of the N^{3/2} behavior for ABJM theory and N=3 quiver Chern-Simons-matter theories. In addition, the full series of 1/N corrections to the original matrix integral can be simply determined by a next-to-leading calculation in the WKB or semiclassical expansion of the quantum gas, and we show that, for several quiver Chern-Simons-matter theories, it is given by an Airy function. This generalizes a recent result of Fuji, Hirano and Moriyama for ABJM theory. It turns out that the semiclassical expansion of the Fermi gas corresponds to a strong coupling expansion in type IIA theory, and it is dual to the genus expansion. This allows us to calculate explicitly non-perturbative effects due to D2-brane instantons in the AdS background.Comment: 52 pages, 11 figures. v3: references, corrections and clarifications added, plus a footnote on the relation to the recent work by Hanada et a

Penner Type Matrix Model and Seiberg-Witten Theory

We discuss the Penner type matrix model recently proposed by Dijkgraaf and Vafa for a possible explanation of the relation between four-dimensional gauge theory and Liouville theory by making use of the connection of the matrix model to two-dimensional CFT. We first consider the relation of gauge couplings defined in UV and IR regimes of N_f = 4, N = 2 supersymmetric gauge theory being related as $q_{{\rm UV}}={\vartheta_2(q_{{\rm IR}})^4/\vartheta_3(q_{{\rm IR}})^4}$. We then use this relation to discuss the action of modular transformation on the matrix model and determine its spectral curve. We also discuss the decoupling of massive flavors from the N_f = 4 matrix model and derive matrix models describing asymptotically free N = 2 gauge theories. We find that the Penner type matrix theory reproduces correctly the standard results of N = 2 supersymmetric gauge theories.Comment: 22 pages; v2: references added, typos corrected; v3: a version to appear in JHE

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices.

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels

Quivers, YBE and 3-manifolds

We study 4d superconformal indices for a large class of N=1 superconformal quiver gauge theories realized combinatorially as a bipartite graph or a set of "zig-zag paths" on a two-dimensional torus T^2. An exchange of loops, which we call a "double Yang-Baxter move", gives the Seiberg duality of the gauge theory, and the invariance of the index under the duality is translated into the Yang-Baxter-type equation of a spin system defined on a "Z-invariant" lattice on T^2. When we compactify the gauge theory to 3d, Higgs the theory and then compactify further to 2d, the superconformal index reduces to an integral of quantum/classical dilogarithm functions. The saddle point of this integral unexpectedly reproduces the hyperbolic volume of a hyperbolic 3-manifold. The 3-manifold is obtained by gluing hyperbolic ideal polyhedra in H^3, each of which could be thought of as a 3d lift of the faces of the 2d bipartite graph.The same quantity is also related with the thermodynamic limit of the BPS partition function, or equivalently the genus 0 topological string partition function, on a toric Calabi-Yau manifold dual to quiver gauge theories. We also comment on brane realization of our theories. This paper is a companion to another paper summarizing the results.Comment: 61 pages, 16 figures; v2: typos correcte

Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS