bluuebunny/crossref_metadata_2025 huggingface dataset:
Interferons Accelerate Decay of Replication-Competent Nucleocapsids of Hepatitis B Virus
Authors: Xu Chunxiao , Guo Haitao , Pan Xiao-Ben , Mao Richeng , Yu Wenquan , Xu Xiaodong , Wei Lai , Chang Jinhong , Block Timothy M. , Guo Ju-Tao
Published: July 2010

Alpha interferon (IFN-α) is an approved medication for chronic hepatitis B. Gamma interferon (IFN-γ) is a key mediator of host antiviral immunity against hepatitis B virus (HBV) infection
in vivo
. However, the molecular mechanism by which these antiviral cytokines suppress HBV replication remains elusive. Using an immortalized murine hepatocyte (AML12)-derived cell line supporting tetracycline-inducible HBV replication, we show in this report that both IFN-α and IFN-γ efficiently reduce the amount of intracellular HBV nucleocapsids. Furthermore, we provide evidence suggesting that the IFN-induced cellular antiviral response is able to distinguish and selectively accelerate the decay of HBV replication-competent nucleocapsids but not empty capsids in a proteasome-dependent manner. Our findings thus reveal a novel antiviral mechanism of IFNs and provide a basis for a better understanding of HBV pathobiology.
Viral Particles of Endogenous Betaretroviruses Are Released in the Sheep Uterus and Infect the Conceptus Trophectoderm in a Transspecies Embryo Transfer Model
Authors: Black Sarah G. , Arnaud Frederick , Burghardt Robert C. , Satterfield M. Carey , Fleming Jo-Ann G. W. , Long Charles R. , Hanna Carol , Murphy Lita , Biek Roman , Palmarini Massimo , Spencer Thomas E.
Published: July 2010

The sheep genome contains multiple copies of endogenous betaretroviruses highly related to the exogenous and oncogenic jaagsiekte sheep retrovirus (JSRV). The endogenous JSRVs (enJSRVs) are abundantly expressed in the uterine luminal and glandular epithelia as well as in the conceptus trophectoderm and are essential for conceptus elongation and trophectoderm growth and development. Of note, enJSRVs are present in sheep and goats but not cattle. At least 5 of the 27 enJSRV loci cloned to date possess an intact genomic organization and are able to produce viral particles
in vitro
. In this study, we found that enJSRVs form viral particles that are released into the uterine lumen of sheep. In order to test the infectious potential of enJSRV particles in the uterus, we transferred bovine blastocysts into synchronized ovine recipients and allowed them to develop for 13 days. Analysis of microdissected trophectoderm of the bovine conceptuses revealed the presence of enJSRV RNA and, in some cases, DNA. Interestingly, we found that RNAs belonging to only the most recently integrated enJSRV loci were packaged into viral particles and transmitted to the trophectoderm. Collectively, these results support the hypothesis that intact enJSRV loci expressed in the uterine endometrial epithelia are shed into the uterine lumen and could potentially transduce the conceptus trophectoderm. The essential role played by enJSRVs in sheep reproductive biology could also be played by endometrium-derived viral particles that influence development and differentiation of the trophectoderm.
Immunization with Wild-Type or CD4-Binding-Defective HIV-1 Env Trimers Reduces Viremia Equivalently following Heterologous Challenge with Simian-Human Immunodeficiency Virus
Authors: Sundling Christopher , O'Dell Sijy , Douagi Iyadh , Forsell Mattias N. , Mörner Andreas , Loré Karin , Mascola John R. , Wyatt Richard T. , Karlsson Hedestam Gunilla B.
Published: July 2010

We recently reported that rhesus macaques inoculated with CD4-binding-competent and CD4-binding-defective soluble YU2-derived HIV-1 envelope glycoprotein (Env) trimers in adjuvant generate comparable levels of Env-specific binding antibodies (Abs) and T cell responses. We also showed that Abs directed against the Env coreceptor binding site (CoRbs) were elicited only in animals immunized with CD4-binding-competent trimers and not in animals immunized with CD4-binding-defective trimers, indicating that a direct interaction between Env and CD4 occurs
in vivo
. To investigate both the overall consequences of
in vivo
Env-CD4 interactions and the elicitation of CoRbs-directed Abs for protection against heterologous simian-human immunodeficiency virus (SHIV) challenge, we exposed rhesus macaques immunized with CD4-binding-competent and CD4-binding-defective trimers to the CCR5-tropic SHIV-SF162P4 challenge virus. Compared to unvaccinated controls, all vaccinated animals displayed improved control of plasma viremia, independent of the presence or absence of CoRbs-directed Abs prior to challenge. Immunization resulted in plasma responses that neutralized the heterologous SHIV challenge stock
in vitro
, with similar neutralizing Ab titers elicited by the CD4-binding-competent and CD4-binding-defective trimers. The neutralizing responses against both the SHIV-SF162P4 stock and a recombinant virus pseudotyped with a cloned SHIV-SF162P4-derived Env were significantly boosted by the SHIV challenge. Collectively, these results suggest that the capacity of soluble Env trimers to interact with primate CD4
in vivo
and to stimulate the production of moderate titers of CoRbs-directed Abs did not influence the magnitude of the neutralizing Ab recall response after viral challenge or the subsequent control of viremia in this heterologous SHIV challenge model.
Reconstitution of CD4 T Cells in Bronchoalveolar Lavage Fluid after Initiation of Highly Active Antiretroviral Therapy
Authors: Knox Kenneth S. , Vinton Carol , Hage Chadi A. , Kohli Lisa M. , Twigg Homer L. , Klatt Nichole R. , Zwickl Beth , Waltz Jeffrey , Goldman Mitchell , Douek Daniel C. , Brenchley Jason M.
Published: July 2010

The massive depletion of gastrointestinal-tract CD4 T cells is a hallmark of the acute phase of HIV infection. In contrast, the depletion of the lower-respiratory-tract mucosal CD4 T cells as measured in bronchoalveolar lavage (BAL) fluid is more moderate and similar to the depletion of CD4 T cells observed in peripheral blood (PB). To understand better the dynamics of disease pathogenesis and the potential for the reconstitution of CD4 T cells in the lung and PB following the administration of effective antiretroviral therapy, we studied cell-associated viral loads, CD4 T-cell frequencies, and phenotypic and functional profiles of antigen-specific CD4 T cells from BAL fluid and blood before and after the initiation of highly active antiretroviral therapy (HAART). The major findings to emerge were the following: (i) BAL CD4 T cells are not massively depleted or preferentially infected by HIV compared to levels for PB; (ii) BAL CD4 T cells reconstitute after the initiation of HAART, and their infection frequencies decrease; (iii) BAL CD4 T-cell reconstitution appears to occur via the local proliferation of resident BAL CD4 T cells rather than redistribution; and (iv) BAL CD4 T cells are more polyfunctional than CD4 T cells in blood, and their functional profile is relatively unchanged after the initiation of HAART. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might aid in the reconstitution of mucosal CD4 T cells.
Identification of Novel Mutations Responsible for Resistance to MK-2048, a Second-Generation HIV-1 Integrase Inhibitor
Authors: Bar-Magen Tamara , Sloan Richard D. , Donahue Daniel A. , Kuhl Björn D. , Zabeida Alexandra , Xu Hongtao , Oliveira Maureen , Hazuda Daria J. , Wainberg Mark A.
Published: July 2010

MK-2048 represents a prototype second-generation integrase strand transfer inhibitor (INSTI) developed with the goal of retaining activity against viruses containing mutations associated with resistance to first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG). Here, we report the identification of mutations (G118R and E138K) which confer resistance to MK-2048 and not to RAL or EVG. These mutations were selected
in vitro
and confirmed by site-specific mutagenesis. G118R, which appeared first in cell culture, conferred low levels of resistance to MK-2048. G118R also reduced viral replication capacity to approximately 1% that of the isogenic wild-type (wt) virus. The subsequent selection of E138K partially restored replication capacity to ≈13% of wt levels and increased resistance to MK-2048 to ≈8-fold. Viruses containing G118R and E138K remained largely susceptible to both RAL and EVG, suggesting a unique interaction between this second-generation INSTI and the enzyme may be defined by these residues as a potential basis for the increased intrinsic affinity and longer “off” rate of MK-2048.
In silico
structural analysis suggests that the introduction of a positively charged arginine at position 118, near the catalytic amino acid 116, might decrease Mg
2+
binding, compromising enzyme function and thus leading to the significant reduction in both integration and viral replication capacity observed with these mutations.
Ectromelia Virus Inhibitor of Complement Enzymes Protects Intracellular Mature Virus and Infected Cells from Mouse Complement
Authors: Moulton Elizabeth A. , Bertram Paula , Chen Nanhai , Buller R. Mark L. , Atkinson John P.
Published: July 2010

Poxviruses produce complement regulatory proteins to subvert the host's immune response. Similar to the human pathogen variola virus, ectromelia virus has a limited host range and provides a mouse model where the virus and the host's immune response have coevolved. We previously demonstrated that multiple components (C3, C4, and factor B) of the classical and alternative pathways are required to survive ectromelia virus infection. Complement's role in the innate and adaptive immune responses likely drove the evolution of a virus-encoded virulence factor that regulates complement activation. In this study, we characterized the ectromelia virus inhibitor of complement enzymes (EMICE). Recombinant EMICE regulated complement activation on the surface of CHO cells, and it protected complement-sensitive intracellular mature virions (IMV) from neutralizationin vitro. It accomplished this by serving as a cofactor for the inactivation of C3b and C4b and by dissociating the catalytic domain of the classical pathway C3 convertase. Infected murine cells initiated synthesis of EMICE within 4 to 6 h postinoculation. The levels were sufficient in the supernatant to protect the IMV, upon release, from complement-mediated neutralization. EMICE on the surface of infected murine cells also reduced complement activation by the alternative pathway. In contrast, classical pathway activation by high-titer antibody overwhelmed EMICE's regulatory capacity. These results suggest that EMICE's role is early during infection when it counteracts the innate immune response. In summary, ectromelia virus produced EMICE within a few hours of an infection, and EMICE in turn decreased complement activation on IMV and infected cells.
SUBMANIFOLDS WITH BIHARMONIC GAUSS MAP
Authors: BALMUŞ A. , ONICIUC C. , MONTALDO S.
Published: July 2010

We generalize the Ruh–Vilms problem by characterizing the submanifolds in Euclidean spaces with proper biharmonic Gauss map and we construct examples of such hypersurfaces.
MINIMAL DYNAMICS AND $\mathcal{Z}$-STABLE CLASSIFICATION
Authors: STRUNG KAREN R. , WINTER WILHELM
Published: July 2010

Let X be an infinite compact metric space, α : X → X a minimal homeomorphism, u the unitary that implements α in the transformation group C*-algebra C(X) ⋊αℤ, and [Formula: see text] a class of separable nuclear C*-algebras that contains all unital hereditary C*-subalgebras of C*-algebras in [Formula: see text]. Motivated by the success of tracial approximation by finite dimensional C*-algebras as an abstract characterization of classifiable C*-algebras and the idea that classification results for C*-algebras tensored with UHF algebras can be used to derive classification results up to tensoring with the Jiang-Su algebra [Formula: see text], we prove that (C(X) ⋊αℤ) ⊗ Mq∞is tracially approximately [Formula: see text] if there exists a y ∈ X such that the C*-subalgebra (C*(C(X), uC0(X\{y}))) ⊗ Mq∞is tracially approximately [Formula: see text]. If the class [Formula: see text] consists of finite dimensional C*-algebras, this can be used to deduce classification up to tensoring with [Formula: see text] for C*-algebras associated to minimal dynamical systems where projections separate tracial states. This is done without making any assumptions on the real rank or stable rank of either C(X) ⋊αℤ or C*(C(X), uC0(X\{y})), nor on the dimension of X. The result is a key step in the classification of C*-algebras associated to uniquely ergodic minimal dynamical systems by their ordered K-groups. It also sets the stage to provide further classification results for those C*-algebras of minimal dynamical systems where projections do not necessarily separate traces.
A CRITERION FOR HOMOGENEOUS PRINCIPAL BUNDLES
Authors: BISWAS INDRANIL , TRAUTMANN GÜNTHER
Published: July 2010

We consider principal bundles over G/P, where P is a parabolic subgroup of a semi-simple and simply connected linear algebraic group G defined over ℂ. We prove that a holomorphic principal H-bundle EH → G/P, where H is a complex reductive group, and is homogeneous if the adjoint vector bundle ad (EH) is homogeneous. Fix a faithful H-module V. We also show that EH is homogeneous if the vector bundle EH ×H V associated to it for the H-module V is homogeneous.
INTRODUCTION TO QUANTUM INTEGRABILITY
Authors: DOIKOU ANASTASIA , EVANGELISTI STEFANO , FEVERATI GIOVANNI , KARAISKOS NIKOS
Published: July 2010

In this paper, we review the basic concepts regarding quantum integrability. Special emphasis is given on the algebraic content of integrable models. The associated algebras are essentially described by the Yang–Baxter and boundary Yang–Baxter equations depending on the choice of boundary conditions. The relation between the aforementioned equations and the braid group is briefly discussed. A short review on quantum groups as well as the quantum inverse scattering method (algebraic Bethe ansatz) is also presented.
LOCAL EXISTENCE AND UNIQUENESS OF SOLUTIONS TO A PDE MODEL FOR CRIMINAL BEHAVIOR
Authors: RODRIGUEZ NANCY , BERTOZZI ANDREA
Published: July 2010

The analysis of criminal behavior with mathematical tools is a fairly new idea, but one which can be used to obtain insight on the dynamics of crime. In a recent work,34 Short et al. developed an agent-based stochastic model for the dynamics of residential burglaries. This model produces the right qualitative behavior, that is, the existence of spatio-temporal collections of criminal activities or "hotspots", which have been observed in residential burglary data. In this paper, we prove local existence and uniqueness of solutions to the continuum version of this model, a coupled system of partial differential equations, as well as a continuation argument. Furthermore, we compare this PDE model with a generalized version of the Keller–Segel model for chemotaxis as a first step to understanding possible conditions for global existence versus blow-up of the solutions in finite time.
Fixed Point Theory for Contractive Mappings Satisfying "Equation missing" -Maps in "Equation missing" -Metric Spaces
Authors: Shatanawi W
Published: July 2010

We prove some fixed point results for self-mapping "Equation missing" in a complete "Equation missing"-metric space "Equation missing" under some contractive conditions related to a nondecreasing map "Equation missing" with "Equation missing" for all "Equation missing". Also, we prove the uniqueness of such fixed point, as well as studying the "Equation missing"-continuity of such fixed point.
Xanthomatous Hypophysitis Mimicking a Pituitary Adenoma: Case Report and Review of the Literature
Authors: Aste Laura , Bellinzona Mattia , Meleddu Veronica , Farci Graziella , Manieli Cristina , Godano Umberto
Published: July 2010

Background. Hypophysitis is an inflammatory disease of the pituitary gland that may mimic pituitary tumors clinically and radiologically.Case Description. We report a case of a xanthomatous hypophysitis initially diagnosed as pituitary adenoma. A 31-year-old woman presented with headache, diabetes insipidus, and amenorrhea. A head CT scan showed no intrasellar changes, while an MRI scan showed a sellar cystic mass. An endocrinological work up revealed mild hypocortisolism and diabetes insipidus (DI). Transsphenoidal surgery was performed. The intraoperative histological examination suggested a pituitary adenoma. The removed tissue showed central necrosis surrounded by accumulation of foamy cells and xanthomatous epithelioid cells. The patient made an uneventful postoperative recovery, Nevertheless, DI persisted and the adenohypophysis hypofunction did not recover.Conclusion. We describe an unusual inflammatory lesion of the pituitary gland mimicking an adenoma. A high level of clinical suspicion of inflammatory disorders is necessary for correct diagnosis and optimal management.
Effects of Composite Formulation on Mechanical Properties of Biodegradable Poly(Propylene Fumarate)/Bone Fiber Scaffolds
Authors: Zhu Xun , Liu Nathan , Yaszemski Michael J. , Lu Lichun
Published: July 2010

The objective of our paper was to determine the effects of composite formulation on the compressive modulus and ultimate strength of a biodegradable, in situ polymerizable poly(propylene fumarate) (PPF) and bone fiber scaffold. The following parameters were investigated: the incorporation of bone fibers (either mineralized or demineralized), PPF molecular weight, N-vinyl pyrrolidinone (NVP) crosslinker amount, benzoyl peroxide (BP) initiator amount, and sodium chloride porogen amount. Eight formulations were chosen based on a resolution III two-level fractional factorial design. The compressive modulus and ultimate strength of these formulations were measured on a materials testing machine. Absolute values for compressive modulus varied from 21.3 to 271 MPa and 2.8 to 358 MPa for dry and wet samples, respectively. The ultimate strength of the crosslinked composites varied from 2.1 to 20.3 MPa for dry samples and from 0.4 to 16.6 MPa for wet samples. Main effects of each parameter on the measured property were calculated. The incorporation of mineralized bone fibers and an increase in PPF molecular weight resulted in higher compressive modulus and ultimate strength. Both mechanical properties also increased as the amount of benzoyl peroxide increased or the NVP amount decreased in the formulation. Sodium chloride had a dominating effect on the increase of mechanical properties in dry samples but showed little effects in wet samples. Demineralization of bone fibers led to a decrease in the compressive modulus and ultimate strength. Our results suggest that bone fibers are appropriate as structural enforcement components in PPF scaffolds. The desired orthopaedic PPF scaffold might be obtained by changing a variety of composite formulation parameters.
Convergence Analysis of Preconditioned AOR Iterative Method for Linear Systems
Authors: Liu Qingbing , Chen Guoliang
Published: July 2010

M‐(H‐)matrices appear in many areas of science and engineering, for example, in the solution of the
linear complementarity problem (LCP) in optimization theory and in the solution of large systems
for real‐time changes of data in fluid analysis in car industry. Classical (stationary) iterative
methods used for the solution of linear systems have been shown to convergence for this class of
matrices. In this paper, we present some comparison theorems on the preconditioned AOR iterative
method for solving the linear system. Comparison results show that the rate of convergence of the
preconditioned iterative method is faster than the rate of convergence of the classical iterative
method. Meanwhile, we apply the preconditioner to H‐matrices and obtain the convergence result.
Numerical examples are given to illustrate our results.
The Possibilities of Reduction of Polychlorinated Dibenzo-P-Dioxins and Polychlorinated Dibenzofurans Emission
Authors: Wielgosiński Grzegorz
Published: July 2010

In the study the most important and known polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzo-furans (PCDFs) emission sources are presented and known methods of reduction of dioxin emission to the atmosphere are discussed in detail. It is indicated that the most relevant emission source is a combustion process. The mechanism of dioxin formation in thermal processes is presented in brief. The author characterized primary methods of reduction of PCDDs/PCDFs emission encompassing the interference into the combustion process to minimize their formation and discussed known secondary methods aimed at their removal from the stream of waste gases. It was attempted to make a critical assessment of PCDD/Fs reduction methods described in literature.
Phosphorylation and Methylation of Proteasomal Proteins of the HaloarcheonHaloferax volcanii
Authors: Humbard Matthew A. , Reuter Christopher J. , Zuobi-Hasona Kheir , Zhou Guangyin , Maupin-Furlow Julie A.
Published: July 2010

Proteasomes are composed of 20S core particles (CPs) ofα- andβ-type subunits that associate with regulatory particle AAA ATPases such as the proteasome-activating nucleotidase (PAN) complexes of archaea. In this study, the roles and additional sites of post-translational modification of proteasomes were investigated using the archaeonHaloferax volcaniias a model. Indicative of phosphorylation, phosphatase-sensitive isoforms ofα1andα2were detected by 2-DE immunoblot. To map these and other potential sites of post-translational modification, proteasomes were purified and analyzed by tandem mass spectrometry (MS/MS). Using this approach, several phosphosites were mapped includingα1Thr147,α2 Thr13/Ser14 and PAN-A Ser340. Multiple methylation sites were also mapped toα1, thus, revealing a new type of proteasomal modification. Probing the biological role ofα1and PAN-A phosphorylation by site-directed mutagenesis revealed dominant negative phenotypes for cell viability and/or pigmentation forα1variants including Thr147Ala, Thr158Ala and Ser58Ala. AnH. volcaniiRio1p Ser/Thr kinase homolog was purified and shown to catalyze autophosphorylation and phosphotransfer toα1. Theα1variants in Thr and Ser residues that displayed dominant negative phenotypes were significantly reduced in their ability to accept phosphoryl groups from Rio1p, thus, providing an important link between cell physiology and proteasomal phosphorylation.
The Structure and Function of Serum Opacity Factor: A Unique Streptococcal Virulence Determinant That Targets High-Density Lipoproteins
Authors: Courtney Harry S. , Pownall Henry J.
Published: July 2010

Serum opacity factor (SOF) is a virulence determinant expressed by a variety of streptococcal and staphylococcal species including both human and animal pathogens. SOF derives its name from its ability to opacify serum where it targets and disrupts the structure of high-density lipoproteins resulting in formation of large lipid vesicles that cause the serum to become cloudy. SOF is a multifunctional protein and in addition to its opacification activity, it binds to a number of host proteins that mediate adhesion of streptococci to host cells, and it plays a role in resistance to phagocytosis in human blood. This article will provide an overview of the structure and function of SOF, its role in the pathogenesis of streptococcal infections, its vaccine potential, its prevalence and distribution in bacteria, and the molecular mechanism whereby SOF opacifies serum and how an understanding of this mechanism may lead to therapies for reducing high-cholesterol concentrations in blood, a major risk factor for cardiovascular disease.
Poly(ADP-Ribose) Polymerase Inhibitor Induces Accelerated Senescence in Irradiated Breast Cancer Cells and Tumors
Authors: Efimova Elena V. , Mauceri Helena J. , Golden Daniel W. , Labay Edwardine , Bindokas Vytautas P. , Darga Thomas E. , Chakraborty Chaitali , Barreto-Andrade Juan Camilo , Crawley Clayton , Sutton Harold G. , Kron Stephen J. , Weichselbaum Ralph R.
Published: July 2010

Persistent DNA double-strand breaks (DSB) may determine the antitumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe, or permanent growth arrest. IR induces rapid modification of megabase chromatin domains surrounding DSBs via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these IR-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked the relocalization of green fluorescent protein fused to a chromatin binding domain of the checkpoint adapter protein 53BP1 after IR of breast cancer cells and tumors. To block DSB repair in breast cancer cells and tumors, we targeted poly(ADP-ribose) polymerase (PARP) with ABT-888 (veliparib), one of several PARP inhibitors currently in clinical trials. PARP inhibition markedly enhanced IRIF persistence and increased breast cancer cell senescence both in vitro and in vivo, arguing for targeting IRIF resolution as a novel therapeutic strategy. Cancer Res; 70(15); 6277–82. ©2010 AACR.
miRNA-96 Suppresses KRAS and Functions as a Tumor Suppressor Gene in Pancreatic Cancer
Authors: Yu Shuangni , Lu Zhaohui , Liu Changzheng , Meng Yunxiao , Ma Yihui , Zhao Wugan , Liu Jianping , Yu Jia , Chen Jie
Published: July 2010

Therapeutic applications of microRNA (miRNA) in KRAS-driven pancreatic cancers might be valuable, but few studies have explored this area. Here, we report that miR-96 directly targets the KRAS oncogene and functions as a tumor-suppressing miRNA in pancreatic cancer cells. Ectopic expression of miR-96 through a synthetic miRNA precursor inhibited KRAS, dampened Akt signaling, and triggered apoptosis in cells. In human clinical specimens, miR-96 was downregulated or deleted where an association with KRAS elevations was observed. In vitro and in vivo assays established that miR-96 decreased cancer cell invasion and migration and slowed tumor growth in a manner associated with KRAS downregulation. Our findings identify miR-96 as a potent regulator of KRAS, which may provide a novel therapeutic strategy for treatment of pancreatic cancer and other KRAS-driven cancers. Cancer Res; 70(14); 6015–25. ©2010 AACR.
Phosphomimetic Mutants of Pigment Epithelium-Derived Factor with Enhanced Antiangiogenic Activity as Potent Anticancer Agents
Authors: Konson Alexander , Pradeep Sunila , Seger Rony
Published: July 2010

Pigment epithelium-derived factor (PEDF) is an endogenous inhibitor of angiogenesis and a promising anticancer agent capable of suppressing solid tumor growth in animal cancer models. We have previously shown that PEDF can be phosphorylated and that distinct phosphorylation states of this factor differentially regulate its physiologic function. Here, we report that phosphomimetic mutants of PEDF, which possess significantly increased antiangiogenic activity, are much more efficient than wild-type (WT) PEDF in inhibiting growth and neovascularization in MDA-MB-231 (breast cancer), HCT116 (colon cancer), and U87-MG (glioblastoma) xenograft models. Importantly, the antitumor activity of the phosphomimetic mutants is comparable with that of the established antiangiogenic agent bevacizumab. However, unlike bevacizumab, these compounds act in a vascular endothelial growth factor (VEGF)–independent manner, as they do not affect the levels of VEGF-A mRNA and VEGF receptor 2 phosphorylation. Further immunohistochemical analysis revealed that PEDF mutants affect mainly tumor-residing endothelial cells and prevent the formation of intratumoral vascular network by facilitating endothelial cell apoptosis. It was also found that PEDF mutants reduce survival of endothelial cells in culture much better than WT-PEDF, an effect that is apparent even in the presence of VEGF or basic fibroblast growth factor, and promote much stronger endothelial cell apoptosis. On the other hand, PEDF and its mutants did not affect survival of cultured cancer cells, indicating that the antiangiogenic activity of these agents is the foremost element of the observed antitumor effect. These findings have specific implications on improving the properties of WT-PEDF, which is currently in preclinical development, and encourage the development of PEDF mutants as specific, neovascularization-targeting anticancer agents. Cancer Res; 70(15); 6247–57. ©2010 AACR.
Transforming Growth Factor-β (TGF-β)–Inducible Gene TMEPAI Converts TGF-β from a Tumor Suppressor to a Tumor Promoter in Breast Cancer
Authors: Singha Prajjal K. , Yeh I-Tien , Venkatachalam Manjeri A. , Saikumar Pothana
Published: July 2010

TMEPAI is a transforming growth factor-β (TGF-β)–induced transmembrane protein that is overexpressed in several cancers. How TMEPAI expression relates to malignancy is unknown. Here, we report high expression of TMEPAI in estrogen receptor/progesterone receptor–negative and human epidermal growth factor receptor-2–negative breast cancer cell lines and primary breast cancers that was further increased by TGF-β treatment. Basal and TGF-β–induced expression of TMEPAI were inhibited by the TGF-β receptor antagonist SB431542 and overexpression of Smad7 or a dominant-negative mutant of Alk-5. TMEPAI knockdown attenuated TGF-β–induced growth and motility in breast cancer cells, suggesting a role for TMEPAI in growth promotion and invasiveness. Further, TMEPAI knockdown decreased breast tumor mass in a mouse xenograft model in a manner associated with increased expression of phosphatase and tensin homologue (PTEN) and diminished phosphorylation of Akt. Consistent with the effects through the phosphatidylinositol 3-kinase pathway, tumors with TMEPAI knockdown exhibited elevated levels of the cell cycle inhibitor p27kip1 and attenuated levels of DNA replication and expression of hypoxia-inducible fator 1α and vascular endothelial growth factor. Together, these results suggest that TMEPAI functions in breast cancer as a molecular switch that converts TGF-β from a tumor suppressor to a tumor promoter. Cancer Res; 70(15); 6377–83. ©2010 AACR.
Comparison of Measurements of Human Papillomavirus Persistence for Postcolposcopic Surveillance for Cervical Precancerous Lesions
Authors: Gage Julia C. , Schiffman Mark , Solomon Diane , Wheeler Cosette M. , Castle Philip E.
Published: July 2010

Objective: Following guidelines, women evaluated by colposcopy, but not found to have a precancerous lesion, could be tested again at 12 months for carcinogenic human papillomavirus (HPV). Compared with pooled-probe testing, measuring HPV genotype–specific persistence might better predict subsequent grade 3 cervical intraepithelial neoplasia (CIN3).

Methods: For women enrolled in the immediate colposcopy arm of the Atypical squamous cells of undetermined significance (ASCUS) and Low-grade squamous intraepithelial lesion (LSIL) Triage Study (ALTS), who underwent enrollment colposcopy but were without prevalently detected CIN2 or worse (CIN2+; n = 671), we compared 1-year HPV persistence, as measured by a pooled HPV genotype test (hybrid capture 2; hc2) versus a research PCR HPV genotyping test (line blot assay; LBA) as predictors of “missed prevalent” or possibly incident CIN3 diagnosed between 12 and 24 months.

Results: Thirty-two (4.8%) women were diagnosed with subsequent CIN3. Testing repeatedly hc2-positive (hc2+) was more common (49.0%) than genotype-specific persistence as detected by LBA (30.3%, P < 0.01). Although absolute risks of CIN3 following repeat hc2+ or genotype-specific persistence were similar (8.8% versus 8.4%, P = 0.86), repeat hc2+ was more sensitive for identifying CIN3 than genotype-specific persistence (90.6% versus 53.1%, P < 0.01). Among 329 women repeatedly hc2+, women with persistent HPV16 were at higher risk of CIN3 than non–HPV16-persistent women (23.1% versus 7.0%, P < 0.01).

Conclusions: For postcolposcopy management, 1-year HPV persistence as measured by hc2 would recall more women but was more sensitive and similarly predictive for CIN3 in the following year than detection of genotype-specific persistence by LBA.

Impact: Although find little utility for measuring type-specific persistence, testing for persistent HPV16 might be clinically useful. Cancer Epidemiol Biomarkers Prev; 19(7); 1668–74. ©2010 AACR.
Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium
Authors: Kelemen Linda E. , Goodman Marc T. , McGuire Valerie , Rossing Mary Anne , Webb Penelope M. , Köbel Martin , Anton-Culver Hoda , Beesley Jonathan , Berchuck Andrew , Brar Sony , Carney Michael E. , Chang-Claude Jenny , Chenevix-Trench Georgia , Cramer Daniel W. , Cunningham Julie M. , DiCioccio Richard A. , Doherty Jennifer A. , Easton Douglas F. , Fredericksen Zachary S. , Fridley Brooke L. , Gates Margaret A. , Gayther Simon A. , Gentry-Maharaj Aleksandra , Høgdall Estrid , Kjær Susanne Krüger , Lurie Galina , Menon Usha , Moorman Patricia G. , Moysich Kirsten , Ness Roberta B. , Palmieri Rachel T. , Pearce Celeste L. , Pharoah Paul D.P. , Ramus Susan J. , Song Honglin , Stram Daniel O. , Tworoger Shelley S. , Van Den Berg David , Vierkant Robert A. , Wang-Gohrke Shan , Whittemore Alice S. , Wilkens Lynne R. , Wu Anna H. , Schildkraut Joellen M. , Sellers Thomas A. , Goode Ellen L.
Published: July 2010

Background: We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large sample of assembled cases to investigate associations by histologic type.

Methods: Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site.

Results: The five polymorphisms were not associated with ovarian carcinoma overall (Ptrend > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04), and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04; Pheterogeneity = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05).

Conclusions: TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathologic classification.

Impact: Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology. Cancer Epidemiol Biomarkers Prev; 19(7); 1822–30. ©2010 AACR.
Increased Cancer Predisposition in Family Members of Colorectal Cancer Patients Harboring the p.V600E BRAF Mutation: a Population-Based Study
Authors: Wish Tyler A. , Hyde Angela J. , Parfrey Patrick S. , Green Jane S. , Younghusband H. Banfield , Simms Michelle I. , Fontaine Dan G. , Dicks Elizabeth L. , Stuckless Susan N. , Gallinger Steven , McLaughlin John R. , Woods Michael O. , Green Roger C.
Published: July 2010

Background: The serrated pathway represents a distinct molecular pathway of colorectal carcinogenesis and is associated with the p.V600E BRAF mutation. The objective of this study is to characterize the cancer family history and clinicopathologic features of colorectal cancer (CRC) patients according to the microsatellite instability (MSI) and BRAF mutation status of their tumors.

Methods: The tumors from 558 population-based CRC patients underwent pathologic examination and molecular analysis for MSI, BRAF, and germline mutations in mismatch repair genes MUTYH and APC. The cancer history in first-degree relatives (FDR) of index patients was ascertained.

Results: The risk of CRC in FDRs of index patients with MSI-H BRAF mutation [hazard ratio (HR) = 2.49; 95% confidence interval (95% CI), 1.57- 3.93] and microsatellite-stable BRAF mutation tumors (HR = 1.64; 95% CI, 1.01-2.66) was significantly elevated compared with FDRs of index patients with microsatellite-stable BRAF wild-type tumors. The incidence of nonmelanoma skin cancer was also significantly elevated in FDRs of patients with BRAF mutation CRC (HR = 2.52; 95% CI, 1.31-4.86). Furthermore, BRAF mutation CRC was associated with a distinct clinical, molecular, and pathologic phenotype.

Conclusions: The increased incidence of cancer in FDRs of index CRC patients with the p.V600E BRAF mutation may be explained by a genetic predisposition to develop cancer through the serrated pathway of colorectal carcinogenesis.

Impact: Family members of BRAF CRC patients have an increased predisposition to develop cancer. Future work should aim to identify the causative genetic factors. Cancer Epidemiol Biomarkers Prev; 19(7); 1831–9. ©2010 AACR.
Association between Genetic Variants in the 8q24 Cancer Risk Regions and Circulating Levels of Androgens and Sex Hormone–Binding Globulin
Authors: Chu Lisa W. , Meyer Tamra E. , Li Qizhai , Menashe Idan , Yu Kai , Rosenberg Philip S. , Huang Wen-Yi , Quraishi Sabah M. , Kaaks Rudolf , Weiss Jocelyn M. , Hayes Richard B. , Chanock Stephen J. , Hsing Ann W.
Published: July 2010

Background: Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder.

Methods: To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphisms (SNPs) in the 8q24 risk regions spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, 3αdiol G, and bioavailable testosterone), and sex hormone–binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial). Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log-transformed biomarker levels.

Results: Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P < 1.1 × 10−3) and bioavailable testosterone (P < 6.3 × 10−4). Suggestive associations were seen for a cluster of nine SNPs in prostate cancer risk region 1 and androstenedione (P < 0.05).

Conclusions: These preliminary findings require confirmation in larger studies but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions might correlate with androgen levels.

Impact: These results might provide some clues for the strong link between 8q24 and prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 19(7); 1848–54. ©2010 AACR.
Urine Accurately Reflects Circulating Isoflavonoids and Ascertains Compliance During Soy Intervention
Authors: Franke Adrian A. , Hebshi Sandra M. , Pagano Ian , Kono Naoko , Mack Wendy J. , Hodis Howard N.
Published: July 2010

Background: Isoflavonoids (IFL) may protect against chronic diseases, including cancer. IFL exposure is traditionally measured from plasma (PL), but the reliability of urine is uncertain. We assessed whether IFL excretion in overnight urine (OU) or spot urine (SU) reliably reflects IFLs in PL and the usefulness of the three matrices to determine soy intake compliance.

Methods: In a randomized, double-blind, placebo-controlled soy intervention trial with 350 postmenopausal women, IFLs (daidzein, genistein, glycitein, equol, O-desmethylangolensin, dihydrodaidzein, dihydrogenistein) were analyzed by liquid chromatography/mass spectrometry in OU, SU, and PL collected at baseline and every 6 months over 2.5 years.

Results: High between-subject intraclass correlations between all three matrices (median, 0.94) and high between-subject Pearson correlations (median rOU-PL = 0.80; median rSU-PL = 0.80; median rOU-SU = 0.92) allowed the development of equations to predict IFL values from any of the three matrices. Equations developed from a randomly selected 87% of all available data were valid because high correlations were found on the residual 13% of data between equation-generated and measured IFL values (median rOU-PL = 0.86; median rSU-PL = 0.78; median rOU-SU = 0.84); median absolute IFL differences for OU-PL, SU-PL, and OU-SU were 8.8 nmol/L, 10.3 nmol/L, and 0.28 nmol/mg, respectively. All three matrices showed highly significant IFL differences between the placebo and soy intervention group at study end (P < 0.0001) and highly significant correlations between IFL values and counted soy doses in the intervention group.

Conclusions: OU and SU IFL excretion reflect circulating PL IFL levels in healthy postmenopausal women accurately.

Impact: Noninvasively-collected urine can be used to reliably determine systemic IFL exposure and soy intake compliance. Cancer Epidemiol Biomarkers Prev; 19(7); 1775–83. ©2010 AACR.
TP53 Arg72Pro Polymorphism and Colorectal Cancer Risk: A Systematic Review and Meta-Analysis
Authors: Dahabreh Issa J. , Linardou Helena , Bouzika Peggy , Varvarigou Vasileia , Murray Samuel
Published: July 2010

Background: The TP53 rs1042522 polymorphism (c.215C>G, Arg72Pro) has been extensively investigated as a potential risk factor for colorectal cancer, but the results have thus far been inconclusive.

Methods: We searched multiple electronic databases to identify studies investigating the association between the Arg72Pro polymorphism and colorectal cancer. Individual study odds ratios (OR) and their confidence intervals were estimated using allele-frequency, recessive, and dominant genetic models. Summary ORs where estimated using random effects models.

Results: We identified 23 eligible case-control studies, investigating 6,514 cases and 9,334 controls. There was significant between-study heterogeneity for all genetic models. The control group in one of the studies was not in Hardy-Weinberg equilibrium; only three studies reported that genotyping was blinded to case/control status and five studies used tumor tissue for case genotyping. Overall, we did not identify any association between rs1042522 and colorectal cancer risk under an allele-frequency comparison (OR, 0.99; 95% confidence interval, 0.89–1.09). Likewise, no association was evident under dominant or recessive models. Studies using tumor tissue for case genotyping found a protective effect for the Pro allele, compared with studies using somatic DNA (Pinteraction = 0.03). Results were also inconsistent between different genotyping methods (Pinteraction = 0.03).

Conclusion: We did not identify an association between TP53 rs1042522 and colorectal cancer. Published results seem to be driven by technical artifacts rather than true biological effects.

Impact: Future genetic association studies should use more rigorous genotyping methods and avoid the use of tumor tissue as a source of DNA to prevent genotype misclassification due to loss of heterozygosity. Cancer Epidemiol Biomarkers Prev; 19(7); 1840–7. ©2010 AACR.
Inherited Variations in AR, ESR1, and ESR2 Genes Are Not Associated With Prostate Cancer Aggressiveness or With Efficacy of Androgen Deprivation Therapy
Authors: Sun Tong , Lee Gwo-Shu Mary , Werner Lillian , Pomerantz Mark , Oh William K. , Kantoff Philip W. , Freedman Matthew L.
Published: July 2010

Background: Sex steroid hormone receptors mediate essential processes in normal prostate growth and contribute to prostate cancer development.

Method: In this study, we investigated the association between common inherited variation of the AR, ESR1, and ESR2 genes and two clinically relevant traits: the risk of developing aggressive prostate cancer and the response to androgen deprivation therapy (ADT) in a hospital-based cohort. A total of 43 tagging single nucleotide polymorphisms covering the loci of AR (n = 4), ESR1 (n = 32), and ESR2 (n = 7) were successfully genotyped in 4,073 prostate cancer cases.

Results: None of these single nucleotide polymorphisms were significantly associated with disease aggressiveness as assessed by the D'Amico risk classification, pathologic stage, or the response to ADT.

Conclusions: Our results suggest that common genetic variations in AR, ESR1, or ESR2 are not strongly associated with prostate cancer aggressiveness or response to ADT.

Impact: Our study did not find convincing evidence of inherited variations in the major receptors for androgens and estrogens and their associations with prostate cancer traits. Cancer Epidemiol Biomarkers Prev; 19(7); 1871–8. ©2010 AACR.
Human Papillomavirus Genotypes in Cervical Intraepithelial Neoplasia Grade 3
Authors: Castle Philip E. , Schiffman Mark , Wheeler Cosette M. , Wentzensen Nicolas , Gravitt Patti E.
Published: July 2010

Background: There are few large case series describing the human papillomavirus (HPV) genotypes found in women diagnosed with rigorously reviewed cervical intraepithelial neoplasia grade 3 (CIN3), cervical precancer.

Methods: The Atypical Squamous Cells of Undetermined Significance (ASCUS) and Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study (ALTS) was a clinical trial to evaluate the best management strategies for women with equivocal (ASCUS) or mildly abnormal (LSIL) Pap tests. During enrollment and the 2-year follow-up, 608 women had a histopathologic diagnosis of CIN3 and PCR-based HPV genotyping results on cervical specimens. The genotyping results were ranked hierarchically according to cancer risk: HPV16 > other carcinogenic HPV > noncarcinogenic HPV > PCR negative.

Results: Among the 608 women diagnosed with CIN3, 601 (98.8%) cases were positive for any HPV genotype and 95.4% for any carcinogenic HPV. HPV16 (59.9%), HPV31 (18.1%), HPV52 (14.8%), HPV51 (14.0%), and HPV18 (13.2%) were the five most common HPV genotypes detected. Younger age, consensus histologic confirmation, smoking, and multiparity increased the likelihood of testing HPV 16 positive. Specifically, HPV16-positive CIN3 occurred at a younger age than CIN3 positive for other carcinogenic HPV genotypes (median of 23.5 years versus 25 years, respectively; P = 0.0003, Kruskal-Wallis).

Conclusions: HPV16-positive CIN3 was more commonly diagnosed in younger women (versus older women), with consensus diagnosis (versus some disagreement between reviewers), and in smokers (versus nonsmokers), and was less commonly diagnosed in multiparous women compared CIN3 positive for other carcinogenic HPV genotypes.

Impact: In populations vaccinated against HPV16 (and HPV18), the median age of CIN3 in women with ASCUS and LSIL cytology should shift to older ages, possibly permitting later age at first screening. Cancer Epidemiol Biomarkers Prev; 19(7); 1675–81. ©2010 AACR.