bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of the blood-testis barrier by coxsackievirus and adenovirus receptor
Authors: Su Linlin , Mruk Dolores D. , Yan Cheng C.
Published: August 2012

The blood-testis barrier (BTB) divides the seminiferous epithelium into the basal and the adluminal compartment. It restricts paracellular diffusion of molecules between Sertoli cells, confers cell polarity, and creates a unique microenvironment in the adluminal compartment for spermatid development. However, it undergoes restructuring during the epithelial cycle so that preleptotene spermatocytes differentiated from type B spermatogonia residing in the basal compartment can traverse the BTB at stage VIII of the cycle, while the immunological barrier is maintained. Herein, coxsackievirus and adenovirus receptor (CAR), a tight junction (TJ) integral membrane protein in the testis and multiple epithelia and endothelia, was found to act as a regulatory protein at the BTB, besides serving as a structural adhesion protein. RNAi-mediated knockdown of CAR in a Sertoli cell epithelium with an established TJ-permeability barrier that mimicked the BTB in vivo resulted in a disruption of the TJ barrier and an increase in endocytosis of the TJ-protein occludin. Furthermore, such an enhancement in occludin endocytosis was accompanied by a downregulation of Thr-phosphorylation in occludin and an increase in the association of endocytosed occludin with early endosome antigen-1. These findings were confirmed by overexpressing CAR in Sertoli cells, which was found to “tighten” the Sertoli cell TJ barrier, promoting BTB function. These findings support the emerging concept that CAR is not only a structural protein, it is involved in conferring the phosphorylation status of other adhesion proteins at the BTB (e.g., occludin) possibly mediated via its structural interactions with nonreceptor protein kinases, thereby modulating endocytic vesicle-mediated protein trafficking.
Comparison of neural targets for neuromodulation of bladder micturition reflex in the rat
Authors: Su () Xin , Nickles Angela , Nelson Dwight E.
Published: August 2012

Spinal nerve (SN) stimulation inhibits the bladder rhythmic contraction (BRC) in anesthetized rats. This preparation was used to study the effects of electrical stimulation of the tibial nerve (TN) and the dorsal nerve of the clitoris (DNC) on BRC. Stimulation of the TN and DNC for 10 min produced a frequency- and intensity-dependent attenuation of the frequency of bladder contractions. As observed with the SN, 10-Hz stimulation of either TN or DNC produced the greatest degree of inhibition, with lower or higher frequencies being either less efficacious or inactive. In contrast to the prolonged inhibition produced by SN stimulation, both TN and DNC stimulation produced “short” lasting inhibition of bladder contractions and the maximal inhibition occurred during stimulation. TN stimulation was effective over only a narrow range of current intensities [3–4 × motor threshold current for inducing a toe twitch ( Tmot)] and only at a frequency of 10 Hz. Stimulation of TN at 10 Hz, 3 × Tmot inhibited BRC to 23% of control. Ten-hertz DNC stimulation at 2 × TEAS, the threshold current for evoking a reflex anal sphincter contraction, decreased the frequency of contractions to 4% of control. Although compared with the respective threshold current the BRC response was more sensitive to DNC compared with TN stimulation, the absolute current required to reduce BRC using DNC stimulation appeared to be higher. Comparing the effects of TN and DNC stimulation to our previous results with SN stimulation, SN stimulation produces the largest duration and efficacy of bladder inhibition.
Fast Detection of Weak Singularities in a Chaotic Signal Using Lorenz System and the Bisection Algorithm
Authors: Song Tiezheng , Cattani Carlo
Published: August 2012

Signals with weak singularities are important for condition monitoring, fault forecasting, and medicine diagnosis. However, the weak singularity in a signal is usually hidden by strong noise. A novel fast method is proposed for detecting a weak singularity in a noised signal by determining a critical threshold towards chaos for the Lorenz system. First, a rough critical threshold value is calculated by local Lyapunov exponents with a step size 0.1. Second, the exact threshold value is calculated by the bisection algorithm. The advantage of the method will not only reduce the computation costs, but also show the weak singular signal which can be accurately identified from strong noise. When the variance of an external signal method embeds into a Lorenz system, according to the parametric equivalent relation between the Lorenz system and the original system, the critical threshold value of the parameter in a Lorenz system is determined.
Exponential Synchronization for Impulsive Dynamical Networks
Authors: Pan Lijun , Cao Jinde
Published: August 2012

This paper is devoted to exponential synchronization for complex dynamical networks with delay and impulsive effects. The coupling configuration matrix is assumed to be irreducible. By using impulsive differential inequality and the Kronecker product techniques, some criteria are obtained to guarantee the exponential synchronization for dynamical networks. We also extend the delay fractioning approach to the dynamical networks by constructing a Lyapunov‐Krasovskii functional and comparing to a linear discrete system. Meanwhile, numerical examples are given to demonstrate the theoretical results.
Lessons Learned from a Case of Abdominal Aortic Aneurysm Accompanied by Unstable Coagulopathy
Authors: Hoshina Katsuyuki , Kaneko Makoto , Hosaka Akihiro , Okamoto Hiroyuki , Shigematsu Kunihiro , Miyata Tetsuro
Published: August 2012

Preoperative examination for abdominal aortic aneurysms (AAAs) occasionally reveals an abnormal decrease in coagulation factors and thrombocytopenia, fulfilling the criteria for disseminated intravascular coagulation (DIC). Treatment of the underlying disorder is indispensable for alleviating DIC. We report an uncommon case of a patient with AAA and DIC who showed prolonged thrombocytopenia despite successful treatment of AAA and temporary recovery of coagulation factors. A 70-year-old man presented with AAA and shaggy aorta accompanied by DIC and underwent aneurysmectomy. Combined preoperative use of nafamostat mesilate and recombinant human soluble thrombomodulin was effective in controlling DIC. Although recovery of coagulation factors was observed after surgery, the thrombocytopenia continued throughout the postoperative course and was refractory to platelet transfusion. Because HPA antibody and PA-IgG were present, a trial administration ofγ-globulin was performed; this resulted in rapid improvement of thrombocytopenia. Although DIC recurred again 2 weeks thereafter, coagulation factors subsequently recovered without any medication.
Acitretin Treatment for Lipoid Proteinosis
Authors: Gündüz Özgür , Şahiner Neriman , Atasoy Pınar , Şenyücel Çağrı
Published: August 2012

Lipoid proteinosis (LP) is a rare, autosomal-recessive disease characterized by the hoarseness and widespread cutaneous scarring, more prominent on sun-exposed areas. Yellow-white plaques can be seen on oral mucosa and on the skin among depressed scars. Histological evaluation of the affected sites shows accumulation of hyaline-like material in dermis and disruption of basement membrane. Although LP is compatible with normal life expectancy, involvement of upper respiratory tract may endanger patient's life, especially in the case of a respiratory tract infection. Involvement of central nervous system has also been reported, but its clinical importance is obscure. Due to the rarity of LP, a definite therapeutical approach is not established. In this paper we describe a 21-year-old LP patient who was treated with acitretin for six months. Although the outcome with cutaneous lesions was not satisfactory, her hoarseness was significantly improved.
Solitary Neurofibroma of the Frontal Sinus
Authors: Sharma Sudhir B. , Hong Paul
Published: August 2012

Isolated or solitary neurofibromas of the paranasal sinuses are rare. Mostly, they involve the maxillary sinus and so far, a solitary neurofibroma of the frontal sinus has never been reported in the literature. We present a case of frontal sinus neurofibroma treated successfully with surgical excision. A 28-year-old male presented with forehead swelling and computed tomography images revealed a tumor involving the left frontal sinus. Histopathological examination showed the tumor to be a neurofibroma. We discuss the clinical and pathological characteristics of neurofibroma arising in the nasal cavity and paranasal sinuses.
Monitoring Edentulism in Older New Zealand Adults over Two Decades: A Review and Commentary
Authors: Thomson William Murray
Published: August 2012

Historically, New Zealand has had the highest rates of edentulism in the world, but that rate has been falling quickly in recent decades. In 1997, projections were made for edentulism prevalence among 65–74-year-olds using national survey data from 1976 (where it was 72.3%) to 1988 (58.6%). That process assumed a logistic decline in edentulism, given that it would never have been 100% and will never get to 0%. This paper examines the validity of the projections using the estimate (29.6%) from the third national oral health survey, conducted in 2009 and considers the implications of this fall.
Balance, Falls-Related Self-Efficacy, and Psychological Factors amongst Older Women with Chronic Low Back Pain: A Preliminary Case-Control Study
Authors: Champagne Annick , Prince François , Bouffard Vicky , Lafond Danik
Published: August 2012

Objective. To investigate balance functions in older women and evaluate the association of the fear-avoidance beliefs model (FABM) factors with balance and mobility performance.Participants. Fifteen older women with CLBP was compared with age-matched pain-free controls (n=15).Main Outcome Measures. Pain intensity, falls-related self-efficacy and intrinsic constructs in the FABM were evaluated. Postural steadiness (centre of pressure (COP)) and mobility functions were assessed. Linear relationships of FABM variables with COP and mobility score were estimated.Results. CLBP showed lower mobility score compared to controls. CLBP presented lower falls-related self-efficacy and it was associated with reduced mobility scores. FABM variables and falls-related self-efficacy were correlated with postural steadiness. Physical activity was reduced in CLBP, but no between-group difference was evident for knee extensor strength. No systematic linkages were observed between FABM variables with mobility score or postural steadiness.Conclusions. Back pain status affects balance and mobility functions in older women. Falls-related self-efficacy is lower in CLBP and is associated with reduced mobility. Disuse syndrome in CLBP elderly is partly supported by the results of this preliminary study.
On the Occurrence of the Blunthead Puffer,Sphoeroides pachygaster(Osteichthyes: Tetraodontidae), in the Strait of Messina (Central Mediterranean)
Authors: Giordano D. , Profeta A. , Pirrera L. , Soraci F. , Perdichizzi F. , Greco S. , Perdichizzi A. , Rinelli P.
Published: August 2012

The record ofSphoeroides pachygasterreveals the presence of the species in the Strait of Messina (Central Mediterranean Sea). The adult species was captured on 15 march 2012. It measured 280 mm of total length and weighed 461.5 g. Morphometric measurements (mm) and meristic counts were reported in this paper.
A Novel Mathematical Approach to Define the Genes/SNPs Conferring Risk or Protection in Sporadic Amyotrophic Lateral Sclerosis Based on Auto Contractive Map Neural Networks and Graph Theory
Authors: Buscema Massimo , Penco Silvana , Grossi Enzo
Published: August 2012

Background. Complex diseases like amyotrophic lateral sclerosis (ALS) implicate phenotypic and genetic heterogeneity. Therefore, multiple genetic traits may show differential association with the disease. The Auto Contractive Map (AutoCM), belonging to the Artificial Neural Network (ANN) architecture, “spatializes” the correlation among variables by constructing a suitable embedding space where a visually transparent and cognitively natural notion such as “closeness” among variables reflects accurately their associations.Results. In this pilot case-control study single nucleotide polymorphism (SNP) in several genes has been evaluated with a novel data mining approach based on an AutoCM. We have divided the ALS dataset into two dataset: Cases and Control dataset; we have applied to each one, independently, the AutoCM algorithm. Six genetic variants were identified which differently contributed to the complexity of the system: three of the above genes/SNPs represent protective factors, APOA4, NOS3, and LPL, since their contribution to the whole complexity resulted to be as high as 0.17. On the other hand ADRB3, LIPC, and MMP3, whose hub relevancies contribution resulted to be as high as 0.13, seem to represent susceptibility factors.Conclusion. The biological information available on these six polymorphisms is consistent with possible pathogenetic pathways related to ALS.
Congenital Double Pylorus
Authors: Naidoo Ruvashni , Singh Bhugwan
Published: August 2012

The double pylorus is an uncommon finding and maybe congenital due to gastrointestinal duplication abnormality or more commonly secondary to peptic ulcer disease. The case we present is an elderly patient with mild dyspeptic symptoms who had an upper endoscopy as part of her investigative workup. The congenital double pylorus, being asymptomatic, may often go undetected. It is sometimes found incidentally on upper endoscopy, but needs no directed therapy. It is not associated with any specific complication.
FastRoute: An Efficient and High‐Quality Global Router
Authors: Pan Min , Xu Yue , Zhang Yanheng , Chu Chris
Published: August 2012

Modern large‐scale circuit designs have created great demand for fast and high‐quality global routing algorithms to resolve the routing congestion at the global level. Rip‐up and reroute scheme has been employed by the majority of academic and industrial global routers today, which iteratively resolve the congestion by recreating the routing path based on current congestion. This method is proved to be the most practical routing framework. However, the traditional iterative maze routing technique converges very slowly and easily gets stuck at local optimal solutions. In this work, we propose a very efficient and high‐quality global router—FastRoute. FastRoute integrates several novel techniques: fast congestion‐driven via‐aware Steiner tree construction, 3‐bend routing, virtual capacity adjustment, multisource multi‐sink maze routing, and spiral layer assignment. These techniques not only address the routing congestion measured at the edges of global routing grids but also minimize the total wirelength and via usage, which is critical for subsequent detailed routing, yield, and manufacturability. Experimental results show that FastRoute is highly effective and efficient to solve ISPD07 and ISPD08 global routing benchmark suites. The results outperform recently published academic global routers in both routability and runtime. In particular, for ISPD07 and ISPD08 global routing benchmarks, FastRoute generates 12 congestion‐free solutions out of 16 benchmarks with a speed significantly faster than other routers.
The Association between Databases for Indexing Studies Intended for an Exercise Meta-Analysis of Arthritis Randomized Controlled Trials
Authors: Kelley George A. , Kelley Kristi S.
Published: August 2012

Objective. The purpose of this study was to determine the database indexing of randomized controlled trials (RCTs) for a meta-analysis addressing the effects of exercise on pain and physical function in adults with arthritis and other rheumatic diseases (AORD). Methods. The number, percentage, and 95% confidence intervals (CIs) for included articles at initial and follow-up periods were calculated from PubMed, EMBASE, CENTRAL, CINAHL, SPORTDiscus, and DAO databases. The number needed to review (NNR) was also calculated along with the number of articles retrieved by expert review. Cross-referencing from reviews and included articles also occurred. Results. Thirty-four of 36 articles (94.4%, 95% CI, 81.3–99.3) were located by database searching. PubMed and CENTRAL yielded 32 of 36 articles (88.9%, 73.9–96.9). Two articles not identified in any of the other databases were found in either CINAHL or SPORTDicsus. Two other articles were located by scanning the reference lists of review articles. The NNR ranged from 2 (CINAHL) to 118 (SPORTDiscus). More articles were identified in EMBASE at follow-up (36%, 12.1–42.2 versus 86.1%, 70.5–95.3). Conclusions. Searching multiple databases and cross-referencing from reviews was important for identifying RCTs addressing the effects of exercise on pain and physical function in adults with AORD.
Photobiomodulation on Stress
Authors: Liu Timon Cheng-Yi , Liu Yan-Ying , Wei En-Xiu , Li Fang-Hui
Published: August 2012

Photobiomodulation (PBM) is a nondamaged modulation of laser irradiation or monochromatic light (LI) on a biosystem function. It depends on whether the function is in its function-specific homeostasis (FSH). An FSH is a negative-feedback response of a biosystem to maintain the function-specific conditions inside the biosystem so that the function is perfectly performed. A function in its FSH is called a normal function. A function far from its FSH is called a dysfunctional function. The process of a function from dysfunctional to normal is called a functional normalization. For a normal function in its FSH, there are FSH-essential subfunctions (FESs), FSH-nonessential subfunctions (FNSs), and an FES/FNS-specific homeostasis (FESH/FNSH). A FSH can resist internal/external disturbances under the threshold, but can be disrupted by an FSH-specific stress (FSS). A normal/dysfunctional FSS is called a successful/chronic stress. An FESH/FNSH-specific stress was called an extraordinary/ordinary stress. A low level LI (LLL) cannot directly affect a normal function, but can modulate a chronic stress. A normal function may have a chronic ordinary stress, and an LLL may modulate the chronic ordinary stress so that it promotes the normalization of the dysfunctional FNS and then upgrades the normal function. A high level LI can modulate a normal function and may be a successful stress.
Eleven-Year Distribution Pattern of Hepatitis C Virus in Southern Italy
Authors: Marascio Nadia , Matera Giovanni , Quirino Angela , Giancotti Aida , Barreca Giorgio S. , Lamberti Angelo G. , Caroleo Benedetto , Liberto Maria Carla , Focà Alfredo
Published: August 2012

Analysis of the Hepatitis C Virus (HCV) genotype spread in a particular area has a crucial impact on public health. In this study, we update information on the distribution of HCV genotypes, by evaluating a hospital-based cohort of 2,153 chronic hepatitis C patients, collected prospectively among subjects attending University Hospital of Catanzaro, within an area of Southern Italy. We assessed the rates (%) of HCV genotypes during two consecutive periods, from 2001 to 2005 and from 2006 to 2011, according to age and gender. Considering overall observation time, subtype 1b was predominant followed by subtypes 2a/2c, genotype 3 and 4. Statistical evaluation of the age of HCV patients stratified by genotypes, revealed a slight but significant increase in the median age of 1b, 2a/2c and 3 HCV genotype-infected subjects, during the 2006–2011 period, whilst genotype 4 patients exhibited a decrease in the median age during the same period studied. Moreover genotype 4 increased between 2002 and 2003 as well as between 2010 and 2011. Due to the peculiar diagnostic/clinical/therapeutic features of HCV-4, our findings warrant a deeper investigation to better control infections caused by such genotype.
σ‐Approximately Contractible Banach Algebras
Authors: Momeni M. , Yazdanpanah T. , Mardanbeigi M. R.
Published: August 2012

We investigate σ‐approximate contractibility and σ‐approximate amenability of Banach algebras, which are extensions of usual notions of contractibility and amenability, respectively, where σ is a dense range or an idempotent bounded endomorphism of the corresponding Banach algebra.
Dynamic Analysis of an Impulsive Predator‐Prey Model with Disease in Prey and Ivlev‐Type Functional Response
Authors: Shao Yuanfu , Li Peiluan , Tang Guoqiang
Published: August 2012

A predator‐prey model with disease in prey, Ivlev‐type functional
response, and impulsive effects is proposed. By using Floquet theory and small amplitude
perturbation skill, sufficient conditions of the existence and global stability of susceptible pest‐eradication periodic solution are obtained. By impulsive comparison theorem, conditions ensuring the permanence of the system are established. Examples and simulation are given to
show the complex dynamics for the key parameters.
Dissertation to Journal Article: A Systematic Approach
Authors: Thomas Brychan , Skinner Heather
Published: August 2012

The aim of the paper is to elucidate a systematic approach to convert a Masters dissertation into a journal article. This approach has involved a fundamental thematic review of the literature concerning the conversion of dissertations into journal articles. From these sources pertinent approaches, processes, lessons, and guidance have been noted and analysed. By undertaking this distillation of relevant material, to enable the efficient conversion of dissertations into journal articles, appropriate procedures and conclusions have been compiled. Findings present current thinking on the conversion of a dissertation into a journal paper in terms of how dissertations differ from journal articles, reframing for publication, rethinking the material, trimming the length, time taken to rewrite the material, specific lessons, and adapting for publication. Recommendations provided in the paper will enable staff to take this course of action when developing their publication portfolio to become more research active and to make an important contribution to the publication output of their department/school/faculty, especially with regard to assessment exercises such as the Research Excellence Framework. The value of the paper is that by following appropriate approaches, processes, and procedures it is possible to convert a good dissertation into a ranked journal article.
Massive Levemir (Long-Acting) Insulin Overdose: Case Report
Authors: Oduru Mamatha , Ahmad Mahmood
Published: August 2012

A 52-year-old insulin-dependant diabetic man presented to the Emergency Department 2 hours after a deliberate massive overdose of 2100 units of long-acting Levemir insulin and a large quantity of whisky. On initial assessment, his GCS was 3/15 and his capillary blood sugar was 2.6 mmol/L. The patient was given a 50 ml bolus of 50% dextrose, followed by intravenous infusions of both 5% and 10% dextrose. Despite the continuous infusions, he experienced 4 symptomatic hypoglycaemic episodes in the first 12 hours after admission. These were managed with oral glucose, IM glucagon, and further dextrose boluses. Blood electrolytes and pH were monitored throughout. Insulin overdoses are relatively common and often occur with an excess of other drugs or alcohol which can enhance its action. Overdoses can result in persistent hypoglycaemia, liver enzyme derangement, electrolyte abnormalities, and neurological damage. Overall mortality is 2.7% with prognosis poorest in patients who are admitted with decreased Glasgow Coma scale (GCS) 12 hours after overdose.
An Approach for Predicting the Shape and Size of a Buried Basic Object on Surface Ground Penetrating Radar System
Authors: Syambas Nana Rachmana
Published: August 2012

Surface ground-penetrating radar (GPR) is one of the radar technology that is widely used in many applications. It is nondestructive remote sensing method to detect underground buried objects. However, the output target is only hyperbolic representation. This research develops a system to identify a buried object on surface GPR based on decision tree method. GPR data of many basic objects (with circular, triangular, and rectangular cross-section) are classified and extracted to generate data training model as a unique template for each type of basic object. The pattern of object under test will be known by comparing its data with the training data using a decision tree method. A simple powerful algorithm to extract feature parameters of object which is based on linear extrapolation is proposed. The result showed that tested buried basic objects can be correctly predicted and the developed system works properly.
Some Formulae of Products of the Apostol‐Bernoulli and Apostol‐Euler Polynomials
Authors: He Yuan , Wang Chunping
Published: August 2012

Some formulae of products of the Apostol‐Bernoulli and Apostol‐Euler polynomials are established by applying the generating function methods and some summation transform techniques, and various known results are derived as special cases.
Innate Immune Cells in Liver Inflammation
Authors: Liaskou Evaggelia , Wilson Daisy V. , Oo Ye H.
Published: August 2012

Innate immune system is the first line of defence against invading pathogens that is critical for the overall survival of the host. Human liver is characterised by a dual blood supply, with 80% of blood entering through the portal vein carrying nutrients and bacterial endotoxin from the gastrointestinal tract. The liver is thus constantly exposed to antigenic loads. Therefore, pathogenic microorganism must be efficiently eliminated whilst harmless antigens derived from the gastrointestinal tract need to be tolerized in the liver. In order to achieve this, the liver innate immune system is equipped with multiple cellular components; monocytes, macrophages, granulocytes, natural killer cells, and dendritic cells which coordinate to exert tolerogenic environment at the same time detect, respond, and eliminate invading pathogens, infected or transformed self to mount immunity. This paper will discuss the innate immune cells that take part in human liver inflammation, and their roles in both resolution of inflammation and tissue repair.
Nearly Quadratic n‐Derivations on Non‐Archimedean Banach Algebras
Authors: Gordji Madjid Eshaghi , Alizadeh Badrkhan , Lee Young Whan , Kim Gwang Hui
Published: August 2012

Let n > 1 be an integer, let A be an algebra, and X be an A‐module. A quadratic function D : A → X is called a quadratic n‐derivation if for all a1,…,an ∈ A. We investigate the Hyers‐Ulam stability of quadratic n‐derivations from non‐Archimedean Banach algebras into non‐Archimedean Banach modules by using the Banach fixed point theorem.
Efficient Knoevenagel Condensation Reactions Catalyzed by Activated Gel Zirconium(IV) Oxide
Authors: Poor Heravi Mohammad Reza , Piri S.
Published: August 2012

The condensation reaction has been carried out very conveniently to obtain the corresponding substituted 2,2′‐(arylmethylene)bis(3‐hydroxy‐5,5‐dimethylcyclohex‐2‐enone) in excellent yields. The reaction conditions are very mild and applicable to various aldehydes as well as active methylene compounds.
Hedgehog Signaling Is a Novel Therapeutic Target in Tamoxifen-Resistant Breast Cancer Aberrantly Activated by PI3K/AKT Pathway
Authors: Ramaswamy Bhuvaneswari , Lu Yuanzhi , Teng Kun-yu , Nuovo Gerard , Li Xiaobai , Shapiro Charles L. , Majumder Sarmila
Published: August 2012

Endocrine resistance is a major challenge in the management of estrogen receptor (ER)-positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of patients developing resistance to endocrine therapy warrants additional studies. Here we show that noncanonical Hedgehog (Hh) signaling is an alternative growth promoting mechanism that is activated in tamoxifen-resistant tumors. Importantly, phosphoinositide 3-kinase inhibitor/protein kinase B (PI3K/AKT) pathway plays a key role in regulating Hh signaling by protecting key components of this pathway from proteasomal degradation. The levels of Hh-signaling molecules SMO and GLI1 and the targets were significantly elevated in tamoxifen-resistant MCF-7 cells and T47D cells. Serial passage of the resistant cells in mice resulted in aggressive tumors that metastasized to distant organs with concurrent increases in Hh marker expression and epithelial mesenchymal transition. RNAi-mediated depletion of SMO or GLI1 in the resistant cells resulted in reduced proliferation, clonogenic survival and delayed G1–S transition. Notably, treatment of resistant cells with PI3K inhibitors decreased SMO and GLI1 protein levels and activity that was rescued upon blocking GSK3β and proteasomal degradation. Furthermore, treatment of tamoxifen-resistant xenografts with anti-Hh compound GDC-0449 blocked tumor growth in mice. Importantly, high GLI1 expression correlated inversely with disease-free and overall survival in a cohort of 315 patients with breast cancer. In summary, our results describe a signaling event linking PI3K/AKT pathway with Hh signaling that promotes tamoxifen resistance. Targeting Hh pathway alone or in combination with PI3K/AKT pathway could therefore be a novel therapeutic option in treating endocrine-resistant breast cancer. Cancer Res; 72(19); 5048–59. ©2012 AACR.
Abstract 1: Oncogenic extracellular domain mutations of ERBB2 in cancer
Authors: Greulich Heidi , Kaplan Bethany , Mertins Philipp , Chen Tzu-Hsiu , Tanaka Kumiko , Yun Cai-Hong , Imielinski Marcin , Banerji Shanatanu , Lawrence Michael S. , Walker Sarah , Winckler Wendy , Getz Gad , Frank David , Eck Michael , Jaffe Jacob D. , Carr Steven A. , Wong Kwok-Kin , Meyerson Matthew
Published: August 2012

The ERBB2 receptor tyrosine kinase gene is frequently amplified and mutated in human cancer. However, mutations characterized to date have been located in the kinase domain of the receptor. Using publically-available sequencing datasets, we have found that extracellular domain mutations of ERBB2 located beneath the dimerization arm recur in lung, breast, and ovarian cancers. We expressed cDNAs harboring these mutations in NIH-3T3 cells and found that the mutants support anchorage-independent proliferation. We furthermore found that substitution of any one of a number of amino acids in this region of the protein is oncogenic. We sought to biochemically characterize the extracellular domain mutations of ERBB2 and found that they cause oncogenic transformation by one of two mechanisms: elevation of C-terminal tail phosphorylation, or reduction-sensitive covalent dimerization unaccompanied by increases in C-terminal phosphorylation. Analysis of tyrosine phosphorylated proteins in the cell by stable isotope labeling followed by mass spectrometry (SILAC) revealed that both classes of mutant receptor phosphorylated the same set of proteins to effect transformation. The most prominent targets were proteins involved in cytoskeletal and membrane dynamics, controlling cell motility. STAT3 was also phosphorylated to a limited extent in ERBB2-transformed cells. Interestingly, STAT3 phosphorylation was mediated solely by a JAK-dependent autocrine loop in cells transformed by the ERBB2 mutants activated by reduction-sensitive dimerization; whereas both ERBB2 and JAK family kinases contributed to STAT3 phosphorylation in cells transformed by ERBB2 mutants exhibiting increased C-terminal phosphorylation. In order to characterize inhibitor sensitivity, we transformed Ba/F3 cells to IL-3 independence with the ERBB2 extracellular domain mutants. All extracellular domain mutants tested were sensitive to irreversible inhibitors of ERBB2, suggesting that treatment with such inhibitors may benefit patients harboring mutations of the extracellular domain of ERBB2.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1. doi:1538-7445.AM2012-1
Abstract 1010: Effect of dietary energy balance modulation on the ability of metformin to inhibit skin tumor promotion
Authors: Checkley Allyson , Moore Tricia , Rho Okkyung , DiGiovanni John
Published: August 2012

The prevalence of obesity has drastically increased over the last decade and is associated with increased risk for several cancers. In contrast, calorie restriction (CR) universally inhibits cancer. Plausible mechanisms for the energy balance-cancer link include differential signaling through Akt/mTOR via the IGF-1R as well as other growth factor receptors. Previous data from our lab, using topical administration of rapamycin, support the hypothesis that pharmacological disruption of mTORC1 signaling mimics some of the effects of CR on skin tumor promotion. To further explore the role of mTORC1 signaling in tumor promotion we have conducted studies using metformin. In the present study, metformin was administered in the drinking water at doses of 250 mg/kg and 50 mg/kg body weight per day to female FVB/N mice, to assess its ability to reverse the effects of overweight/obesity on skin tumor promotion during two-stage skin carcinogenesis. Metformin treatment during skin tumor promotion significantly inhibited tumor multiplicity in a dose dependent manner in mice on an overweight control diet (AIN76A). There was a 70% reduction in papillomas per mouse at the 250 mg/kg dose and a 35% reduction at the 50 mg/kg dose. Short term mechanistic experiments with these same doses revealed significant decreases in TPA-induced epidermal hyperproliferation (as measured by epidermal hyperplasia and labeling index) after oral administration of metformin. Metformin also activated AMP Kinase in the epidermis as measured by pAMPKαT172 at both doses used as well as attenuated signaling through mTORC1 at the highest dose as measured by downstream signaling proteins p70S6KT389 and prS6S235/236. Treatment with the higher dose of metformin also prevented TPA-induced mTORC1 mediated degradation of translational repressor PDCD4. Current experiments are assessing the ability of metformin to suppress skin tumor promotion in mice maintained on an obesity inducing diet (60kcal% fat) and these studies will also be presented. Overall, the current data support the hypothesis that selectively targeting mTORC1, either directly (rapamycin) or indirectly via AMPK activation, may be an effective strategy for reversing the effects of overweight and obesity on tumor development during epithelial carcinogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1010. doi:1538-7445.AM2012-1010
Abstract 1014: Targeting cancer stem cells by a Notch2/Notch3 cross-reactive antibody inhibits tumor growth and delays tumor recurrence in pancreatic cancer
Authors: Fischer Marcus M. , Yen Wan-Ching , Wang Min , Kapoun Ann M. , Sato Aaron , Lewicki John , Gurney Austin , Hoey Timothy
Published: August 2012

Pancreatic cancer is a devastating disease with very poor prognosis and few treatment options. The Notch pathway has been implicated in the development of pancreatic cancer, and in particular both Notch2 and Notch3 are known to be important in this disease. In this report, we examined the in vivo efficacy of an antibody that was initially identified by binding to Notch2 and was subsequently shown to block signaling of both human and mouse Notch2 and Notch3. Utilizing a panel of minimally-passaged, patient-derived, pancreatic adenocarcinoma xenograft tumors, we performed in vivo growth inhibition and tumorigenicity studies with the Notch2/3 antibody alone or combined with the standard-of-care chemotherapeutic gemcitabine. We demonstrated that the Notch2/3 antibody was active as a single agent, and when combined with gemcitabine, the combination therapy resulted in improved efficacy over that of gemcitabine alone. Utilizing an in vivo limiting dilution tumorigenicity assay, we found that the cancer stem cell (CSC) frequency was increased by gemcitabine as a single agent, but significantly decreased by the combination of anti-Notch2/3 and gemcitabine. Analysis of cell surface markers associated with pancreatic cancer stem cells indicated that gemcitabine treatment results in an increase in the percentage of CSCs, while the Notch2/3 antibody significantly reduced the CSC population. Utilizing this pancreatic cancer xenograft model, we analyzed the ability of the Notch 2/3 antibody to delay tumor recurrence following gemcitabine induced tumor regression. While gemcitabine-treated tumors re-grew rapidly following treatment termination, the ability of tumors to recur was significantly delayed by the Notch2/3 antibody suggesting that the delay in tumor recurrence is in part due to the Notch2/3 antibody-mediated decrease in CSC frequency. Gene set enrichment analysis in tumors that responded to anti-Notch2/3 revealed that various stem cell gene sets were up-regulated in tumors treated by gemcitabine alone, but down-regulated by the combination of anti-Notch2/3 and gemcitabine. Findings from this study suggest that antagonists of Notch signaling may act as chemotherapeutic-sensitizing agents by interfering with CSC self renewal pathways and thereby enhancing the cytotoxic effects of chemotherapy on CSCs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1014. doi:1538-7445.AM2012-1014
Abstract 1017: Protooncogenic TLR4 generates NANOG-dependent tumor-initiating stem-like cells through LIN28-Let7 pathway in experimental and clinical carcinogenesis
Authors: Machida Keigo , Chen Chia-Lin , Liu Jian-Chang , Sher Linda , Mishra Lopa , Tsukamoto Hidekazu
Published: August 2012

[Background] TLR4 signaling activated by alcohol/obesity-associated endotoxemia, induces the stem cell marker Nanog to generate tumor-initiating stem-like cells (TISCs) and liver tumors in the HCV nonstructural protein Ns5a transgenic (Tg) mice but not in wild type or Ns5a Tg mice deficient in TLR4 (Machida and Tsukamoto, PNAS, 2009). However, it is unknown whether the TLR4-NANOG pathway serves as a universal oncogenic signaling in the genesis of TISCs and HCC in other etiological animal models and patients or how TLR4 is upregulated in TLR4-NANOG-dependent TISCs. [Aim] We aimed to determine whether TLR4 is a putative proto-oncogene for TIC in liver oncogenesis due to different etiologies and how TLR4 is regulated at the transcriptional and epigenetic levels. [Methods] CD133+/CD49f+ TISCs were isolated using FACS from HCC developed in HCV Core Tg mice fed alcohol, diethylnitrosamine (DEN)-treated mice, and alcoholic patients with or without HCV infection. We generated Tg mice with liver-selective overexpression of constitutively active (ca) TLR4 using LAP promoter-driven tTA and Tet-caTLR4. TLR4 promoter-reporter analysis was performed on TISCs from alcohol-fed Core Tg mice. [Results] CD133+/CD49f+ cells isolated from the animal models and patients are tumorigenic both in vitro and in a xenograft model, and TLR4 or NANOG silencing with shRNA attenuates their tumor initiating property. Hepatocyte specific expression of caTLR4 results in spontaneous development of HCC in 35% of the mice. LIN28 and TLR4 expression is 6-fold higher in TISCs compared to CD133-/CD49f+ cells, and the expression of LIN28 increases TLR4 expression with reduction of Let7 microRNA in CD133- cells but not TISCs, suggesting LIN28-mediated Let7 reduction drive TLR4 induction. TLR4 expression and promoter activity are further reduced by a silencing of LIN28 or expression of Let7. LIN28 and NANOG overexpression transform liver stem cells through activation of TLR4-NANOG pathway. [Conclusions] These results demonstrate that CD133+/CD49f+ cells are TLR4/NANOG-dependent TISCs in both experimental and clinical HCC. TLR4 is induced by LIN28 signaling and is a universal proto-oncogene responsible for the genesis of TLR4-NANOG dependent TISCs, and this pathway serves as a novel therapeutic target for HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1017. doi:1538-7445.AM2012-1017
Abstract 1027: Helicobacter pylori blood biomarkers for gastric cancer risk in the Shanghai Men's Health Study
Authors: Epplein Meira , Zheng Wei , Xiang Yong-Bing , Peek Richard M. , Li Honglan , Correa Pelayo , Gao Jing , Michel Angelika , Pawlita Michael , Cai Qiuyin , Shu Xiao-Ou
Published: August 2012

Background: Helicobacter pylori is the leading identified risk factor for distal gastric cancer, yet only a fraction of infected individuals ever develop neoplasia. To identify potential risk markers in a Chinese population where over 90% of individuals are infected with H. pylori, we assessed the association between antibodies to 15 Helicobacter pylori proteins and gastric cancer risk in a case-control study nested in a population-based cohort study. Methods: Each incident distal gastric cancer case (n = 227) identified between 2002 and 2009 among members of the Shanghai Men's Health Study was matched to two controls based on age, timing of blood collection, and recent antibiotic use. Serum levels of antibodies to 15 Helicobacter pylori proteins were assessed using multiplex serology. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Results: Sero-positivity to three (Omp, HP0305, HyuA) of fifteen proteins assessed were associated with an approximate two-fold significantly increased risk for gastric cancer. When excluding cases who were diagnosed within two years of study enrollment (and their matched controls), sero-positivity to two additional proteins (HpaA and NapA) showed significant associations with risk. An association with CagA sero-positivity was also suggested. Compared to individuals with ≤3 sero-positive results to the six virulent proteins identified in this population, individuals with 4-5 sero-positive results were at a two-fold increased risk (OR=1.93, 95% CI: 1.25-3.00) and individuals sero-positive to all 6 proteins had an over 3-fold increase in risk (OR=3.31, 95% CI: 1.86-5.89) for distal gastric cancer. Among individuals least likely to have begun cascade of events leading to gastric cancer, these associations were even stronger (OR=2.74, 95% CI: 1.58-4.73 and OR=4.72, 95% CI: 2.22-10.03, respectively). Conclusions: In the Chinese population, among whom H. pylori-infection is highly prevalent, increasing number of sero-positives to six H. pylori proteins (Omp, HP0305, HyuA, HpaA, CagA, and VacA) may predict the risk of gastric cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1027. doi:1538-7445.AM2012-1027
Abstract 1033: Transcriptional factor ZBP-89 interacts with DNMT1 and HDAC3 to regulate Bak expression
Authors: Caiguo Ye , George Chen Gong , Paul Lai
Published: August 2012

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide with a very high mortality. Because the success of the conventional therapies is limited, epigenetic therapy may represent an alternative for HCC management. The present study was designed to investigate whether DNA methyltransferases and histone acetylases were involved in regulation of ZBP-89-induced Bak expression. After adenovirus Ad-ZBP-89 transfection, bisulfate modificated DNA sequencing, immunofluorence staining, siRNA interference, western blotting, and enzymatic activity assays were used to analyze DNA methylation, histone modifications and the enzyme activity in human HCC cell. Based on our previous report that ZBP-89 up-regulated Bak expression, the current study revealed that ZBP-89 regulated Bak expression through interacting with HDAC3 and DNMT1. ZBP-89 could also demethylate the CpG island in Bak promoter to facilitate Bak expression and apoptosis. Additionally, ZBP-89 contributed to maintain histone H3 and H4 acetylation by inhibiting HDACs activity. ZBP-89 was found to suppress DNMT1 activity and HDAC3 activity. Conclusively, our study demonstrates a novel mechanism how the transcription factor ZBP-89 mediates epigenetic modification to promote Bak expression. The new pathway discovered may help to develop certain epigenetic therapy against HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1033. doi:1538-7445.AM2012-1033
Abstract 1039: Histone deacetylase 8 (HDAC8) target identification and mechanism of action of HDAC8 isoform-specific inhibitors
Authors: Balasubramanian Sriram , Sirisawad Mint , Steggerda Susanne , Mani Chitra , Thiemann Patti , Buggy Joseph J.
Published: August 2012

HDAC8 is a member of the histone deacetylase family, but no acetylation target in cells has yet been identified. Due to a different pocket structure, most of the pan-HDAC inhibitors currently in the clinic bind poorly to it. HDAC8 knockout mice were shown to have an embryonic defect in neural crest development, but the adult mice have no other published phenotype, and its functions in adult normal or tumor cells are not well understood. In this work, we have undertaken extensive cellular and tissue localization studies, knockdown and isoform-specific inhibition studies, whole genome expression profiling, proteomics experiments to identify differentially acetylated and expressed proteins, and kinome siRNA knockdown experiments to identify pathways of activity. In total, these results point to HDAC8's essential function in many tumor cell types, not all of which are dependent upon the enzymatic activity of the enzyme.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1039. doi:1538-7445.AM2012-1039