bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantum Brownian Representation for the Quantum Field Modes
Authors: Arteaga Daniel
Published: August 2009

When analyzing the particle‐like excitations in quantum field theory it is natural to regard
the field mode corresponding to the particle momentum as an open quantum system, together
with the opposite momentum mode. Provided that the state of the field is stationary,
homogeneous, and isotropic, this scalar two‐mode system can be equivalently represented in
terms of a pair of quantum Brownian oscillators under a Gaussian approximation. In other
words, the two‐mode system behaves as if it were interacting linearly with some effective
environment. In this paper we build the details of the effective linear coupling and the
effective environment, and argue that this quantum Brownian representation provides a
simple, universal, and nonperturbative characterization of any single particle‐like excitation.
As immediate applications of the equivalence, we reanalyze the interpretation of the self‐energy
in terms of decay rates in a general background state and present the master equation
for the field mode corresponding to the particle momentum.
Pinellia ternata,Citrus reticulata, and Their Combinational Prescription Inhibit Eosinophil Infiltration and Airway Hyperresponsiveness by Suppressing CCR3+ and Th2 Cytokines Production in the Ovalbumin-Induced Asthma Model
Authors: Ok In-Soo , Kim Seung-Hyung , Kim Bok-Kyu , Lee Jang-Cheon , Lee Young-Cheol
Published: August 2009

Background and Objective. This study was aimed to analyse the curative effects ofPinellia ternata,Citrus reticulata, and their combination on airway hyperresponsiveness (AHR) to inhaled methacholine, pulmonary eosinophilic infiltration, Th2 cytokine production, and IgE and histamine production in a murine model of asthma.Methods. For this purpose, BALB/c mice were systemically sensitized to ovalbumin (OVA) followed intratracheally, intraperitoneally, and by aerosol allergen challenges for 12 weeks. We examined the development of pulmonary eosinophilic accumulation, control of Th2 cytokine, immunoglobulin E (IgE), and histamine productions in a murine model of asthma.Results. Our data suggest that the therapeutic mechanism by whichPinellia ternata,Citrus reticulata, and their combinational prescription effectively treats asthma is based on reductions of eosinophil infiltration, eotaxin receptor (CCR3), histamine, OVA-specific IgE productions in serum, and Th2 cytokines (IL-5, IL-13) by marked reductions of IL-5 and IL-13 mRNA expression in lung tissue.Conclusions. These findings provide evidence thatPinellia ternata,Citrus reticulata, and their combination play a regulatory role in allergic inflammation and offer therapeutic approaches as novel CCR3 antagonists for treatment asthma. However, it is not clear whether pharmacological activities of prescription composed of two herbs are potentiated due to synergistic effect or additive effect.
A Review of Carbon Nanotubes‐Based Gas Sensors
Authors: Wang Yun , Yeow John T. W.
Published: August 2009

Gas sensors have attracted intensive research interest due to the demand of sensitive, fast response, and stable sensors for industry, environmental monitoring, biomedicine, and so forth. The development of nanotechnology has created huge potential to build highly sensitive, low cost, portable sensors with low power consumption. The extremely high surface‐to‐volume ratio and hollow structure of nanomaterials is ideal for the adsorption of gas molecules. Particularly, the advent of carbon nanotubes (CNTs) has fuelled the inventions of gas sensors that exploit CNTs′ unique geometry, morphology, and material properties. Upon exposure to certain gases, the changes in CNTs′ properties can be detected by various methods. Therefore, CNTs‐based gas sensors and their mechanisms have been widely studied recently. In this paper, a broad but yet in‐depth survey of current CNTs‐based gas sensing technology is presented. Both experimental works and theoretical simulations are reviewed. The design, fabrication, and the sensing mechanisms of the CNTs‐based gas sensors are discussed. The challenges and perspectives of the research are also addressed in this review.
Small-bowel Diverticulosis: Imaging Findings and Review of Three Cases
Authors: De Peuter B. , Box I. , Vanheste R. , Dymarkowski S.
Published: August 2009

Complicated small-bowel diverticulosis is a rather uncommon cause of upper abdominal pain. It may lead to symptoms presenting with an acute onset or to chronic and nonspecific complaints. As the presentation is often similar to other pathologies (acute appendicitis, pancreatitis, or acute cholecystis) and in many cases diagnosis is made on basis of surgical findings, careful analysis of the imaging landmarks may be warranted to aid in the early stages of detection. In this report, we present clinical and morphological findings in three patients where small-bowel diverticulitis was surgically proven. The relevant literature is reviewed, and typical imaging properties are discussed.
A Kinetic Comparison between Laboratory and Industrial Scales in the Copper Blowing Process
Authors: Roselló A. , Martínez J. , Carrillo F.
Published: August 2009

An experimental investigation into the oxidation kinetics of molten sulfide has been conducted at laboratory scale to provide information concerning the influence of the gas feed (flow and oxygen pressure) and melt temperature on the desulfurization rate. Data showed that the reaction rate was strongly dependent on the gas flow rate and significantly from oxygen pressure, whereas the influence of temperature was negligible. The variation of the sulfur conversion with the operation time was similar to that found in industrial trials when “white metal” was blown to blister copper in a Peirce-Smith converter. A unique equation for both scales could be established. This correlation made it possible to calculate the operation time in the converter at different gas flow rates and oxygen enrichments.
Functional Morphology of Secretion by the Large Wax Glands (Sensilla Sagittiformia) Involved in Tick Defense
Authors: Yoder Jay A. , Benoit Joshua B. , Bundy Megan R. , Hedges Brian Z. , Gribbins Kevin M.
Published: August 2009

Ticks are protected against ants by release of an allomonal defense secretion from the large wax glands (or type 2 glands) that line their bodies. To explore how the large wax glands operate, before and after microscopic observations of these glands (nonsecreted versus secreted test groups), mass determinations were made forRhipicephalus sanguineusthat had been exhausted of secretion by repeated leg pinching to simulate attack by a predator. Prior to secretion, the glandular organ is fully intact histologically and matches thesensillum sagittiforme, a key taxonomic structure described in the 1940s. The large wax gland is innervated and responds to pressure stimulation as a proprioceptor that stimulates the secretory response. Histological observations after secretion has occurred show that the entire glandular contents and associated cells are jettisoned out of the gland like a syringe. The glandular cellular components are subsequently rebuilt by underlying hypodermal cells within a few days so that secretion can take place again. Presumably, the active allomonal ingredients (hydrocarbons) are released when these derived epidermal cells reach and burst onto the cuticular surface. Our conclusion is that the large wax glands are holocrine and feature intermittent regeneration.
Enhanced Stochastic Methodology for Combined Architecture of E‐Commerce and Security Networks
Authors: Kim Song-Kyoo
Published: August 2009

This paper deals with network architecture which is a combination of electronic commerce and security systems in the typical Internet ecosystems. The e‐commerce
model that is typically known as online shopping can be considered as a multichannel
queueing system. In the other hand, stochastic security system is designed for improving
the reliability and availability of the e‐commerce system. The security system in this
paper deals with a complex system that consists of main unreliable servers, backups,
and repair facilities to repair the broken servers. The results are applied for analyzing the
current Internet ecosystem, and the mathematical methods can be also applied to the
various areas such as human resources, manufacturing processes, and military operations.
The solution presents the analytical solutions of the combined architecture of two
queueing systems, and these tractable results are used for demonstration in the
framework of optimization problems.
Spurious Regression
Authors: Ventosa-Santaulària D.
Published: August 2009

The spurious regression phenomenon in least squares occurs for a wide range
of data generating processes, such as driftless unit roots, unit roots with drift,
long memory, trend and broken‐trend stationarity. Indeed, spurious regressions
have played a fundamental role in the building of modern time series econometrics
and have revolutionized many of the procedures used in applied macroeconomics. Spin‐offs from this research range from unit‐root tests to cointegration and error‐correction models. This paper provides an overview of results about spurious
regression, pulled from disperse sources, and explains their implications.
Direct Solution of nth‐Order IVPs by Homotopy Analysis Method
Authors: Bataineh A. Sami , Noorani M. S. M. , Hashim I.
Published: August 2009

Direct solution of a class of nth‐order initial value problems (IVPs) is considered based on the homotopy analysis method (HAM). The HAM solutions contain an auxiliary parameter which provides a convenient way of controlling the convergence region of the series solutions. The HAM gives approximate analytical solutions which are of comparable accuracy to the seven‐ and eight‐order Runge‐Kutta method (RK78).
Synthesis, Characterization, Antibacterial and Anti‐Inflammatory Activities of Enoxacin Metal Complexes
Authors: Arayne Saeed , Sultana Najma , Haroon Urooj , Mesaik M. Ahmed
Published: August 2009

The present work comprises the synthesis of enoxacin (Heno) complexes with various transition metals. Two types of complexes and were obtained. The complexes were characterized by different physicochemical, spectroscopic, and elemental analysis. Results suggest that enoxacin interacts with the metals as a monoanionic bidentate ligand. These complexes were also tested for their antibacterial activity against eleven (11) different microorganisms, and the results were compared with the parent drug. Moreover all the metal complexes were also tested for their ability to scavenge reactive oxygen species where by MnII and CuII complexes exhibited potential to mediate anti‐inflammatory response.
Molecular Diagnostic Tests for Microsporidia
Authors: Ghosh Kaya , Weiss Louis M.
Published: August 2009

The Microsporidia are a ubiquitous group of eukaryotic obligate intracellular parasites which were recognized over 100 years ago with the description ofNosema bombycis, a parasite of silkworms. It is now appreciated that these organisms are related to the Fungi. Microsporidia infect all major animal groups most often as gastrointestinal pathogens; however they have been reported from every tissue and organ, and their spores are common in environmental sources such as ditch water. Several different genera of these organisms infect humans, but the majority of infections are due to eitherEnterocytozoon bieneusiorEncephalitozoonspecies. These pathogens can be difficult to diagnose, but significant progress has been made in the last decade in the development of molecular diagnostic reagents for these organisms. This report reviews the molecular diagnostic tests that have been described for the identification of the microsporidia that infect humans.
Fixed Points of Single- and Set-Valued Mappings in Uniformly Convex Metric Spaces with No Metric Convexity
Authors: Espínola Rafa , Fernández-León Aurora , Piątek Bożena
Published: August 2009

We study the existence of fixed points and convergence of iterates for asymptotic pointwise contractions in uniformly convex metric spaces. We also study the existence of fixed points for set-valued nonexpansive mappings in the same class of spaces. Our results do not assume convexity of the metric which makes a big difference when studying the existence of fixed points for set-valued mappings.
GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-Induced MAPKs p38 and JNK and Proapoptotic Protein Bax
Authors: Fister Stefanie , Günthert Andreas R. , Aicher Babette , Paulini Klaus W. , Emons Günter , Gründker Carsten
Published: August 2009

Recently, we could show that gonadotropin-releasing hormone (GnRH)-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells in vitro and in vivo. In the present study, we have ascertained receptor binding and effects of GnRH-II antagonists on mitogenic signal transduction and on activation of proapoptotic protein Bax. The GnRH-II antagonists tested showed EC50 values for GnRH-I receptor binding in the range of 1 to 2 nmol/L. The GnRH-II agonist [d-Lys6]GnRH-II showed an EC50 value for GnRH-I receptor binding of ∼1,000 nmol/L. Agonistic activity on GnRH-I receptor function with an EC50 of 13 nmol/L has been determined for [d-Lys6]GnRH-II. Antagonistic activities with EC50 values in the range of 1 nmol/L were determined for the GnRH-II antagonists. Treatment of human endometrial, ovarian, and breast cancer cells with GnRH-II antagonists resulted in time-dependent activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase. In addition, treatment with GnRH-II antagonists induced time-dependent activation of proapoptotic protein Bax. GnRH-II antagonists are not involved in activation of protein kinase B/Akt or extracellular signal-regulated kinase 1/2. The GnRH-II antagonists tested had similar binding affinities to the GnRH-I receptor comparable with that of GnRH-I antagonist Cetrorelix. Referring to the cyclic AMP response element reporter gene activation assay, the GnRH-II agonist [d-Lys6]GnRH-II has to be classified as an agonist at the GnRH-I receptor, whereas the GnRH-II antagonists tested are clear antagonists at the GnRH-I receptor. GnRH-II antagonists induce apoptotic cell death in human endometrial, ovarian, and breast cancer cells via activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase followed by activation of proapoptotic protein Bax. [Cancer Res 2009;69(16):6473–81]
Follicle-Stimulating Hormone Peptide Can Facilitate Paclitaxel Nanoparticles to Target Ovarian Carcinoma In vivo
Authors: Zhang Xiao-yan , Chen Jun , Zheng Yu-fang , Gao Xiao-ling , Kang Yu , Liu Jia-chi , Cheng Ming-jun , Sun Hong , Xu Cong-jian
Published: August 2009

Chemotherapy is an important treatment for ovarian cancer. However, conventional chemotherapy has inevitable drawbacks due to side effects from nonspecific biodistribution of the chemotherapeutic drugs. To solve such problem, targeted delivery approaches were developed. The targeted delivery approaches combine drug carriers with the targeting system and can preferentially bring drugs to the targeted sites. Follicle-stimulating hormone receptor (FSHR) is an ovarian cancer–specific receptor. By using a peptide derived from FSH (amino acids 33–53 of the FSH β chain, named as FSH33), we developed a conjugated nanoparticle, FSH33-NP, to target FSHR in ovarian cancer. FSH33-NP was tested for recognition specificity and uptake efficiency on FSHR-expressing cells. Then, the antitumor efficiency of paclitaxel (PTX)-loaded FSH33-NP (FSH33-NP-PTX) was determined. FSH33-NP-PTX displayed stronger antiproliferation and antitumor effects compared with free PTX or naked PTX-loaded nanoparticles (NP-PTX) both in vitro and in vivo. In summary, this novel FSH33-NP delivery system showed very high selectivity and efficacy for FSHR-expressing tumor tissues. Therefore, it has good potential to become a new therapeutic approach for patients with ovarian cancer. [Cancer Res 2009;69(16):6506–14]
Nucleophosmin Redistribution following Heat Shock: A Role in Heat-Induced Radiosensitization
Authors: Vanderwaal Robert P. , Maggi Leonard B. , Weber Jason D. , Hunt Clayton R. , Roti Roti Joseph L.
Published: August 2009

Cellular survival from radiation-induced DNA damage requires access to sites of damage for the assembly of repair complexes and the subsequent repair, particularly the repair of DNA double strand breaks (DSB). Hyperthermia causes changes in protein-protein/DNA interactions in the nucleus that block access to sites of DNA damage. Studies presented here indicate that the nucleolar protein, nucleophosmin (NPM), redistributes from the nucleolus following hyperthermia, increases its association with DNA, and blocks access to DNA DSBs. Reduction of NPM significantly reduces heat-induced radiosensitization, but reduced NPM level does not alter radiation sensitivity per se. NPM knockdown reduces heat-induced inhibition of DNA DSB repair. Also, these results suggest that NPM associates with nuclear matrix attachment region DNA in heat-shocked cells. [Cancer Res 2009;69(16):6454–62]
Targeting Janus Kinase 2 in Her2/neu-Expressing Mammary Cancer: Implications for Cancer Prevention and Therapy
Authors: Sakamoto Kazuhito , Lin Wan-chi , Triplett Aleata A. , Wagner Kay-Uwe
Published: August 2009

The Janus kinase 2 (Jak2) is essential for normal mammary gland development, but this tyrosine kinase and its main effector, signal transducer and activator of transcription 5, are also active in a significant subset of human breast cancers. We have recently reported that Jak2 controls the expression and nuclear accumulation of cyclin D1. Because this particular D-type cyclin has been suggested to be a key mediator for ErbB2-associated mammary tumorigenesis, we deleted Jak2 from ErbB2-expressing mammary epithelial cells prior to tumor onset and in neoplastic cells to address whether this tyrosine kinase plays a role in the initiation as well as progression of mammary cancer. Similar to cyclin D1–deficient mice, the functional ablation of Jak2 protects against the onset of mammary tumorigenesis. In contrast, the deletion of Jak2 from neoplastic cells or the acute, ligand-inducible down-regulation of this tyrosine kinase in an orthotopic transplant model did not affect the growth and survival of cancer cells. The constitutive activation of ErbB2 signaling, which is an initial event in the formation of mammary cancer, was able to override the functional role of Jak2 in regulating the expression of Akt1 and cyclin D1. This might be a compensatory mechanism that explains why Jak2 is a relevant target for preventing the initiation but not the progression of ErbB2-associated mammary cancer. [Cancer Res 2009;69(16):6642–50]
Systems Biology Reveals New Strategies for Personalizing Cancer Medicine and Confirms the Role of PTEN in Resistance to Trastuzumab
Authors: Faratian Dana , Goltsov Alexey , Lebedeva Galina , Sorokin Anatoly , Moodie Stuart , Mullen Peter , Kay Charlene , Um In Hwa , Langdon Simon , Goryanin Igor , Harrison David J.
Published: August 2009

Resistance to targeted cancer therapies such as trastuzumab is a frequent clinical problem not solely because of insufficient expression of HER2 receptor but also because of the overriding activation states of cell signaling pathways. Systems biology approaches lend themselves to rapid in silico testing of factors, which may confer resistance to targeted therapies. Inthis study, we aimed to develop a new kinetic model that could be interrogated to predict resistance to receptor tyrosine kinase (RTK) inhibitor therapies and directly test predictions in vitro and in clinical samples. The new mathematical model included RTK inhibitor antibody binding, HER2/HER3 dimerization and inhibition, AKT/mitogen-activated protein kinase cross-talk, and the regulatory properties of PTEN. The model was parameterized using quantitative phosphoprotein expression data from cancer cell lines using reverse-phase protein microarrays. Quantitative PTEN protein expression was found to be the key determinant of resistance to anti-HER2 therapy in silico, which was predictive of unseen experiments in vitro using the PTEN inhibitor bp(V). When measured in cancer cell lines, PTEN expression predicts sensitivity to anti-HER2 therapy; furthermore, this quantitative measurement is more predictive of response (relative risk, 3.0; 95% confidence interval, 1.6–5.5; P < 0.0001) than other pathway components taken in isolation and when tested by multivariate analysis in a cohort of 122 breast cancers treated with trastuzumab. For the first time, a systems biology approach has successfully been used to stratify patients for personalized therapy in cancer and is further compelling evidence that PTEN, appropriately measured in the clinical setting, refines clinical decision making in patients treated with anti-HER2 therapies. [Cancer Res 2009;69(16):6713–20]
The Peptidyl-Prolyl Isomerase Pin1 Regulates Cytokinesis through Cep55
Authors: van der Horst Armando , Khanna Kum Kum
Published: August 2009

Failure of cytokinesis results in tetraploidy and can increase the genomic instability frequently observed in cancer. The peptidyl-prolyl isomerase Pin1, which is deregulated in many tumors, regulates several processes, including cell cycle progression. Here, we show a novel role for Pin1 in cytokinesis. Pin1 knockout mouse embryonic fibroblasts show a cytokinesis delay, and depletion of Pin1 from HeLa cells also causes a cytokinesis defect. Furthermore, we provide evidence that Pin1 localizes to the midbody ring and regulates the final stages of cytokinesis by binding to centrosome protein 55 kDa (Cep55), an essential component of this ring. This interaction induces Polo-like kinase 1–mediated phosphorylation of Cep55, which is critical for the function of Cep55 during cytokinesis. Importantly, Pin1 knockdown does not enhance the cytokinesis defect in Cep55-depleted cells, indicating that Pin1 and Cep55 act in the same pathway. These data are the first evidence that Pin1 regulates cytokinesis and may provide a mechanistic explanation as to how pathologic levels of Pin1 can stimulate tumorigenesis. [Cancer Res 2009;69(16):6651–9]
Stress-Activated Mitogen-Activated Protein Kinases c-Jun NH2-Terminal Kinase and p38 Target Cdc25B for Degradation
Authors: Uchida Sanae , Yoshioka Katsuji , Kizu Ryoichi , Nakagama Hitoshi , Matsunaga Tsukasa , Ishizaka Yukihito , Poon Randy Y.C. , Yamashita Katsumi
Published: August 2009

Cdc25 dual specificity phosphatases positively regulate the cell cycle by activating cyclin-dependent kinase/cyclin complexes. Of the three mammalian Cdc25 isoforms, Cdc25A is phosphorylated by genotoxic stress–activated Chk1 or Chk2, which triggers its SCFβ-TrCP–mediated degradation. However, the roles of Cdc25B and Cdc25C in cell stress checkpoints remain inconclusive. We herein report that c-Jun NH2-terminal kinase (JNK) induces the degradation of Cdc25B. Nongenotoxic stress induced by anisomycin caused rapid degradation of Cdc25B as well as Cdc25A. Cdc25B degradation was dependent mainly on JNK and partially on p38 mitogen-activated protein kinase (p38). Accordingly, cotransfection with JNK1, JNK2, or p38 destabilized Cdc25B. In vitro kinase assays and site-directed mutagenesis experiments revealed that the critical JNK and p38 phosphorylation site in Cdc25B was Ser101. Cdc25B with Ser101 mutated to alanine was refractory to anisomycin-induced degradation, and cells expressing such mutant Cdc25B proteins were able to override the anisomycin-induced G2 arrest. These results highlight the importance of a novel JNK/p38-Cdc25B axis for a nongenotoxic stress–induced cell cycle checkpoint. [Cancer Res 2009;69(16):6438–44]
Cyclin D1 Degradation Is Sufficient to Induce G1 Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in Ovarian Cancer Cells
Authors: Masamha Chioniso Patience , Benbrook Doris Mangiaracina
Published: August 2009

D- and E-type cyclins mediate G1-S phase cell cycle progression through activation of specific cyclin-dependent kinases (cdk) that phosphorylate the retinoblastoma protein (pRb), thereby alleviating repression of E2F-DP transactivation of S-phase genes. Cyclin D1 is often overexpressed in a variety of cancers and is associated with tumorigenesis and metastasis. Loss of cyclin D can cause G1 arrest in some cells, but in other cellular contexts, the downstream cyclin E protein can substitute for cyclin D and facilitate G1-S progression. The objective of this study was to determine if a flexible heteroarotinoid anticancer compound, SHetA2, regulates cell cycle proteins and cell cycle progression in ovarian cancer cells. SHetA2 induced cyclin D1 phosphorylation, ubiquitination, and proteasomal degradation, causing G1 arrest in ovarian cancer cells despite continued cyclin E2 expression and independently of p53 and glycogen synthase kinase-3β. Cyclin D1 loss inhibited pRb S780 phosphorylation by cyclin D1-cdk4/6 and released p21 from cyclin D1-cdk4/6-p21 protein complexes to form cyclin E2-cdk2-p21 complexes, which repressed phosphorylation of pRb S612 by cyclin E2-cdk2 and ultimately E2F-DP transcriptional activity. G1 arrest was prevented by overexpression or preventing degradation of cyclin D1 but not by restoration of pRb S612 phosphorylation through p21 knockdown. In conclusion, we show that loss of cyclin D1 in ovarian cancer cells treated with SHetA2 is sufficient to induce G1 cell cycle arrest and this strategy is not impeded by the presence of cyclin E2. Therefore, cyclin D1 is a sufficient therapeutic target in ovarian cancer cells. [Cancer Res 2009;69(16):6565–72]
Sorafenib Inhibits Non–Small Cell Lung Cancer Cell Growth by Targeting B-RAF in KRAS Wild-Type Cells and C-RAF in KRAS Mutant Cells
Authors: Takezawa Ken , Okamoto Isamu , Yonesaka Kimio , Hatashita Erina , Yamada Yuki , Fukuoka Masahiro , Nakagawa Kazuhiko
Published: August 2009

Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK) signaling pathway but which also have distinct downstream targets. The relative effects of sorafenib on B-RAF and C-RAF signaling in tumor cells remain unclear, however. We have now examined the effects of sorafenib as well as of B-RAF or C-RAF depletion by RNA interference on cell growth and ERK signaling in non–small cell lung cancer (NSCLC) cell lines with or without KRAS mutations. Sorafenib inhibited ERK phosphorylation in cells with wild-type KRAS but not in those with mutant KRAS. Despite this difference, sorafenib inhibited cell growth and induced G1 arrest in both cell types. Depletion of B-RAF, but not that of C-RAF, inhibited ERK phosphorylation as well as suppressed cell growth and induced G1 arrest in cells with wild-type KRAS. In contrast, depletion of C-RAF inhibited cell growth and induced G1 arrest, without affecting ERK phosphorylation, in cells with mutant KRAS; depletion of B-RAF did not induce G1 arrest in these cells. These data suggest that B-RAF-ERK signaling and C-RAF signaling play the dominant roles in regulation of cell growth in NSCLC cells with wild-type or mutant KRAS, respectively. The G1 arrest induced by either C-RAF depletion or sorafenib in cells with mutant KRAS was associated with down-regulation of cyclin E. Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS. [Cancer Res 2009;69(16):6515–21]
Epigenetic Repression of DNA Mismatch Repair by Inflammation and Hypoxia in Inflammatory Bowel Disease–Associated Colorectal Cancer
Authors: Edwards Robert A. , Witherspoon Mavee , Wang Kehui , Afrasiabi Kambiz , Pham Trang , Birnbaumer Lutz , Lipkin Steven M.
Published: August 2009

Sporadic human mismatch repair (MMR)–deficient colorectal cancers account for ∼12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein α subunit Giα2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Giα2−/− colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Giα2−/− cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Giα2−/− colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Giα2−/− crypts. Treating Giα2−/− mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase–dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer. [Cancer Res 2009;69(16):6423–9]
A Prospective Study of Dietary Polyunsaturated Fatty Acids and Colorectal Cancer Risk in Chinese Women
Authors: Murff Harvey J. , Shu Xiao-Ou , Li Honglan , Dai Qi , Kallianpur Asha , Yang Gong , Cai Hui , Wen Wanqing , Gao Yu-Tang , Zheng Wei
Published: August 2009

In animal models of colon cancer, n-3 polyunsaturated fatty acids (PUFA) have antineoplastic properties, whereas n-6 PUFAs may promote carcinogenesis. Prior epidemiologic studies have been inconsistent regarding the association of PUFAs and colorectal cancer. We prospectively evaluated the association between PUFA intake and colorectal cancer in a cohort of 73,242 Chinese women who were interviewed in person at the baseline survey for the Shanghai Women's Health Study. Dietary fatty acid consumption was derived using data collected from two food frequency questionnaires administered at baseline and 2 to 3 years later. The dietary total n-6 to n-3 PUFA ratio was strongly associated with colorectal cancer risk. Compared with women in the lowest quintile group, elevated relative risks (RR) were observed for the second [RR, 1.52; 95% confidence intervals (CI), 1.00-2.32], third (RR, 2.20; 95% CI, 1.41-3.45), fourth (RR, 1.65; 95% CI, 0.99-2.75), and fifth (RR, 1.95; 95% CI, 1.07-3.54) quintile groups. Arachidonic acid was associated with colorectal cancer risk with elevated RRs of 1.20Q2-Q1 (95% CI, 0.87-1.64), 1.44Q3-Q1 (95% CI, 1.05-1.98), 1.61Q4-Q1 (95% CI, 1.17-2.23), and 1.39Q5-Q1 (95% CI, 0.97-1.99; Ptrend = 0.03) with increasing dietary quintile. In a subset of 150 cancer cases and 150 controls, we found a statistically significant trend between an increasing n-6 to n-3 PUFA ratio and increasing production of prostaglandin E2 (PGE2) as measured by urinary PGE2 metabolites (P = 0.03). These results suggest that dietary PUFA and the ratio of n-6 to n-3 PUFA intake may be positively associated with colorectal cancer risk, and this association may be mediated in part through PGE2 production. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2283–91)
Socioeconomic and Racial Patterns of Colorectal Cancer Screening among Medicare Enrollees in 2000 to 2005
Authors: Doubeni Chyke A. , Laiyemo Adeyinka O. , Reed George , Field Terry S. , Fletcher Robert H.
Published: August 2009

Background: Lower rates of screening among minorities and low-income populations contribute to colorectal cancer health disparities. Therefore, we examined patterns of colorectal cancer screening and associations with race-ethnicity, education, and income over time.

Methods: Repeated cross-sectional data from the Medicare Current Beneficiary Survey of noninstitutionalized colorectal cancer–free Medicare enrollees ages 65 to 80 years interviewed in 2000 (n = 8,355), 2003 (n = 7,922), and 2005 (n = 7,646). We examined rates of colonoscopy/sigmoidoscopy use within 5 years (recent endoscopy), colonoscopy/sigmoidoscopy use >5 years previously, or fecal occult blood test (FOBT) within 2 years.

Results: Among those included in the analyses, there was a steady increase in recent endoscopy rates and decrease in FOBT use over the 6-year period among all racial, educational, and income groups. During each of the survey years, those less educated or in lower-income groups were less likely to undergo colorectal cancer screening in a dose-response fashion. In multinomial regression analyses that adjusted for factors including health insurance, there were no significant differences in recent endoscopy or FOBT rates between Blacks or Hispanics and Whites, but differences by education and income remained. Compared with those in higher-income group, lower-income enrollees had lower rates of screening, and differences by income were larger for enrollees residing in metropolitan areas.

Conclusion: Among Medicare beneficiaries, there are persistent colorectal cancer screening disparities due to a complex combination of socioeconomic disadvantages from lower education and income, place of residence, and inadequate insurance. However, insurance alone does not eliminate socioeconomic differences in colorectal cancer screening. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2170–5)
Uptake of Risk-Reducing Surgery in Unaffected Women at High Risk of Breast and Ovarian Cancer Is Risk, Age, and Time Dependent
Authors: Evans D. Gareth R. , Lalloo Fiona , Ashcroft Linda , Shenton Andrew , Clancy Tara , Baildam Andrew D. , Brain Anne , Hopwood Penelope , Howell Anthony
Published: August 2009

Purpose: The uptake of risk-reducing surgery in women at increased risk of breast and ovarian cancer is highly variable between countries and centers within countries. We have investigated the rate, timing, and age of uptake of surgery in the northwest of England to report the results after up to 7 years in a Regional Genetics center.

Methods: Uptake was documented in 211 known unaffected BRCA1/2 mutation carriers from 509 families and in 3,515 women at >25% lifetime risk of breast cancer without known mutations.

Results: Of the 211 mutation carriers, 40% opted for bilateral risk-reducing mastectomy (BRRM) and 45% underwent bilateral risk-reducing salpingo-oophorectomy (BRRSPO). Uptake of BRRM was significantly related to lifetime risk and age but continued over several years. In women not known to carry a BRCA mutation, 6.4% of women at 40% to 45% lifetime risk, 2.5% of women at 33% to 39% lifetime risk, and 1.8% of women at 25% to 32% lifetime risk underwent BRRM (P < 0.005). BRRSPO uptake was greater in BRCA1 (52%) than BRCA2 (28%) carriers but in both groups tended to occur within the first 2 years after gene test (except in the youngest age group) and in women between the ages of 35 and 45.

Conclusion: To truly assess the uptake of risk-reducing surgery, longer-term follow-up is necessary particularly in younger women who are likely to delay BRRSPO. Careful risk counseling does seem to influence women's decisions for surgery, although the effect is not immediate. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2318–24)
Genetic Variation in Immune Regulation and DNA Repair Pathways and Stomach Cancer in China
Authors: Hussain Shehnaz K. , Mu Li-Na , Cai Lin , Chang Shen-Chih , Park Sungshim Lani , Oh Sam S. , Wang Yiren , Goldstein Binh Y. , Ding Bao-Guo , Jiang Qingwu , Rao Jianyu , You Nai-Chieh Y. , Yu Shun-Zhang , Papp Jeanette C. , Zhao Jin-Kou , Wang Hua , Zhang Zuo-Feng
Published: August 2009

The incidence of stomach cancer is high in certain parts of the world, particularly in China. Chronic Helicobacter pylori infection is the main risk factor, yet the vast majority of infected individuals remain unaffected with cancer, suggesting an important role of other risk factors. We conducted a population-based case-control study including 196 incident stomach cancer cases and 397 matched controls to test the hypothesis that adverse single nucleotide polymorphism (SNP) genotypes and haplotypes within genes of the DNA repair and immune regulatory pathways are associated with increased stomach cancer risk. Genomic DNA isolated from blood samples was used for genotyping, and results were obtained for 57 putatively functional SNPs in 28 genes. Odds ratios (OR) and 95% confidence intervals (95% CI) were obtained from adjusted logistic regression models. For PTGS2, a gene involved in the inflammatory response, associations with stomach cancer risk were observed for TC genotype carriers of rs5279 (OR, 0.24; 95% CI, 0.08-0.73), CT genotype carriers of the 3′-untranslated region SNP rs689470 (OR, 7.49; 95% CI, 1.21-46.20), and CTTC haplotype carriers of rs5277, rs5278, rs5279, and rs689470 (OR, 0.41; 95% CI, 0.18-0.95). For ERCC5, a gene involved in nucleotide excision repair, TC genotype carriers of rs1047768 (OR, 0.65; 95% CI, 0.41-1.03), GC genotype carriers of the nonsynonymous SNP rs2227869 (OR, 0.30; 95% CI, 0.13-0.67), and CCG haplotype carriers of rs1047768, rs17655, and rs2227869 (OR, 0.45; 95% CI, 0.20-1.04) were associated with reduced stomach cancer risk. In conclusion, PTGS2 and ERCC5 were associated with stomach cancer risk in a Chinese population. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2304–9)
Qualitative Age Interactions between Low-grade and High-grade Serous Ovarian Carcinomas
Authors: Grimley Philip M. , Matsuno Rayna K. , Rosenberg Philip S. , Henson Donald E. , Schwartz Arnold M. , Anderson William F.
Published: August 2009

Purpose: Ovarian epithelial carcinomas, including the predominant serous ovarian carcinoma (SOC) type, are heterogeneous malignancies. Even though invasive SOCs of low and high grade can be distinguished by morphology and molecular or immunohistochemical profiles, age-specific risks relevant to their separate carcinogenic pathways and clinical features have not been fully explored.

Methods: In search of further clues to the etiology/pathogenesis of low-grade and high-grade SOCs, we analyzed incidence rate patterns. Case and age-adjusted population data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for years 1990 through 2005. Descriptive epidemiology for n = 19,899 cases was supplemented with age-period-cohort models fitted by grade.

Results: SOC age-adjusted incidence rate ratios (IRR) of high to low grade (IRRH/L) were <1.0 before age 40, and >1.0 thereafter. Accordingly, SOC age-specific incidence rates were also greater for low grade before age 40 years, and then greater for high grade. The reversals of IRRH/L, with crossings of the age-specific incidence rate near age 40 years occurred irrespective of early or late SOC stage. These results were reproducible and reliable in age-period-cohort models that were adjusted for period and cohort effects (P ≈ 0 for age interactions by grade).

Conclusions: Robust qualitative age interactions between low-grade and high-grade SOC showed that grade is an age-specific effect modifier in these malignancies. With increasing research interest in identifying the genomic determinants of SOC risk, therapeutic response, and outcome, future analytic studies and clinical trials should be powered to account for age-dependent grade interactions. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2256–61)
Uncovering Disparities in Survival after Non–Small–Cell Lung Cancer among Asian/Pacific Islander Ethnic Populations in California
Authors: Chang Ellen T. , Shema Sarah J. , Wakelee Heather A. , Clarke Christina A. , Gomez Scarlett Lin
Published: August 2009

Asians may have better survival after non–small-cell lung cancer (NSCLC) than non-Asians. However, it is unknown whether survival varies among the heterogeneous U.S. Asian/Pacific Islander (API) populations. Therefore, this study aimed to quantify survival differences among APIs with NSCLC. Differences in overall and disease-specific survival were analyzed in the California Cancer Registry among 16,577 API patients diagnosed with incident NSCLC between 1988 and 2007. Adjusted hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression models with separate baseline hazards by disease stage. Despite better overall and disease-specificsurvival among APIs compared with non-HispanicWhites, differences were evident across API populations. Among women, Japanese (overall survival HR, 1.16; 95% CI, 1.06-1.27) and APIs other than those in the six largest ethnic groups (other APIs; HR, 1.19; 95% CI, 1.07-1.33) had significantly poorer overall and disease-specific survival than Chinese. By contrast, South Asian women had significantly better survival than Chinese (HR, 0.79; 95% CI, 0.63-0.97). Among men, Japanese (HR, 1.15; 95% CI, 1.07-1.24), Vietnamese (HR, 1.07; 95% CI, 1.00-1.16), and other APIs (HR, 1.18; 95% CI, 1.08-1.28) had significantly poorer overall and disease-specific survival than Chinese. Other factors independently associated with poorer survival were lower neighborhood socioeconomic status, involvement with a nonuniversity hospital, unmarried status, older age, and earlier year of diagnosis. APIs have significant ethnic differences in NSCLC survival that may be related to disparate lifestyles, biology, and especially health care access or use. To reduce the nationwide burden of lung cancer mortality, it is critical to identify and ameliorate hidden survival disparities such as those among APIs. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2248–55)
Alcohol Consumption not Associated with Lung Cancer Mortality in Lifelong Nonsmokers
Authors: Thun Michael J. , Hannan Lindsay M. , DeLancey John Oliver L.
Published: August 2009

Although alcohol consumption is associated with increased lung cancer risk in some studies, this relationship is difficult to interpret because of potential confounding by smoking. We measured lung cancer death rates in relation to self-reported alcohol consumption among 223,216 adults who reported no history of regular smoking when enrolled in a large prospective mortality study begun by the American Cancer Society in 1982. Participants were at least 30 years of age when enrolled and, consequently, were considered unlikely to initiate smoking during follow-up. During 24 years of follow-up, we identified 1,058 deaths from lung cancer. Cox proportional hazards analyses were conducted, adjusting for age, education, occupation, and race. No association between lung cancer mortality and any level of alcohol consumption was seen in men or women. Even among those who consumed four or more alcoholic drinks per day, the risk did not differ from those who abstained from alcohol [hazard ratios 0.97 (95% confidence interval, 0.76-1.22) and 0.69 (0.41-1.16) for men and women, respectively]. Due to the large population of lifelong nonsmokers in our cohort and the long period of follow-up, these findings provide substantial evidence against the hypothesis that alcohol consumption independently increases lung cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2269–72)
Desmoglein-2 and Desmocollin-2 Mutations in Dutch Arrhythmogenic Right Ventricular Dysplasia/Cardiomypathy Patients
Authors: Bhuiyan Zahurul A. , Jongbloed Jan D.H. , van der Smagt Jasper , Lombardi Paola M. , Wiesfeld Ans C.P. , Nelen Marcel , Schouten Meyke , Jongbloed Roselie , Cox Moniek G.P.J. , van Wolferen Marleen , Rodriguez Luz M. , van Gelder Isabelle C. , Bikker Hennie , Suurmeijer Albert J.H. , van den Berg Maarten P. , Mannens Marcel M.A.M. , Hauer Richard N.W. , Wilde Arthur A.M. , van Tintelen J. Peter
Published: August 2009

Background—

This study aimed to evaluate the prevalence and type of mutations in the major desmosomal genes, Plakophilin-2 (
PKP2
), Desmoglein-2 (
DSG2
), and Desmocollin-2 (
DSC2
), in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We also aimed to distinguish relevant clinical and ECG parameters.

Methods and Results—

Clinical evaluation was performed according to the Task Force Criteria (TFC). We analyzed the genes in (a) 57 patients who fulfilled the ARVD/C TFC (TFC+), (b) 28 patients with probable ARVD/C (1 major and 1 minor, or 3 minor criteria), and (c) 31 patients with 2 minor or 1 major criteria. In the TFC+ ARVD/C group, 23 patients (40%) had
PKP2
mutations, 4 (7%) had
DSG2
mutations, and 1 patient (2%) carried a mutation in
DSC2
, whereas 1 patient (2%) had a mutation in both
DSG2
and
DSC2
. Among the
DSG2
and
DSC2
mutation-positive TFC+ ARVD/C probands, 2 carried compound heterozygous mutations and 1 had digenic mutations. In probable ARVD/C patients and those with 2 minor or 1 major criteria for ARVD/C, mutations were less frequent and they were all heterozygous. Negative T waves in the precordial leads were observed more (
P
<0.002) among mutation carriers than noncarriers and in particular in
PKP2
mutation carriers.

Conclusions—

Mutations in
DSG2
and
DSC2
are together less prevalent (10%) than
PKP2
mutations (40%) in Dutch TFC+ ARVD/C patients. Interestingly, biallelic or digenic
DSC2
and/or
DSG2
mutations are frequently identified in TFC+ ARVD/C patients, suggesting that a single mutation is less likely to cause a full-blown ARVD/C phenotype. Negative T waves on ECG were prevalent among mutation carriers (
P
<0.002).
Calcium/Calmodulin-Dependent Protein Kinase II Contributes to Cardiac Arrhythmogenesis in Heart Failure
Authors: Sag Can M. , Wadsack Daniel P. , Khabbazzadeh Sepideh , Abesser Marco , Grefe Clemens , Neumann Kay , Opiela Marie-Kristin , Backs Johannes , Olson Eric N. , Brown Joan Heller , Neef Stefan , Maier Sebastian K.G. , Maier Lars S.
Published: August 2009

Background—Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)δCmice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo.

Methods and Results—Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10−8M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca]irose clearly on ISO in TG but not in wild-type cells (+20�5% versus +3�4% at 10−6M ISO,P<0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9�0.5 versus 2.0�0.4 sparks per 100 μm−1�s−1,P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKIIδ-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%,P<0.05) and late (86% versus 43%,P<0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P<0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P<0.05).

Conclusions—We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIδCmice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.