bluuebunny/crossref_metadata_2025 huggingface dataset:
Competition between recolonizing wolves and resident lynx in Sweden
Authors: Wikenros Camilla , Liberg Olof , Sand Håkan , Andrén Henrik
Published: March 2010

We studied the effect of a recolonizing wolf ( Canis lupus L., 1758) population on a resident lynx ( Lynx lynx (L., 1758)) population in south-central Sweden. Wolf and lynx share the same prey species, western roe deer ( Capreolus capreolus (L., 1758)), and the size difference between the two species suggests a strong potential for interference competition. The spatial distributions of lynx family groups (n = 378) over four winters were not significantly affected by the increase in size and range of the wolf population. Survival of lynx kittens until 9 months of age did not differ significantly inside (54%; n = 37) and outside (62%; n = 42) wolf territories, and female lynx (n = 3) selected natal den sites (n = 19) in the same local area before and after wolf establishment. Furthermore, lynx home-range size (n = 42) did not increase as a result of presence of wolves and space use by female lynx (n = 3) was not affected by wolf establishment. We found no evidence of cleptoparasitism by wolves on roe deer killed by lynx. We conclude that the intensity of interference and exploitation competition between wolves and lynx was low.
SPATIAL GROWTH OF FUNDAMENTAL SOLUTIONS FOR CERTAIN PERTURBATIONS OF THE HARMONIC OSCILLATOR
Authors: JENSEN ARNE , YAJIMA KENJI
Published: March 2010

We consider the fundamental solution for the Cauchy problem for perturbations of the harmonic oscillator by time dependent potentials which grow at spatial infinity slower than quadratic but faster than linear functions and whose Hessian matrices have a fixed sign. We prove that the fundamental solution at resonant times grows indefinitely at spatial infinity with an algebraic growth rate, which increases indefinitely when the growth rate of perturbations at infinity decreases from the near quadratic to the near linear ones.
Progress Toward the Healthy People 2010 Goals and Objectives
Authors: Sondik Edward J. , Huang David T. , Klein Richard J. , Satcher David
Published: March 2010

Healthy People 2010 is a comprehensive framework for improving the health of Americans, built on the foundation of several decades of predecessor initiatives. Its two overarching goals, to “[i]ncrease the quality and years of healthy life” and “[e]liminate health disparities,” subsume 28 focus areas and comprise 955 objectives and subobjectives. This review evaluates progress toward meeting the Healthy People 2010 program's challenging agenda in the context of leading health indicator (LHI) measures, developed by the Department of Health and Human Services (DHHS), augmented by additional objectives for a total of 31 measures. Our evaluation of progress includes analysis of changes in objective values, including progress toward Healthy People 2010 targets, where appropriate, and analysis of changes in disparities. The Healthy People 2010 LHI measures suggest that although some progress has been made, there is much work to be done toward the Healthy People 2010 targets and both overarching goals.
A Review of Unintentional Injuries in Adolescents
Authors: Sleet David A. , Ballesteros Michael F. , Borse Nagesh N.
Published: March 2010

Unintentional injuries are the largest source of premature morbidity and mortality and the leading cause of death among adolescents 10–19 years of age. Fatal injury rates of males are twice those of females, and racial disparities in injury are pronounced. Transportation is the largest source of these injuries, principally as drivers and passengers, but also as cyclists and pedestrians. Other major causes involve drowning, poisonings, fires, sports and recreation, and work-related injuries. Implementing known and effective prevention strategies such as using seat belts and bicycle and motorcycle helmets, installing residential smoke alarms, reducing misuse of alcohol, strengthening graduated driver licensing laws, promoting policy change, using safety equipment in sports and leisure, and protecting adolescents at work will all contribute to reducing injuries. The frequency, severity, potential for death and disability, and costs of these injuries, together with the high success potential of prevention strategies, make injury prevention a key public health goal to improve adolescent health in the future.
Post-Approval Drug Safety Surveillance
Authors: Gibbons Robert D. , Amatya Anup K. , Brown C. Hendricks , Hur Kwan , Marcus Sue M. , Bhaumik Dulal K. , Mann J. John
Published: March 2010

Following the drug-approval process, concerns remain regarding the safety of new drugs that are introduced into the marketplace. In the case of rare adverse events, the number of subjects that are treated in randomized controlled trials is invariably inadequate to determine the safety of the new pharmaceutical. Identifying safety signals for new and/or existing drugs is a major priority in the protection of public health. Unfortunately, design, analysis, and available data are often quite limited for detecting in a timely fashion any potentially harmful effects of drugs. In this review, we examine a variety of approaches for determining the possibility of adverse drug reactions. Our review includes spontaneous reports, meta-analysis of randomized controlled clinical trials, ecological studies, and analysis of medical claims data. We consider both experimental design and analytic problems as well as potential solutions. Many of these methodologies are then illustrated through application to data on the possible relationship between taking antidepressants and increased risk of suicidality.
Genome-Wide Association Studies and Beyond
Authors: Witte John S.
Published: March 2010

Genome-wide association studies (GWAS) provide an important avenue for undertaking an agnostic evaluation of the association between common genetic variants and risk of disease. Recent advances in our understanding of human genetic variation and the technology to measure such variation have made GWAS feasible. Over the past few years a multitude of GWAS have identified and replicated many associated variants. These findings are enriching our knowledge about the genetic basis of disease and leading some to advocate using GWA study results for genetic testing. For many of the GWA study results, however, the underlying mechanisms remain unclear and the findings explain only a limited amount of heritability. These issues may be clarified by more detailed investigations, including analyses of less common variants, sequence-level data, and environmental exposures. Such studies should help clarify the potential value of genetic testing to the public's health.
Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans
Authors: Dray Cédric , Debard Cyrille , Jager Jennifer , Disse Emmanuel , Daviaud Danièle , Martin Pascal , Attané Camille , Wanecq Estelle , Guigné Charlotte , Bost Frédéric , Tanti Jean-François , Laville Martine , Vidal Hubert , Valet Philippe , Castan-Laurell Isabelle
Published: March 2010

Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of apelin and APJ (apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/ db mice. In skeletal muscle, apelin expression was similar in control and HF-fed mice and decreased in db/ db mice. APJ expression was decreased in both HF-fed and db/ db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal apelin and APJ expression in AT and muscle between control and diabetic patients. However, apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.
Insulin and insulin-like growth factor I signaling pathways in rainbow trout (Oncorhynchus mykiss) during adipogenesis and their implication in glucose uptake
Authors: Bouraoui L. , Capilla E. , Gutiérrez J. , Navarro I.
Published: March 2010

Primary cultures of rainbow trout ( Oncorhynchus mykiss ) adipocytes were used to examine the main signaling pathways of insulin and insulin-like growth factor I (IGF-I) during adipogenesis. We first determined the presence of IGF-I receptors (IGF-IR) and insulin receptors (IR) in trout preadipocytes ( day 5) and adipocytes ( day 14). IGF-IRs were more abundant and appeared to be in higher levels in differentiated cells than in preadipocytes, whereas IRs were detected in lower but constant levels throughout the culture. The cells were immunoreactive against ERK1/2 MAPK, and AKT/PI3K, components of the two main signal transduction pathways for insulin and IGF-I receptors. Stimulation of MAPK phosphorylation by IGF-I was higher in preadipocytes than in adipocytes, while no effects were observed in MAPK phosphorylation after incubation of cells with insulin. AKT phosphorylation increased in the presence of both insulin and IGF-I, with higher levels of stimulation in adipocytes than in preadipocytes. Activation of both pathways was blocked by the use of specific inhibitors of MAPK (PD98059) and AKT (wortmannin). We describe here, for the first time, the effects of IGF-I and insulin on 2-deoxyglucose uptake in primary culture of trout adipocytes. IGF-I was more potent in stimulating glucose uptake than insulin, and PD98059 and wortmannin inhibited the stimulation of glucose uptake by this growth factor, suggesting that IGF-I plays an important metabolic role in trout adipocytes. Our results suggest that differential activation of the MAPK and AKT pathways are involved in the IGF-I- and insulin-induced effects of trout adipocytes during the various stages of adipogenesis.
Enhanced progenitor cell recruitment and endothelial repair after selective endothelial injury of the mouse kidney
Authors: Hohenstein Bernd , Kuo Mei-Chuan , Addabbo Francesco , Yasuda Kaoru , Ratliff Brian , Schwarzenberger Claudia , Eckardt Kai-Uwe , Hugo Christian P. M. , Goligorsky Michael S.
Published: March 2010

Primary and/or secondary injury of the renal microvascular endothelium is a common finding in various renal diseases. Besides well-known endothelial repair mechanisms, including endothelial cell (EC) proliferation and migration, homing of extrinsic cells such as endothelial progenitor cells (EPC) and hematopoietic stem cells (HSC) has been shown in various organs and may contribute to microvascular repair. However, these mechanisms have so far not been studied after selective microvascular injury in the kidney. The present study investigated the time course of EPC and HSC stimulation and homing following induction of selective EC injury in the mouse kidney along with various angiogenic factors potentially involved in EC repair and progenitor cell stimulation. Erythropoietin was used to stimulate progenitor cells in a therapeutic approach. We found that selective EC injury leads to a marked stimulation of EPCs, HSCs, and various angiogenic factors to orchestrate microvascular repair. Angiogenic factors started to increase as early as 30 min after disease induction. Progenitor cells could be first detected in the circulation and the spleen before they selectively homed to the diseased kidney. Injection of a high dose of erythropoietin 2 h after disease induction markedly attenuated vascular injury through nonhemodynamic mechanisms, possibly involving vascular endothelial growth factor release.
Increased Intrinsic Excitability of Lateral Wing Serotonin Neurons of the Dorsal Raphe: A Mechanism for Selective Activation in Stress Circuits
Authors: Crawford LaTasha K. , Craige Caryne P. , Beck Sheryl G.
Published: March 2010

The primary center of serotonin (5-HT) projections to the forebrain is the dorsal raphe nucleus (DR), a region known for its role in the limbic stress response. The ventromedial subregion of the DR (vmDR) has the highest density of 5-HT neurons and is the major target in experiments that involve the DR. However, studies have demonstrated that a variety of stressors induce activation of neurons that is highest in the lateral wing subregion (lwDR) and includes activation of lwDR 5-HT neurons. Despite the functional role that the lwDR is known to play in stress circuits, little is known about lwDR 5-HT neuron physiology. Whole cell patch clamp electrophysiology in mice revealed that lwDR 5-HT cells have active and passive intrinsic membrane properties that make them more excitable than vmDR 5-HT neurons. In addition, lwDR 5-HT neurons demonstrated faster in vitro firing rates. Finally, within the vmDR there was a positive correlation between rostral position and increased excitability, among several other membrane parameters. These results are consistent with stressor induced patterns of activation of 5-HT neurons that includes, in addition to lwDR neurons, a small subset of rostral vmDR neurons. Thus increased intrinsic excitability likely forms a major part of the mechanism underlying the propensity to be activated by a stressor. The membrane properties identified in lwDR recordings may thereby contribute to a unique role of lwDR 5-HT neurons in adaptive responses to stress and in the pathobiology of stress-related mood disorders.
Structural and Electrochemical Characterization of PureLiFePO4and Nanocomposite C-LiFePO4Cathodes for Lithium Ion Rechargeable Batteries
Authors: Kumar Arun , Thomas R. , Karan N. K. , Saavedra-Arias J. J. , Singh M. K. , Majumder S. B. , Tomar M. S. , Katiyar R. S.
Published: March 2010

Pure lithium iron phosphate (LiFePO4) and carbon-coatedLiFePO4(C-LiFePO4) cathode materials were synthesized for Li-ion batteries. Structural and electrochemical properties of these materials were compared. X-ray diffraction revealed orthorhombic olivine structure. Micro-Raman scattering analysis indicates amorphous carbon, and TEM micrographs show carbon coating onLiFePO4particles. Ex situ Raman spectrum of C-LiFePO4at various stages of charging and discharging showed reversibility upon electrochemical cycling. The cyclic voltammograms ofLiFePO4and C-LiFePO4showed only a pair of peaks corresponding to the anodic and cathodic reactions. The first discharge capacities were 63, 43, and 13 mAh/g for C/5, C/3, and C/2, respectively forLiFePO4where as in case of C-LiFePO4that were 163, 144, 118, and 70 mAh/g for C/5, C/3, C/2, and 1C, respectively. The capacity retention of pureLiFePO4was 69% after 25 cycles where as that of C-LiFePO4was around 97% after 50 cycles. These results indicate that the capacity and the rate capability improved significantly upon carbon coating.
On a Periodic Predator‐Prey System with Holling III Functional Response and Stage Structure for Prey
Authors: Kong Xiangzeng , Chen Zhiqin , Xu Li , Yang Wensheng
Published: March 2010

We propose and study the permanence of the following periodic Holling
III predator‐prey system with stage structure for prey and both two predators which
consume immature prey. Sufficient and necessary conditions which guarantee the
predator and the prey species to be permanent are obtained.
Selection of Housekeeping Genes for Transgene Expression Analysis in Eucommia ulmoides Oliver Using Real-Time RT-PCR
Authors: Chen Ren , Gyokusen Mayumi , Nakazawa Yoshihisa , Gyokusen Koichiro
Published: March 2010

In order to select appropriate housekeeping genes for accurate calibration of experimental variations in real-time (RT-) PCR results in transgene expression analysis, particularly with respect to the influence of transgene on stability of endogenous housekeeping gene expression in transgenic plants, we outline a reliable strategy to identify the optimal housekeeping genes from a set of candidates by combining statistical analyses of their (RT-) PCR amplification efficiency, gene expression stability, and transgene influences. We used the strategy to select two genes, ACTα and EF1α, from 10 candidate housekeeping genes, as the optimal housekeeping genes to evaluate transgenic Eucommia ulmoides Oliver root lines overexpressing IPPI or FPPS1 genes, which are involved in isoprenoid biosynthesis.
In Vitro Determination of the Allergenic Potential of Egg White in Processed Meat
Authors: Hildebrandt Sabine , Schütte Larsen , Stoyanov Stefan , Hammer Günther , Steinhart Hans , Paschke Angelika
Published: March 2010

Hen's egg white has been reported as a causative agent of allergic reactions, with ovalbumin, conalbumin, ovomucoid, and lysozyme being the major allergens. However, little is known about the effects of processing with heat and high pressure on the allergenicity of egg white proteins as ingredients in meat. For this purpose, the allergenic characteristics of such treated preparations were studied. The IgE-binding capacity was analyzed by EAST inhibition in raw and processed meat preparations using sera from patients with hen's egg specific IgE. Increasing heat treatment as well as the application of high pressure decreased IgE binding, which is a measure of allergenic potential. The combined application of heat (70∘C) and high pressure had synergistic effects in reducing the allergenic potential nearly twice as the sum of the single treatments conducted separately.
A V530I Mutation in c-KIT Exon 10 Is Associated to Imatinib Response in Extraabdominal Aggressive Fibromatosis
Authors: Kurtz Jean-Emmanuel , Asmane Irène , Voegeli Anne-Claire , Neuville Agnès , Dufresne Armelle , Litique Valère , Chevreau Christine , Bergerat Jean-Pierre
Published: March 2010

Aggressive fibromatosis (AF) or desmoid tumor is a rare condition, characterized by deep tissue invasion by a monoclonal fibroblastic neoplasm, developed from musculoaponeurotic structures. Surgery is the treatment of choice, but negative margins can hardly been achieved in large tumors, and can lead to major functional disability. AF medical therapy includes nonsteroids anti-inflammatory drugs, tamoxifen, with inconsistent results. Several reports of imatinib efficacy in AF appear in the literature. Here, we describe for the first time a V530IKITexon 10 mutant that was associated to a dramatic imatinib response in an extraabdominal aggressive fibromatosis. The previously discovered V530I substitution was characterized in the core binding factor AML, but had never been reported in any other condition, so far. In this paper, we discuss theKITexon 10 mutations or polymorphisms that have been described in a variety of KIT-related conditions, including acute myelogenous leukemia, mastocytosis, and aggressive fibromatosis.
Building Representative‐Based Data Aggregation Tree in Wireless Sensor Networks
Authors: Zheng Yanfei , Chen Kefei , Qiu Weidong
Published: March 2010

Data aggregation is an essential operation to reduce energy consumption in large‐scale wireless sensor networks (WSNs). A compromised node may forge an aggregation result and mislead base station into trusting a false reading. Efficient and secure aggregation scheme is critical in WSN applications due to the stringent resource constraints. In this paper, we propose a method to build up the representative‐based aggregation tree in the WSNs such that the sensing data are aggregated along the route from the leaf cell to the root of the tree. In the cinema of large‐scale and high‐density sensor nodes, representative‐based aggregation tree can reduce the data transmission overhead greatly by directed aggregation and cell‐by‐cell communications. It also provides security services including the integrity, freshness, and authentication, via detection mechanism in the cells.
Toll-like Receptor 3–Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type I Interferons in Tumor Immune Surveillance
Authors: Chin Arnold I. , Miyahira Andrea K. , Covarrubias Anthony , Teague Juli , Guo Beichu , Dempsey Paul W. , Cheng Genhong
Published: March 2010

Inflammation has increasingly been recognized as a critical component influencing tumor growth. Recent reports have revealed conflicting evidence for the role of Toll-like receptors (TLR) in modulating tumorigenesis. In our study, we implicate TLR3 in mediating immune surveillance with increased growth of implanted transgenic adenocarcinoma of the mouse prostate (TRAMP) tumors in TLR3−/− compared with TLR3+/+ mice. Activation of TLR3 by polyinosinic-polycytidylic acid (polyI:C) leads to induction of multiple inflammatory pathways, including NF-κB, mitogen-activated protein kinases, and interferon (IFN) regulatory factors. We explored the potential of TLR3 stimulation in prostate cancer immunotherapy and showed that treatment with polyI:C can strongly suppress both s.c. implanted TRAMP tumors in syngenic mice as well as orthotopic prostate cancers in TRAMP C57Bl6 × FvB F1 Tg+/− transgenic mice. Treated tumors remained well differentiated to moderately differentiated with increased infiltration of T lymphocytes and natural killer (NK) cells compared with poorly differentiated adenocarcinoma observed in untreated tumors. Like TLR3−/− mice, IFN-α receptor 1 (IFNAR1)−/− mice exhibited reduced tumor surveillance and impaired tumor suppression following polyI:C treatment. We observed that type I IFN–dependent induction of cytokines was responsible for NK activation, with depletion of NK cells leading to increased tumor growth as well as expansion of CD4+CD25+Foxp3+ T regulatory lymphocytes. Our study therefore delineates the importance of IFNAR-dependent functions in TLR3-mediated tumor suppression and supports the use of TLR3 agonists for prostate cancer immune-based therapies. Cancer Res; 70(7); 2595–603
CpG Island Hypermethylation in Human Astrocytomas
Authors: Wu Xiwei , Rauch Tibor A. , Zhong Xueyan , Bennett William P. , Latif Farida , Krex Dietmar , Pfeifer Gerd P.
Published: March 2010

Astrocytomas are common and lethal human brain tumors. We have analyzed the methylation status of over 28,000 CpG islands and 18,000 promoters in normal human brain and in astrocytomas of various grades using the methylated CpG island recovery assay. We identified 6,000 to 7,000 methylated CpG islands in normal human brain. Approximately 5% of the promoter-associated CpG islands in the normal brain are methylated. Promoter CpG island methylation is inversely correlated whereas intragenic methylation is directly correlated with gene expression levels in brain tissue. In astrocytomas, several hundred CpG islands undergo specific hypermethylation relative to normal brain with 428 methylation peaks common to more than 25% of the tumors. Genes involved in brain development and neuronal differentiation, such as BMP4, POU4F3, GDNF, OTX2, NEFM, CNTN4, OTP, SIM1, FYN, EN1, CHAT, GSX2, NKX6-1, PAX6, RAX, and DLX2, were strongly enriched among genes frequently methylated in tumors. There was an overrepresentation of homeobox genes and 31% of the most commonly methylated genes represent targets of the Polycomb complex. We identified several chromosomal loci in which many (sometimes more than 20) consecutive CpG islands were hypermethylated in tumors. Seven such loci were near homeobox genes, including the HOXC and HOXD clusters, and the BARHL2, DLX1, and PITX2 genes. Two other clusters of hypermethylated islands were at sequences of recent gene duplication events. Our analysis offers mechanistic insights into brain neoplasia suggesting that methylation of the genes involved in neuronal differentiation, in cooperation with other oncogenic events, may shift the balance from regulated differentiation towards gliomagenesis. Cancer Res; 70(7); 2718–27
An Optimized Telomerase-Specific Lentivirus for Optical Imaging of Tumors
Authors: Yu Song-Tao , Yang Yin-Bing , Liang Guang-Ping , Li Chuan , Chen Ling , Shi Chun-Meng , Tang Xu-Dong , Li Chang-Zhu , Li Ling , Wang Guo-Zheng , Wu Yu-Yun , Yang Shi-Ming , Fang Dian-Chun
Published: March 2010

Advances in medical imaging techniques, such as ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography, have made great progress in detecting tumors. However, these imaging techniques are unable to differentiate malignant tumors from benign ones. Recently developed optical imaging of tumors in small animals provides a useful method to distinguish malignant tumors from their surrounding normal tissues. Human telomerase reverse transcriptase (hTERT) is normally inactivated in most somatic cells, whereas it is commonly reactivated in many cancer cells. In this study, we constructed a lentiviral vector that expresses green fluorescent protein (GFP) driven by an optimized hTERT promoter to create a noninvasive tumor-specific imaging methodology. The activity of this optimized hTERT promoter was found to be equal to the activity of SV40 and cytomegalovirus promoters. In vitro experiments showed that GFP was only expressed in telomerase-positive tumor cells infected with this lentivirus, whereas there was no GFP expression in telomerase-negative tumor cells or normal somatic cells. We also found that subcutaneous telomerase-positive tumors could be visualized 24 hours after an intratumoral injection with this lentivirus by using a charge-coupled device (CCD) camera. In contrast, telomerase-negative tumors could not be imaged after an intratumoral injection even for 30 days. These results suggest that infection with lentivirus containing this optimized hTERT promoter might be a useful diagnostic tool for the real-time visualization of macroscopically invisible tumor tissues using a highly sensitive CCD imaging system. Cancer Res; 70(7); 2585–94
A Small Interfering RNA Screen of Genes Involved in DNA Repair Identifies Tumor-Specific Radiosensitization by POLQ Knockdown
Authors: Higgins Geoff S. , Prevo Remko , Lee Yin-Fai , Helleday Thomas , Muschel Ruth J. , Taylor Steve , Yoshimura Michio , Hickson Ian D. , Bernhard Eric J. , McKenna W. Gillies
Published: March 2010

The effectiveness of radiotherapy treatment could be significantly improved if tumor cells could be rendered more sensitive to ionizing radiation (IR) without altering the sensitivity of normal tissues. However, many of the key therapeutically exploitable mechanisms that determine intrinsic tumor radiosensitivity are largely unknown. We have conducted a small interfering RNA (siRNA) screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumor radiosensitivity. Parallel siRNA screens were conducted in irradiated and unirradiated tumor cells (SQ20B) and irradiated normal tissue cells (MRC5). Using γH2AX foci at 24 hours after IR, we identified several genes, such as BRCA2, Lig IV, and XRCC5, whose knockdown is known to cause increased cell radiosensitivity, thereby validating the primary screening end point. In addition, we identified POLQ (DNA polymerase θ) as a potential tumor-specific target. Subsequent investigations showed that POLQ knockdown resulted in radiosensitization of a panel of tumor cell lines from different primary sites while having little or no effect on normal tissue cell lines. These findings raise the possibility that POLQ inhibition might be used clinically to cause tumor-specific radiosensitization. Cancer Res; 70(7); 2984–93
An Unexpectedly Large Polyclonal Repertoire of HPV-Specific T Cells Is Poised for Action in Patients with Cervical Cancer
Authors: de Vos van Steenwijk Peggy J. , Heusinkveld Moniek , Ramwadhdoebe Tamara H. , Löwik Margriet J. , van der Hulst Jeanette M. , Goedemans Renske , Piersma Sytse J. , Kenter Gemma G. , van der Burg Sjoerd H.
Published: March 2010

The diversity and extent of the local tumor-specific T-cell response in a given individual is largely unknown. We have performed an in-depth study of the local T-cell repertoire in a selected group of patients with cervical cancer, by systematic analyses of the proportion, breadth, and polarization of human papillomavirus (HPV) E6/E7-specific T cells within the total population of tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC). Isolated T cells were stimulated with sets of overlapping E6 and E7 peptides and analyzed by multiparameter flow cytometry with respect to activation, cytokine production, and T-cell receptor Vβ usage. HPV-specific CD4+ and CD8+ T-cell responses were detected in TIL and TDLNC and their relative contribution varied between <1% and 66% of all T cells. In general, these HPV-specific responses were surprisingly broad, aimed at multiple E6 and E7 epitopes and involved multiple dominant and subdominant T-cell receptor Vβs per single peptide-epitope. In most patients, only few IFNγ-producing T cells were found and the amount of IFNγ produced was low, suggesting that these are poised T cells, rendered functionally inactive within the tumor environment. Importantly, stimulation of the TIL and TDLNC with cognate antigen in the presence of commonly used Toll-like receptor ligands significantly enhanced the effector T-cell function. In conclusion, our study suggests that within a given patient with HPV-specific immunity many different tumor-specific CD4+ and CD8+ T cells are locally present and poised for action. This vast existing local T-cell population is awaiting proper stimulation and can be exploited for the immunotherapy of cancer. Cancer Res; 70(7); 2707–17
DNA Copy Numbers Profiles in Affinity-Purified Ovarian Clear Cell Carcinoma
Authors: Kuo Kuan-Ting , Mao Tsui-Lien , Chen Xu , Feng Yuanjian , Nakayama Kentaro , Wang Yue , Glas Ruth , Ma M. Joe , Kurman Robert J. , Shih Ie-Ming , Wang Tian-Li
Published: March 2010

Purpose: Advanced ovarian clear cell carcinoma (CCC) is one of the most aggressive ovarian malignancies, in part because it tends to be resistant to platinum-based chemotherapy. At present, little is known about the molecular genetic alterations in CCCs except that there are frequent activating mutations in PIK3CA. The purpose of this study is to comprehensively define the genomic changes in CCC based on DNA copy number alterations.

Experimental Design: We performed 250K high-density single nucleotide polymorphism array analysis in 12 affinity-purified CCCs and 10 CCC cell lines. Discrete regions of amplification and deletion were also analyzed in additional 21 affinity-purified CCCs using quantitative real-time PCR.

Results: The level of chromosomal instability in CCC as defined by the extent of DNA copy number changes is similar to those previously reported in low-grade ovarian serous carcinoma but much less than those in high-grade serous carcinoma. The most remarkable region with DNA copy number gain is at chr20, which harbors a potential oncogene, ZNF217. This discrete amplicon is observed in 36% of CCCs but rarely detected in serous carcinomas regardless of grade. In addition, homozygous deletions are detected at the CDKN2A/2B and LZTS1 loci. Interestingly, the DNA copy number changes observed in fresh CCC tissues are rarely detected in the established CCC cell lines.

Conclusions: This study provides the first high resolution, genome-wide view of DNA copy number alterations in ovarian CCC. The findings provide a genomic landscape for future studies aimed at elucidating the pathogenesis and developing new target-based therapies for CCCs. Clin Cancer Res; 16(7); 1997–2008. ©2010 AACR.
Transcriptional Profiles Predict Disease Outcome in Patients with Cutaneous T-Cell Lymphoma
Authors: Litvinov Ivan V. , Jones David A. , Sasseville Denis , Kupper Thomas S.
Published: March 2010

Purpose: Average survival of cutaneous T-cell lymphoma (CTCL) is associated with clinical stage at diagnosis, where stage I has a favorable survival prognosis, whereas patients with more advanced stages succumb to their disease within 5 years. Although the majority of patients present with an early-stage CTCL, 15% to 20% of them will inevitably progress. Current state-of-the-art clinical criteria cannot identify individuals with stage I disease who are at risk of progression. The purpose of the current work is to gain novel molecular insight into the pathophysiology of CTCL to be able to identify patients with poor versus favorable prognosis. Our previous work used microarray analysis of skin biopsies from 62 CTCL patients to perform an unsupervised analysis of gene expression, which revealed three distinct transcription profile clusters.

Experimental Design: In the present study, we used reverse transcription-PCR to confirm gene expression levels for a subset of representative genes in each cluster. We also performed a Kaplan-Meier analysis of survival and disease progression based on the 6 years of clinical follow-up.

Results: Our reverse transcription-PCR results confirmed the upregulation of representative genes for each cluster, whereas clinical analysis documents that all stage I cases that progressed to stage II and beyond were in poor and intermediate prognosis clusters 1 and 3 and none were in favorable prognosis cluster 2. This analysis also identified certain genes that were preferentially expressed in favorable (e.g., WIF-1) versus poor (e.g., IL-17F) prognosis clusters.

Conclusion: This work suggests that it may be possible to stratify CTCL patients into low-risk, intermediate-risk, and high-risk groups based on gene expression. Clin Cancer Res; 16(7); 2106–14. ©2010 AACR.
Bcl2 and Human Papilloma Virus 16 as Predictors of Outcome following Concurrent Chemoradiation for Advanced Oropharyngeal Cancer
Authors: Nichols Anthony C. , Finkelstein Dianne M. , Faquin William C. , Westra William H. , Mroz Edmund A. , Kneuertz Peter , Begum Shahnaz , Michaud William A. , Busse Paul M. , Clark John R. , Rocco James W.
Published: March 2010

Purpose: Oropharyngeal squamous cell carcinoma (OPSCC) associated with human papilloma virus (HPV) is rapidly growing in incidence. Despite better prognosis than OPSCC associated with traditional risk factors, treatment failure still occurs in a significant proportion of patients. We had identified the antiapoptotic protein Bcl2 as a marker for poor outcome in advanced OPSCC treated with concurrent chemoradiation. To determine whether Bcl2 and HPV together might further characterize treatment response, we examined whether the prognostic value of Bcl2 was independent of HPV status.

Experimental Design: Pretreatment tumor biopsies from 68 OPSCC patients were tested for HPV by in situ hybridization and were immunostained for Bcl2 to evaluate relations with disease-free (DFS) and overall survival following platin-based concurrent chemoradiation. Median follow-up among surviving patients was 47 months (range, 10-131 months).

Results: Bcl2 and HPV independently predicted DFS and overall survival. Hazard ratios (with 95% confidence interval) for positive versus negative status in bivariate Cox proportional hazard analysis of DFS were 6.1 (1.8-21) for Bcl2 and 0.11 (0.035-0.37) for HPV. Only 1 of 32 HPV-positive/Bcl2-negative tumors recurred. Pretreatment Bcl2 expression was specifically associated with distant metastasis; five of six distant metastases occurred in the <40% of patients whose primary tumors were Bcl2 positive.

Conclusions: Independent of HPV status, pretreatment Bcl2 expression identifies a subset of OPSCC patients having increased risk of treatment failure, particularly through distant metastasis, after concurrent chemoradiation. Considering HPV and Bcl2 together should help in devising better personalized treatments for OPSCC. Clin Cancer Res; 16(7); 2138–46. ©2010 AACR.
Gene Signatures for the Prediction of Response to Bacillus Calmette-Guérin Immunotherapy in Primary pT1 Bladder Cancers
Authors: Kim Yong-June , Ha Yun-Sok , Kim Seon-Kyu , Yoon Hyung Yoon , Lym Min Su , Kim Min-Ju , Moon Sung-Kwon , Choi Yung Hyun , Kim Wun-Jae
Published: March 2010

Purpose: Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is effective in the prevention of recurrence and progression in many cases of nonmuscle invasive bladder cancer, but many patients fail to respond. The aim of this study was to identify gene sets of markers that could predict the response to BCG immunotherapy in primary pT1 bladder cancer using microarray gene expression profiling.

Experimental Design: We used 80 patients with primary pT1 bladder cancer treated with BCG immunotherapy as training (48) and test (32) sets. Microarray gene expression profiling was done in the training set to identify genes differentially expressed between responder and nonresponder to BCG immunotherapy according to the events (recurrence or progression). Using a real-time reverse-transcriptase PCR, our findings were validated in the test set.

Results: In the training set, 424 and 287 genes were significantly associated with recurrence- and progression-free survival, respectively. Functional annotation of these genes included cell-mediated immune response, inflammatory response, cellular growth, and proliferation. From these predictive gene signatures, 24 genes (12 in recurrence and 12 in progression) with the highest score of expression ratio were extracted for validation in the test set. In multivariate regression analyses, predictive gene signatures were the only independent predictors of recurrence (hazard ratio, 3.38; P = 0.048) or progression (hazard ratio, 10.49; P = 0.048) in the test set.

Conclusions: Predictive gene signatures have diagnostic value for determining the response to intravesical BCG immunotherapy in primary pT1 bladder cancer. Clin Cancer Res; 16(7); 2131–7. ©2010 AACR.
Weight Loss via Exercise with Controlled Dietary Intake May Affect Phospholipid Profile for Cancer Prevention in Murine Skin Tissues
Authors: Ouyang Ping , Jiang Yu , Doan Hieu M. , Xie Linglin , Vasquez David , Welti Ruth , Su Xiaoyu , Lu Nanyan , Herndon Betty , Yang Shie-Shien , Jeannotte Richard , Wang Weiqun
Published: March 2010

Exercise has been linked to a reduced cancer risk in animal models. However, the underlying mechanisms are unclear. This study assessed the effect of exercise with dietary consideration on the phospholipid profile in 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced mouse skin tissues. CD-1 mice were randomly assigned to one of the three groups: ad libitum–fed sedentary control; ad libitum–fed treadmill exercise at 13.4 m/min for 60 min/d, 5 d/wk (Ex+AL); and treadmill-exercised but pair-fed with the same amount as the control (Ex+PF). After 14 weeks, Ex+PF but not Ex+AL mice showed ∼25% decrease in both body weight and body fat when compared with the controls. Of the total 338 phospholipids determined by electrospray ionization–tandem mass spectrometry, 57 were significantly changed, and 25 species could distinguish effects of exercise and diet treatments in a stepwise discriminant analysis. A 36% to 75% decrease of phosphatidylinositol (PI) levels in Ex+PF mice occurred along with a significant reduction of PI 3-kinase in TPA-induced skin epidermis, as measured by both Western blotting and immunohistochemistry. In addition, ∼2-fold increase of the long-chain polyunsaturated fatty acids, docosahexaenoic and docosapentaenoic acids, in phosphatidylcholines, phosphatidylethanolamines, and lysophosphatidylethanolamines was observed in the Ex+PF group. Microarray analysis indicated that the expression of fatty acid elongase-1 increased. Taken together, these data indicate that exercise with controlled dietary intake, but not exercise alone, significantly reduced body weight and body fat as well as modified the phospholipid profile, which may contribute to cancer prevention by reducing TPA-induced PI 3-kinase and by enhancing ω-3 fatty acid elongation. Cancer Prev Res; 3(4); 466–77
STAT2 Contributes to Promotion of Colorectal and Skin Carcinogenesis
Authors: Gamero Ana M. , Young Matthew R. , Mentor-Marcel Roycelynn , Bobe Gerd , Scarzello Anthony J. , Wise Jennifer , Colburn Nancy H.
Published: March 2010

Signal transducer and activator of transcription 2 (STAT2) is an essential transcription factor in the type I IFN (IFN-α/β) signal transduction pathway and known for its role in mediating antiviral immunity and cell growth inhibition. Unlike other members of the STAT family, IFNs are the only cytokines known to date that can activate STAT2. Given the inflammatory and antiproliferative dual nature of IFNs, we hypothesized that STAT2 prevents inflammation-induced colorectal and skin carcinogenesis by altering the inflammatory immune response. Contrary to our hypothesis, deletion of STAT2 inhibited azoxymethane/dextran sodium sulfate–induced colorectal carcinogenesis as measured by prolonged survival, lower adenoma incidence, smaller polyps, and less chronic inflammation. STAT2 deficiency also inhibited 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate–induced skin carcinogenesis as indicated by reduced papilloma multiplicity. A potential mechanism by which STAT2 promotes carcinogenesis is through activation of proinflammatory mediators. Deletion of STAT2 decreased azoxymethane/dextran sodium sulfate–induced expression and release of proinflammatory mediators, such as interleukin-6 and CCL2, and decreased interleukin-6 release from skin carcinoma cells, which then decreased STAT3 activation. Our findings identify STAT2 as a novel contributor to colorectal and skin carcinogenesis that may act to increase the gene expression and secretion of proinflammatory mediators, which in turn activate the oncogenic STAT3 signaling pathway. Cancer Prev Res; 3(4); 495–504. ©2010 AACR.
Sex Allocation and Sex Determination in Squamate Reptiles
Authors: Wapstra E. , Warner D.A.
Published: March 2010

Reptiles possess a wide variety of sex determining mechanisms, more so than any other vertebrate group. They offer outstanding opportunities to understand the evolutionary transitions between modes of sex determination. In this review, we argue that sex allocation theory is fundamental for understanding the selective causes of such shifts. Whether selection for biased sex allocation actually results in evolutionary shifts in sex determination depends on the overall strength, direction and consistency of selection and to what extent existing reproductive systems can establish novel links between factors causing sex-specific fitness and mechanisms of sex determination. Perhaps one of the most exciting advances in recent years has been the phylogenetically diverse range in reptile taxa that form the basis of research on the evolution of sex determination. The traditional use of long-lived oviparous species (especially turtles and crocodiles) is now expanded to include a range of short-lived taxa that exhibit both genetic sex determination and environment-/temperature-dependent sex determination (particularly agamid lizards), as well as a greater emphasis on viviparous species. If selection on differential sex allocation is a key selective pressure for the evolution of sex-determining mechanisms, these taxa will provide considerable insights into the integrated fields of sex allocation biology and sex determination.
Are Reptiles Predisposed to Temperature- Dependent Sex Determination?
Authors: Georges A. , Ezaz T. , Quinn A.E. , Sarre S.D.
Published: March 2010

Vertebrates show an astonishing array of sex determining mechanisms, including male and female heterogamety, multiple sex chromosome systems, environmental sex determination, parthenogenesis and hermaphroditism. Sex determination in mammals and birds is extraordinarily conservative compared to that of reptiles, amphibians and fish. In this paper, we explore possible explanations for the diversity of sex determining modes in reptiles, and in particular, address the prevalence of reptilian temperature-dependent sex determination (TSD) and its almost haphazard distribution across the reptile phylogeny. We suggest that reptiles are predisposed to evolving TSD from genotypic sex determination (GSD) by virtue of the uniquely variable thermal environment experienced by their embryos during the critical period in which sex is determined. Explicit mechanisms for canalization of sexual phenotype in the face of high thermal variation during development provide a context for thermolability in sex determination at extremes and the raw material for natural selection to move this thermolability into the developmental mainstream when there is a selective advantage to do so. Release of cryptic variation when canalization is challenged and fails at extremes may accelerate evolutionary transitions between GSD and TSD.
Modeling Thermal Influence on Animal Growth and Sex Determination in Reptiles: Being Closer to the Target Gives New Views
Authors: Girondot M. , Ben Hassine S. , Sellos C. , Godfrey M. , Guillon J.-M.
Published: March 2010

Many species of oviparous reptiles, including crocodilians, a majority of turtles, some lizards and the 2 closely related species of Sphenodon have been shown to display temperature-dependent sex determination (TSD). Whereas it has been demonstrated very early that TSD also occurs in natural conditions, the relationship between a time series of changing temperatures and sex ratio remains a challenging problem for reptiles. We describe how a physiological model of embryo growth, gonadal development and aromatase activity can produce outputs that mimic well TSD. We provide an enhancement of a previously published model taking into account direct effect of temperature on aromatase activity. The comparison between the original model and the new one suggests that aromatase expression is controlled by a repressor factor expressed at masculinizing temperatures rather than its enhancement at feminizing temperatures.
Effect of Genetic Counseling and Testing for BRCA1 and BRCA2 Mutations in African American Women: A Randomized Trial
Authors: Halbert C.H. , Kessler L. , Troxel A.B. , Stopfer J.E. , Domchek S.
Published: March 2010

Background: Limited empirical data are available on the effects of genetic counseling and testing among African American women. Objective: To evaluate the effects of genetic counseling and testing in African American women based on different levels of exposure: (a) women who were randomized to culturally tailored (CTGC) and standard genetic counseling (SGC) to women who declined randomization (non-randomized group), (b) participants and non-participants in genetic counseling, and (c) BRCA1 and BRCA2 (BRCA1/2) test result acceptors and decliners. Design: Randomized trial of genetic counseling conducted from February 2003 to November 2006. Measures: We evaluated changes in perceived risk of developing breast cancer and cancer worry. Results: Women randomized to CTGC and SGC did not differ in terms of changes in risk perception and cancer worry compared to decliners. However, counseling participants had a significantly greater likelihood of reporting reductions in perceived risk compared to non-participants (p = 0.03). Test result acceptors also had a significantly greater likelihood of reporting decreases in cancer worry (p = 0.03). However, having a cancer history (p = 0.03) and a BRCA1/2 prior probability (p = 0.04) were associated with increases in cancer worry. Conclusions: Although CTGC did not lead to significant improvements in perceived risk or psychological functioning, African American women may benefit from genetic counseling and testing. Continued efforts should be made to increase access to genetic counseling and testing among African American women at increased risk for hereditary disease. But, follow-up support may be needed for women who have a personal history of cancer and those with a greater prior probability of having a BRCA1/2 mutation.