bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual research, evaluation and assessment in the age of computer graphics
Authors: Westman Hans
Published: February 2010

Often, I get some of my best ideas in the morning, when it's quiet, closing my eyes and envisioning my thoughts. By the time I've had my coffee and ready to walk out the door, they may not be as apparent, if at all. If I were hardwired to a computer, my thoughts could be reviewed and analyzed, adding an additional dimension to assessing their applicable value.

Though it may not be currently possible to store and retrieve actual thoughts from a hard drive, content that is stored and retrievable is derived through a conscious thought process. Computer graphics applications allow for a visual analysis of the data for use in multiple areas. This issue takes up four.
T1r3 taste receptor involvement in gustatory neural responses to ethanol and oral ethanol preference
Authors: Brasser Susan M. , Norman Meghan B. , Lemon Christian H.
Published: February 2010

Elevated alcohol consumption is associated with enhanced preference for sweet substances across species and may be mediated by oral alcohol-induced activation of neurobiological substrates for sweet taste. Here, we directly examined the contribution of the T1r3 receptor protein, important for sweet taste detection in mammals, to ethanol intake and preference and the neural processing of ethanol taste by measuring behavioral and central neurophysiological responses to oral alcohol in T1r3 receptor-deficient mice and their C57BL/6J background strain. T1r3 knockout and wild-type mice were tested in behavioral preference assays for long-term voluntary intake of a broad concentration range of ethanol, sucrose, and quinine. For neurophysiological experiments, separate groups of mice of each genotype were anesthetized, and taste responses to ethanol and stimuli of different taste qualities were electrophysiologically recorded from gustatory neurons in the nucleus of the solitary tract. Mice lacking the T1r3 receptor were behaviorally indifferent to alcohol (i.e., ∼50% preference values) at concentrations typically preferred by wild-type mice (5–15%). Central neural taste responses to ethanol in T1r3-deficient mice were significantly lower compared with C57BL/6J controls, a strain for which oral ethanol stimulation produced a concentration-dependent activation of sweet-responsive NTS gustatory neurons. An attenuated difference in ethanol preference between knockouts and controls at concentrations >15% indicated that other sensory and/or postingestive effects of ethanol compete with sweet taste input at high concentrations. As expected, T1r3 knockouts exhibited strongly suppressed behavioral and neural taste responses to sweeteners but did not differ from wild-type mice in responses to prototypic salt, acid, or bitter stimuli. These data implicate the T1r3 receptor in the sensory detection and transduction of ethanol taste.
Minocycline-Associated Pseudotumor Cerebri with Severe Papilledema
Authors: Bababeygy Simon R. , Repka Michael X. , Subramanian Prem S.
Published: February 2010

Background. Pseudotumor cerebri is an acknowledged but unusual complication of oral minocycline use. Vision loss and papilledema have been described as mild and transient, and some authors suggest that treatment is not needed.Methods. Case series of 2 patients with severe papilledema and visual field loss.Results. Severe pseudotumor cerebri developed in 2 nonobese patients taking minocycline. Their disease required further treatment even upon drug discontinuation because of visual field loss and papilledema.Conclusions. Minocycline-associated pseudotumor cerebri is not always a self-limited condition and may require aggressive medical or surgical management.
One Year Sustainability of Risk Factor Change from a 9-Week Workplace Intervention
Authors: Rush Elaine C. , Cumin Michelle B. , Migriauli Lela , Ferguson Lynnette R. , Plank Lindsay D.
Published: February 2010

We examined the effect of a 9-week diet and physical activity intervention provided in the workplace by a group education session where personal dietary and physical activity goals were proposed. Measurements of anthropometry, fasting blood lipids, glucose and insulin, assays for antioxidant activity (AOA) and questionnaires were completed at 0, 3, 6, 9, and 12 weeks in 50 healthy workers (50% male, mean age 46y). Followup measurements in 39 (56% male) were possible at 52 weeks. At week 3 a group dietary and physical activity “motivational seminar” was held. At week 6, half the group were supplied daily kiwifruit for 3 weeks with cross over at week 9 until week 12. Compared to baseline, lipid, glucose, insulin and AOA measurements were improved at 12 and 52 weeks. Body measurements did not change. Group diet and physical activity advice reinforced over 9 weeks is associated with a sustained improvement in cardiovascular risk factors at 52 weeks.
Contributions of Matrix Metalloproteinases to Neural Plasticity, Habituation, Associative Learning and Drug Addiction
Authors: Wright John W. , Harding Joseph W.
Published: February 2010

The premise of this paper is that increased expression of matrix metalloproteinases (MMPs) permits the reconfiguration of synaptic connections (i.e., neural plasticity) by degrading cell adhesion molecules (CAMs) designed to provide stability to those extracellular matrix (ECM) proteins that form scaffolding supporting neurons and glia. It is presumed that while these ECM proteins are weakened, and/or detached, synaptic connections can form resulting in new neural pathways. Tissue inhibitors of metalloproteinases (TIMPs) are designed to deactivate MMPs permitting the reestablishment of CAMs, thus returning the system to a reasonably fixed state. This review considers available findings concerning the roles of MMPs and TIMPs in reorganizing ECM proteins thus facilitating the neural plasticity underlying long-term potentiation (LTP), habituation, and associative learning. We conclude with a consideration of the influence of these phenomena on drug addiction, given that these same processes may be instrumental in the formation of addiction and subsequent relapse. However, our knowledge concerning the precise spatial and temporal relationships among the mechanisms of neural plasticity, habituation, associative learning, and memory consolidation is far from complete and the possibility that these phenomena mediate drug addiction is a new direction of research.
A SiGe BiCMOS Instrumentation Channel for Extreme Environment Applications
Authors: Ulaganathan Chandradevi , Nambiar Neena , Cornett Kimberly , Greenwell Robert L. , Yager Jeremy A. , Prothro Benjamin S. , Tham Kevin , Chen Suheng , Broughton Richard S. , Fu Guoyuan , Blalock Benjamin J. , Britton Charles L. , Ericson M. Nance , Mantooth H. Alan , Mojarradi Mohammad M. , Berger Richard W. , Cressler John D.
Published: February 2010

An instrumentation channel is designed, implemented, and tested in a 0.5-μm SiGe BiCMOS process. The circuit features a reconfigurable Wheatstone bridge network that interfaces an assortment of external sensors to signal processing circuits. Also, analog sampling is implemented in the channel using a flying capacitor configuration. The analog samples are digitized by a low-power multichannel A/D converter. Measurement results show that the instrumentation channel supports input signals up to 200 Hz and operates across a wide temperature range of -180°C to 125°C. This work demonstrates the use of a commercially available first generation SiGe BiCMOS process in designing circuits suitable for extreme environment applications.
Existence of Solutions and Algorithm for a System of Variational Inequalities
Authors: Zhao Yali , Xia Zunquan , Pang Liping , Zhang Liwei
Published: February 2010

We obtain some existence results for a system of variational inequalities (for short, denoted by SVI) by Brouwer fixed point theorem. We also establish the existence and uniqueness theorem using the projection technique for the SVI and suggest an iterative algorithm and analysis convergence of the algorithm.
Demiclosed Principle for Asymptotically Nonexpansive Mappings in CAT(0) Spaces
Authors: Nanjaras B , Panyanak B
Published: February 2010

We prove the demiclosed principle for asymptotically nonexpansive mappings in CAT(0) spaces. As a consequence, we obtain a "Equation missing"-convergence theorem of the Krasnosel'skii-Mann iteration for asymptotically nonexpansive mappings in this setting. Our results extend and improve many results in the literature.
Application of the Rotation Matrix Natural Invariants to Impedance Control of Rotational Parallel Robots
Authors: Bruzzone L. , Callegari M.
Published: February 2010

Force control of parallel robots with rotational degrees of freedom through impedance algorithms is considerably influenced by the representation method of the end-effector orientation. Using the natural invariants of the rotation matrix and the angular velocity vector in the impedance control law has some theoretical advantages, which derive from the Euclidean-geometric meaning of these entities. These benefits are particularly evident in case of robotic architectures with three rotational degrees of freedom (serial or parallel wrists with spherical motion). The behaviour of a 3-CPU parallel robot controlled by an impedance algorithm based on this concepts is assessed through multibody simulations, and the results confirm the effectiveness of the proposed approach.
The Fixed Point Property of Unital Abelian Banach Algebras
Authors: Fupinwong W , Dhompongsa S
Published: February 2010

We give a general condition for infinite dimensional unital Abelian Banach algebras to fail the fixed point property. Examples of those algebras are given including the algebras of continuous functions on compact sets.
Immunogenetics and the Pathological Mechanisms of Human T-Cell Leukemia Virus Type 1- (HTLV-1-)Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)
Authors: Saito Mineki
Published: February 2010

Human T-cell leukemia virus type 1 (HTLV-1) is a replication-competent human retrovirus associated with two distinct types of disease only in a minority of infected individuals: the malignancy known as adult T-cell leukemia (ATL) and a chronic inflammatory central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the factors that cause these different manifestations of HTLV-1 infection are not fully understood, accumulating evidence suggests that complex virus-host interactions play an important role in determining the risk of HAM/TSP. This review focuses on the role of the immune response in controlling or limiting viral persistence in HAM/TSP patients, and the reason why some HTLV-1-infected people develop HAM/TSP whereas the majority remains asymptomatic carriers of the virus.
An Iterative Algorithm for Mixed Equilibrium Problems and Variational Inclusions Approach to Variational Inequalities
Authors: Liou Yeong-Cheng
Published: February 2010

We present an iterative algorithm for finding a common element "Equation missing" of the set of solutions of a mixed equilibrium problem and the set of a variational inclusion in a real Hilbert space. Furthermore, we prove that the proposed iterative algorithms strongly converge to "Equation missing" which solves some variational inequality.
Applicability of the Filter Paper Technique for Detection of Antifilarial Antibodies Using the Bm14 Filariasis CELISA
Authors: Joseph Hayley M. , Melrose Wayne
Published: February 2010

Demonstration of successful elimination of lymphatic filariasis (LF) in endemic countries requires sensitive diagnostics for accurate definitions of endpoints and future surveillance. There has been interest in complementing available diagnostics with antibody serology testing in children, since negative serology would correspond with cessation of LF transmission. The Filariasis CELISA detects antifilarial and has favourable results with serum samples but field application requires an easier sampling method. Ninety-four paired plasma and filter paper samples were assayed with promising results. The filter paper method resulted in a sensitivity of 92% and a specificity of 77% when compared to the paired plasma. One hundred and one filter paper samples were assessed for storage effects. Following 10-month storage at there was a significant reduction in reactivity (). Overall the results indicated that filter paper sampling would be a favourable sensitive and specific alternative for blood collection in surveys.
Hybrid Steepest-Descent Methods for Solving Variational Inequalities Governed by Boundedly Lipschitzian and Strongly Monotone Operators
Authors: He Songnian , Liang Xiao-Lan
Published: February 2010

Let "Equation missing" be a real Hilbert space and let "Equation missing" be a boundedly Lipschitzian and strongly monotone operator. We design three hybrid steepest descent algorithms for solving variational inequality "Equation missing" of finding a point "Equation missing" such that "Equation missing", for all "Equation missing", where "Equation missing" is the set of fixed points of a strict pseudocontraction, or the set of common fixed points of finite strict pseudocontractions. Strong convergence of the algorithms is proved.
Transvesicoscopic Repair of Vesicovaginal Fistula
Authors: Nerli R. B. , Reddy Mallikarjun
Published: February 2010

Introduction. Vesicovaginal fistula has been a social and surgical problem for centuries. Many surgical techniques have been developed to correct this abnormality, including transabdominal, transvaginal, and endoscopic approaches. The best approach is probably the one with which the surgeon feels most experienced and comfortable. Laparoscopy has become increasingly popular in urology, reducing the invasiveness of treatment and shortening the period of convalescence. We report our results of transvesicoscopic approach for VVF repair. Materials and Methods. Patients with VVF were offered repair using the transvesicoscopic route. With the patient under general anaesthesia and in modified lithotomy position cystoscopy was performed with gas insufflation. Under cystoscopic guidance the bladder was fixed to anterior abdominal wall and ports inserted into the bladder. The fistula was repaired under endoscopic vision. Results. Four women, who had VVF following abdominal hysterectomy, underwent this procedure. The operating time ranged from 175 to 235 minutes. There was minimal bleeding. Post operative complications included ileus in one and fever in another. No recurrence of VVF was noted in any patient. Conclusions. Transvesicoscopic repair of VVF is feasible, safe, and results in lower morbidity and quicker recovery time.
On the Generalized Hardy Spaces
Authors: Fatehi M.
Published: February 2010

We introduce new spaces that are extensions of the Hardy spaces and
we investigate the continuity of the point evaluations as well as the boundedness
and the compactness of the composition operators on these spaces.
Life-Threatening Cardiac Manifestations of Pheochromocytoma
Authors: Leite Luiz R. , Macedo Paula G. , Santos Simone N. , Quaglia Luiz , Mesas Cezar E. , De Paola Angelo
Published: February 2010

Pheochromocytoma is a catecholamine-secreting tumor of the adrenal glands, usually with benign manifestations, whose typical clinical presentation includes the triad of headache, palpitations and diaphoresis. However, a wide range of signs and symptoms may be present. In the cardiovascular system, the most common signs are labile hypertension and sinus tachycardia. Systolic heart failure and ST-segment deviations mimicking myocardial infarction have also been reported, as well as QT interval prolongation and, rarely, ventricular tachycardia. We describe a challenging diagnosis of pheochromocytoma with many cardiovascular manifestations, which could have been missed due to the absence of typical symptoms.
Tumor Detection by Imaging Proteolytic Activity
Authors: Darragh Molly R. , Schneider Eric L. , Lou Jianlong , Phojanakong Paul J. , Farady Christopher J. , Marks James D. , Hann Byron C. , Craik Charles S.
Published: February 2010

The cell surface protease membrane-type serine protease-1 (MT-SP1), also known as matriptase, is often upregulated in epithelial cancers. We hypothesized that dysregulation of MT-SP1 with regard to its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1), a situation that increases proteolytic activity, might be exploited for imaging purposes to differentiate malignant from normal tissue. In this study, we show that MT-SP1 is active on cancer cells and that its activity may be targeted in vivo for tumor detection. A proteolytic activity assay with several MT-SP1–positive human cancer cell lines showed that MT-SP1 antibodies that inhibit recombinant enzyme activity in vitro also bind and inhibit the full-length enzyme expressed on cells. In contrast, in the same assay, MT-SP1–negative cancer cell lines were inactive. Fluorescence microscopy confirmed the cell surface localization of labeled antibodies bound to MT-SP1–positive cells. To evaluate in vivo targeting capability, 0.7 to 2 nmoles of fluorescently labeled antibodies were administered to mice bearing tumors that were positive or negative for MT-SP1. Antibodies localized to MT-SP1–positive tumors (n = 3), permitting visualization of MT-SP1 activity, whereas MT-SP1–negative tumors (n = 2) were not visualized. Our findings define MT-SP1 activity as a useful biomarker to visualize epithelial cancers using a noninvasive antibody-based method. Cancer Res; 70(4); 1505–12
Polo-like Kinase 1 (Plk1) as a Novel Drug Target in Chronic Myeloid Leukemia: Overriding Imatinib Resistance with the Plk1 Inhibitor BI 2536
Authors: Gleixner Karoline V. , Ferenc Veronika , Peter Barbara , Gruze Alexander , Meyer Renata A. , Hadzijusufovic Emir , Cerny-Reiterer Sabine , Mayerhofer Matthias , Pickl Winfried F. , Sillaber Christian , Valent Peter
Published: February 2010

In most patients with chronic myeloid leukemia (CML), the disease can be kept under control using the BCR/ABL kinase inhibitor imatinib. Nevertheless, resistance or intolerance to imatinib and other BCR/ABL inhibitors may occur during therapy. Therefore, CML research is focusing on novel targets and targeted drugs. Polo-like kinase 1 (Plk1) is a serine/threonine kinase that plays an essential role in mitosis. In this study, we examined the expression of Plk1 in CML cells and its potential role as a therapeutic target. Plk1 was found to be expressed in phosphorylated form in the CML cell line K562 as well as in primary CML cells in all patients tested. Inhibition of BCR/ABL by imatinib or nilotinib (AMN107) led to decreased expression of the Plk1 protein in CML cells, suggesting that BCR/ABL promotes Plk1 generation. Silencing of Plk1 in CML cells by a small interfering RNA approach was followed by cell cycle arrest and apoptosis. Furthermore, the Plk1-targeting drug BI 2536 was found to inhibit proliferation of imatinib-sensitive and imatinib-resistant CML cells, including leukemic cells, carrying the T315 mutation of BCR/ABL with reasonable IC50 values (1–50 nmol/L). The growth-inhibitory effects of BI 2536 on CML cells were found to be associated with cell cycle arrest and apoptosis. Moreover, BI 2536 was found to synergize with imatinib and nilotinib in producing growth inhibition in CML cells. In conclusion, Plk1 is expressed in CML cells and may represent a novel, interesting target in imatinib-sensitive and imatinib-resistant CML. Cancer Res; 70(4); 1513–23
Oncolysis of Prostate Cancers Induced by Vesicular Stomatitis Virus in PTEN Knockout Mice
Authors: Moussavi Maryam , Fazli Ladan , Tearle Howard , Guo Yubin , Cox Michael , Bell John , Ong Christopher , Jia William , Rennie Paul S.
Published: February 2010

Vesicular stomatitis virus (VSV) is an oncolytic virus which selectively infects and kills cancer cells. The goal of the present study was to determine the safety and efficacy of VSV treatment of prostate tumors that arise in situ in immunocompetent, transgenic prostate-specific PTEN-null (PTEN−/−) mice. Interferon-sensitive VSV(AV3 strain), which expresses luciferase, was injected intraprostatically into tumor-bearing PTEN−/− and control mice and then monitored for tissue bioluminescence over 96 hours. Virus readily dispersed throughout the bodies of mice after only 3 hours; however, it persisted at high levels for >72 hours in PTEN−/− mice, but at relatively low levels and for only ∼48 hours in controls. Plaque assays provided a similar pattern, with much higher concentrations of replicating virus in prostates of PTEN−/− mice than in controls. Transient, low levels of virus were detected in the spleens of both groups. Apoptotic analyses by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining revealed that VSV(AV3) is able to selectively infect and kill prostate cells in PTEN−/− mice, while sparing normal cells in control mice. The primary mechanism for cell kill is apparently apoptotic oncolysis as opposed to neutrophil invasion as has been reported using xenograft models. These results suggest that control of locally advanced human prostate cancer may be achievable through intraprostatic injection and amplification of a safe oncolytic virus, such as VSV(AV3). Cancer Res; 70(4); 1367–76
Tumor Suppressor HLJ1 Binds and Functionally Alters Nucleophosmin via Activating Enhancer Binding Protein 2α Complex Formation
Authors: Chang Tzu-Pei , Yu Sung-Liang , Lin Sheng-Yi , Hsiao Yi-Jing , Chang Gee-Chen , Yang Pan-Chyr , Chen Jeremy J.W.
Published: February 2010

HLJ1, a member of the heat shock protein 40 chaperone family, is a newly identified tumor suppressor that has been implicated in tumorigenesis and metastasis in non–small cell lung cancer. However, the mechanism of HLJ1 action is presently obscure. In this study, we report that HLJ1 specifically interacts with the nuclear protein nucleophosmin (NPM1), forming a multiprotein complex that alters the nucleolar distribution and oligomerization state of NPM1. Enforced accumulation of NPM1 oligomers by overexpression in weakly invasive but high HLJ1-expressing cells induced the activity of signal transducer and activator of transcription 3 (STAT3) and increased cellular migration, invasiveness, and colony formation. Furthermore, silencing HLJ1 accelerated NPM1 oligomerization, inhibited the activity of transcription corepressor activating enhancer binding protein 2α (AP-2α), and increased the activities of matrix metalloproteinase-2 (MMP-2) and STAT3. Our findings suggest that HLJ1 switches the role of NPM1, which can act as tumor suppressor or oncogene, by modulating the oligomerization of NPM1 via HLJ1-NPM1 heterodimer formation and recruiting AP-2α to the MMP-2 promoter. Cancer Res; 70(4); 1656–67
p53 Is a Direct Transcriptional Target of MYCN in Neuroblastoma
Authors: Chen Lindi , Iraci Nunzio , Gherardi Samuele , Gamble Laura D. , Wood Katrina M. , Perini Giovanni , Lunec John , Tweddle Deborah A.
Published: February 2010

MYCN amplification occurs in ∼25% of neuroblastomas, where it is associated with rapid tumor progression and poor prognosis. MYCN plays a paradoxical role in driving cellular proliferation and inducing apoptosis. Based on observations of nuclear p53 accumulation in neuroblastoma, we hypothesized that MYCN may regulate p53 in this setting. Immunohistochemical analysis of 82 neuroblastoma tumors showed an association of high p53 expression with MYCN expression and amplification. In a panel of 5 MYCN-amplified and 5 nonamplified neuroblastoma cell lines, and also in the Tet21N-regulatable MYCN expression system, we further documented a correlation between the expression of MYCN and p53. In MYCN-amplified neuroblastoma cell lines, MYCN knockdown decreased p53 expression. In Tet21N MYCN+ cells, higher levels of p53 transcription, mRNA, and protein were observed relative to Tet21N MYCN- cells. In chromatin immunoprecipitation and reporter gene assays, MYCN bound directly to a Myc E-Box DNA binding motif located close to the transcriptional start site within the p53 promoter, where it could initiate transcription. E-Box mutation decreased MYCN-driven transcriptional activation. Microarray analysis of Tet21N MYCN+/− cells identified several p53-regulated genes that were upregulated in the presence of MYCN, including MDM2 and PUMA, the levels of which were reduced by MYCN knockdown. We concluded that MYCN transcriptionally upregulates p53 in neuroblastoma and uses p53 to mediate a key mechanism of apoptosis. Cancer Res; 70(4); 1377–88
Heterogeneous Nuclear Ribonucleoprotein H Blocks MST2-Mediated Apoptosis in Cancer Cells by Regulating a-raf Transcription
Authors: Rauch Jens , O'Neill Eric , Mack Brigitte , Matthias Christoph , Munz Markus , Kolch Walter , Gires Olivier
Published: February 2010

A-Raf belongs to the family of oncogenic Raf kinases that are involved in mitogenic signaling by activating the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)–ERK pathway. Low kinase activity of A-Raf toward MEK suggested that A-Raf might have alternative functions. Here, we show that A-Raf prevents cancer cell apoptosis contingent on the expression of the heterogeneous nuclear ribonucleoprotein H (hnRNP H) splice factor, which is required for the correct transcription and expression of a-raf. Apoptosis was prevented by A-Raf through sequestration and inactivation of the proapoptotic MST2 kinase. Small interfering RNA–mediated knockdown of hnRNP H or A-Raf resulted in MST2-dependent apoptosis. In contrast, enforced expression of either hnRNP H or A-Raf partially counteracted apoptosis induced by etoposide. In vivo expression studies of colon specimens corroborated the overexpression of hnRNP H in malignant tissues and its correlation with A-Raf levels. Our findings define a novel mechanism that is usurped in tumor cells to escape naturally imposed apoptotic signals. Cancer Res; 70(4); 1679–88
Blockade of Tumor Necrosis Factor α Signaling in Tumor-Associated Macrophages as a Radiosensitizing Strategy
Authors: Meng Yuru , Beckett Michael A. , Liang Hua , Mauceri Helena J. , van Rooijen Nico , Cohen Kenneth S. , Weichselbaum Ralph R.
Published: February 2010

Most cancer patients receive radiotherapy during the course of their disease. Improvements in the therapeutic index have been based mainly on physical improvements in delivery, as radiosensitizer development to target tumor cells has yet to yield effective agents. Recent investigations have focused on the tumor stroma as a target for radiosensitization. Here, we report that depletion of tumor-associated macrophages (TAMϕ) by systemic or local injection of the macrophage-depleting liposomal clodronate before radiotherapy can increase the antitumor effects of ionizing radiation (IR), either as a large single dose (20 Gy) or as a fractionated dose (2 Gy × 10). Coimplantation of tumor cells with bone marrow–derived macrophages (BMDMϕ) increased tumor radioresistance. Studies using mice with germline deletions in tumor necrosis factor receptors 1 and 2 (TNFR1,2−/−) or TNFα (TNF−/−), or treatment of wild-type mice with a soluble TNF receptor fusion protein (Enbrel), revealed that radioresistance mediated by BMDMϕ required intact TNFα signaling. Radiation exposure upregulated vascular endothelial growth factor (VEGF) in macrophages and VEGF-neutralizing antibodies enhanced the antitumor response to IR. Thus, the radioprotective effect of TNFα was mediated by TAM-produced VEGF. Our findings offer a mechanistic basis to target macrophage populations generally or TNFα-induced macrophage VEGF specifically as tractable strategies to improve the efficacy of radiotherapy. Cancer Res; 70(4); 1534–43
Genetic Polymorphisms in Vitamin D Receptor VDR/RXRA Influence the Likelihood of Colon Adenoma Recurrence
Authors: Egan Jan B. , Thompson Patricia A. , Ashbeck Erin L. , Conti David V. , Duggan David , Hibler Elizabeth , Jurutka Peter W. , LeRoy Elizabeth C. , Martínez María Elena , Mount David , Jacobs Elizabeth T.
Published: February 2010

Low circulating levels of vitamin D affect colorectal cancer risk. The biological actions of the hormonal form of vitamin D, 1,25(OH)2D3, are mediated by the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptors (RXR). Using a single nucleotide polymorphism (SNP) tagging approach, we assessed the association between genetic variations in RXRA and VDR and odds of recurrent (metachronous) colorectal neoplasia in a pooled population of two studies. A total of 32 tag SNPs in RXRA and 42 in VDR were analyzed in 1,439 participants. A gene-level association was observed for RXRA and any (P = 0.04) or proximal (P = 0.03) metachronous neoplasia. No gene-level associations were observed for VDR, nor was any single SNP in VDR related to any metachronous adenoma after correction for multiple comparisons. In contrast, the association between RXRA SNP rs7861779 and proximal metachronous neoplasia was of borderline statistical significance [odds ratio (OR), 0.68; 95% confidence interval (95% CI), 0.53-0.86; unadjusted P = 0.001; adjusted P = 0.06], including when observed independently in each individual study. Haplotypes within linkage blocks of RXRA support an ∼30% reduction in odds of metachronous neoplasia arising in the proximal colon among carriers of specific haplotypes, which was strongest (ORproximal, 0.67; 95% CI, 0.52–0.86) for carriers of a CGGGCA haplotype (rs1805352, rs3132297, rs3132296, rs3118529, rs3118536, and rs7861779). Our results indicate that allelic variation in RXRA affects metachronous colorectal neoplasia, perhaps of particular importance in the development of proximal lesions. Cancer Res; 70(4); 1496–504
Dendritic Cell-Derived Exosomes for Cancer Immunotherapy: What's Next?
Authors: Viaud Sophie , Théry Clotilde , Ploix Stéphanie , Tursz Thomas , Lapierre Valérie , Lantz Olivier , Zitvogel Laurence , Chaput Nathalie
Published: February 2010

Exosomes are nanovesicles originating from late endosomal compartments and secreted by most living cells in ex vivo cell culture conditions. The interest in exosomes was rekindled when B-cell and dendritic cell-derived exosomes were shown to mediate MHC-dependent immune responses. Despite limited understanding of exosome biogenesis and physiological relevance, accumulating evidence points to their bioactivity culminating in clinical applications in cancer. This review focuses on the preclinical studies exploiting the immunogenicity of dendritic cell-derived exosomes (Dex) and will elaborate on the past and future vaccination trials conducted using Dex strategy in melanoma and non-small cell lung cancer patients. Cancer Res; 70(4); 1281–5
Low Levels of Phosphorylated Epidermal Growth Factor Receptor in Nonmalignant and Malignant Prostate Tissue Predict Favorable Outcome in Prostate Cancer Patients
Authors: Hammarsten Peter , Karalija Amar , Josefsson Andreas , Rudolfsson Stina Häggström , Wikström Pernilla , Egevad Lars , Granfors Torvald , Stattin Pär , Bergh Anders
Published: February 2010

Purpose: To explore if the expression of phosphorylated epidermal growth factor receptor (pEGFR) in nonmalignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients.

Experimental Design: We used formalin-fixed tissues obtained through the transurethral resection of the prostate from 259 patients diagnosed with prostate cancer after the transurethral resection of the prostate, and patients were then followed with watchful waiting. Tissue microarrays of nonmalignant and malignant prostate tissue were stained with an antibody against pEGFR. The staining pattern was scored and related to clinicopathologic parameters and to outcome.

Results: Low phosphorylation of EGFR in prostate epithelial cells, both in the tumor and surprisingly also in the surrounding nonmalignant tissue, was associated with significantly longer cancer-specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were added together with pEGFR to a Cox regression model. Tumor epithelial pEGFR immunoreactivity was significantly correlated to tumor cell proliferation, tumor vascular density, and nonmalignant epithelial pEGFR immunoreactivity. Patients with metastases had significantly higher immunoreactivity for tumor and nonmalignant epithelial pEGFR compared with patients without metastases.

Conclusions: Low pEGFR immunoreactivity is associated with the favorable prognosis in prostate cancer patients and may provide information about which patients with Gleason score 6 and 7 tumors that will survive their disease even without treatment. Changes in the nonmalignant tissue adjacent to prostate tumors give prognostic information. Clin Cancer Res; 16(4); 1245–55
Tipifarnib Plus Tamoxifen in Tamoxifen-Resistant Metastatic Breast Cancer: A Negative Phase II and Screening of Potential Therapeutic Markers by Proteomic Analysis
Authors: Dalenc Florence , Doisneau-Sixou Sophie F. , Allal Ben C. , Marsili Sabrina , Lauwers-Cances Valérie , Chaoui Karima , Schiltz Odile , Monsarrat Bernard , Filleron Thomas , Renée Nicole , Malissein Emilie , Meunier Elise , Favre Gilles , Roché Henri
Published: February 2010

Purpose: Tipifarnib, a farnesyltransferase inhibitor, has antitumor activity in heavily pretreated metastatic breast cancer patients. Preclinical data suggest that FTIs could restore tamoxifen responsiveness in tamoxifen-resistant disease. Thus, combining FTIs and tamoxifen may be a promising clinical approach after relapse or progression on tamoxifen.

Experimental Design: Postmenopausal patients with measurable estrogen receptor– and/or progesterone receptor–expressing metastatic breast cancers were enrolled. Only patients with disease progression on tamoxifen were eligible, but there was no limitation regarding prior chemotherapy or hormone therapy regimens. Patients were immediately treated with 300 mg (n = 12) or 200 mg (n = 10) tipifarnib twice daily for 21 of 28-day cycles plus tamoxifen once daily. Serum was collected at baseline and after 8 weeks of treatment to enable proteomic comparison and identify possible predictive response markers.

Results: Twenty patients were enrolled and evaluated for efficacy: one patient had an objective response (liver metastasis) and nine had stable disease after 6 months for a clinical benefit rate of 50%; median duration of benefit was 10.3 (range, 7.4-20.2) months. The proteomic analysis by SELDI-TOF and LTQ-FT-Orbitrap identified a known peptide of fibrinogen α, the intensity of which was significantly increased in patients with progression compared with patients who benefited from the combined treatment after 8 weeks.

Conclusions: Because the primary end point of efficacy (three objective responses) was not achieved, the study is negative. Nevertheless, the identified peptide could be of interest in discriminating, at 8 weeks of treatment, responders from nonresponders. Clin Cancer Res; 16(4); 1264–71
A New Therapy Paradigm for Prostate Cancer Founded on Clinical Observations
Authors: Efstathiou Eleni , Logothetis Christopher J.
Published: February 2010

Efficacy equivalent to that reported in other common adult solid tumors considered to be chemotherapy-sensitive has been reported with Docetaxel in patients with castrate-resistant prostate cancer. However, in contrast to other cancers, the expected increase in efficacy with the use of chemotherapy in earlier disease states has not been reported to date in prostate cancer. On the basis of these observations, we speculated that the therapy development paradigm used successfully in other cancers may not apply to the majority of prostate cancers. Several lines of supporting clinical and experimental observations implicate the tumor microenvironment in prostate carcinogenesis and resistance to therapy. We conclude that a foundation to guide the development of therapy for prostate cancer is required. The therapy paradigm we propose accounts for the central role of the tumor microenvironment in bone and, if correct, will lead to microenvironment-targeted therapy. Clin Cancer Res; 16(4); 1100–7
Chromosome 17 Polysomy without Human Epidermal Growth Factor Receptor 2 Amplification Does Not Predict Response to Lapatinib Plus Paclitaxel Compared with Paclitaxel in Metastatic Breast Cancer
Authors: Downey Leona , Livingston Robert B. , Koehler Maria , Arbushites Michael , Williams Lisa , Santiago Angela , Guzman Roberta , Villalobos Ivonne , Di Leo Angelo , Press Michael F.
Published: February 2010

Purpose: It has been suggested that a subgroup of human epidermal growth factor receptor 2 (HER2)–negative breast cancer patients with chromosome 17 (Chr-17) polysomy benefit from HER2-directed therapy. This hypothesis was examined using the data from a phase III trial that randomized patients with HER2-negative or HER2-untested metastatic breast cancer to first-line therapy with paclitaxel along with either lapatinib or placebo.

Experimental Design: HER2 expression level by immunohistochemistry, fluorescence in situ hybridization (FISH), and mean HER2 ratio of Chr-17 values were determined centrally using archival tissue. Polysomy means of 2.0 and 2.2 served as thresholds.

Results: Of 580 patients on the original trial, 406 were HER2 negative by FISH. Progression-free survival (PFS) data were available for 405 patients, of whom 44 (11%) met the definition of polysomy (Chr-17 ≥2.2, FISH negative for HER2). Median PFS in the polysomy group was 20.9 and 24.4 weeks for paclitaxel plus lapatinib and paclitaxel plus placebo, respectively. In the nonpolysomy group, median PFS was 24.6 and 23.1 weeks for paclitaxel plus lapatinib and paclitaxel plus placebo, respectively. Log-rank testing showed no treatment advantage for either group. Similar results were found using a Chr-17 polysomy cutoff of 2.0. Response rates in the polysomy group were 17% for paclitaxel plus lapatinib and 10% for paclitaxel plus placebo. In the nonpolysomy group, response rates were 32% for paclitaxel plus lapatinib and 25% for paclitaxel plus placebo. Neither comparison was statistically significant.

Conclusion: This analysis could not confirm the hypothesis that Chr-17 polysomy in HER2-nonamplified patients improved chemotherapy outcome when lapatinib is added as a HER2-targeted treatment. Clin Cancer Res; 16(4); 1281–8
The Predictive Value of HLA Class I Tumor Cell Expression and Presence of Intratumoral Tregs for Chemotherapy in Patients with Early Breast Cancer
Authors: de Kruijf Esther M. , van Nes Johanna G.H. , Sajet Anita , Tummers Quirijn R.J.G. , Putter Hein , Osanto Susanne , Speetjens Frank M. , Smit Vincent T.H.B.M. , Liefers Gerrit Jan , van de Velde Cornelis J.H. , Kuppen Peter J.K.
Published: February 2010

Purpose: We hypothesized that T-cell immune interaction affects tumor development and thus clinical outcome. Therefore, we examined the clinical impact of human leukocyte antigen (HLA) class I tumor cell expression and regulatory T-cell (Treg) infiltration in breast cancer.

Experimental Design: Our study population (N = 677) is consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Formalin-fixed, paraffin-embedded tumor tissue was immunohistochemically stained using HCA2, HC10, and Foxp3 monoclonal antibodies.

Results: HLA class I expression was evaluated by combining results from HCA2 and HC10 antibodies and classified into three groups: loss, downregulation, and expression. Remarkably, only in patients who received chemotherapy, both presence of Treg (P = 0.013) and higher HLA class I expression levels (P = 0.002) resulted in less relapses, independently of other variables. Treg and HLA class I were not of influence on clinical outcome in patients who did not receive chemotherapy.

Conclusions: We showed that HLA class I and Treg affect prognosis exclusively in chemotherapy-treated patients and are therefore one of the few predictive factors for chemotherapy response in early breast cancer patients. Chemotherapy may selectively eliminate Treg, thus enabling CTLs to kill tumor cells that have retained HLA class I expression. As a consequence, HLA class I and Treg can predict response to chemotherapy with high discriminative power. These markers could be applied in response prediction to chemotherapy in breast cancer patients. Clin Cancer Res; 16(4); 1272–80
Smoking and Colorectal Cancer in Lynch Syndrome: Results from the Colon Cancer Family Registry and The University of Texas M.D. Anderson Cancer Center
Authors: Pande Mala , Lynch Patrick M. , Hopper John L. , Jenkins Mark A. , Gallinger Steve , Haile Robert W. , LeMarchand Loic , Lindor Noralane M. , Campbell Peter T. , Newcomb Polly A. , Potter John D. , Baron John A. , Frazier Marsha L. , Amos Christopher I.
Published: February 2010

Purpose: Lynch syndrome family members with inherited germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), and cases typically have tumors that exhibit a high level of microsatellite instability (MSI). There is some evidence that smoking is a risk factor for CRCs with high MSI; however, the association of smoking with CRC among those with Lynch syndrome is unknown.

Experimental Design: A multicentered retrospective cohort of 752 carriers of pathogenic MMR gene mutations was analyzed, using a weighted Cox regression analysis, adjusting for sex, ascertainment source, the specific mutated gene, year of birth, and familial clustering.

Results: Compared with never smokers, current smokers had a significantly increased CRC risk [adjusted hazard ratio (HR), 1.62; 95% confidence interval (95% CI), 1.01-2.57] and former smokers who had quit smoking for 2 or more years were at decreased risk (HR, 0.53; 95% CI, 0.35-0.82). CRC risk did not vary according to age at starting. However, light smoking (<10 cigarettes per day) and shorter duration of smoking (<10 years) were associated with decreased CRC risk (HR, 0.51; 95% CI, 0.29-0.91 and HR, 0.52; 95% CI, 0.30-0.89, respectively). For former smokers, CRC risk decreased with years since quitting (P trend <0.01).

Conclusions: People with Lynch syndrome may be at increased risk of CRC if they smoke regularly. Although our data suggest that former smokers, short-term smokers, and light smokers are at decreased CRC risk, these findings need further confirmation, preferably using prospective designs. Clin Cancer Res; 16(4); 1331–9
Randomized Phase III Trial of Gefitinib versus Docetaxel in Non–Small Cell Lung Cancer Patients Who Have Previously Received Platinum-Based Chemotherapy
Authors: Lee Dae Ho , Park Keunchil , Kim Joo Hang , Lee Jong-Seok , Shin Sang Won , Kang Jin-Hyoung , Ahn Myung-Ju , Ahn Jin Seok , Suh Cheolwon , Kim Sang-We
Published: February 2010

Purpose: The ISTANA (IRESSA as Second-line Therapy in Advanced NSCLC—KoreA) study compared gefitinib with docetaxel in patients with advanced or metastatic non–small cell lung carcinoma (NSCLC) pretreated with platinum-based chemotherapy.

Experimental Design: We conducted a multicenter, randomized, open-label phase III trial of gefitinib (250 mg/d) versus docetaxel (75 mg/m2 day 1 every 3 weeks) in patients with advanced or metastatic NSCLC treated with one previous platinum-based chemotherapy. The primary endpoint was progression-free survival.

Results: A total of 161 patients (male, 62%; never smoker, 41%; adenocarcinoma, 68%) were enrolled. Progression-free survival was longer for gefitinib compared with docetaxel (hazard ratio, 0.729; 90% confidence interval, 0.533-0.998; one-sided P = 0.0441). Gefitinib significantly improved objective response rate (28.1% versus 7.6%; two-sided P = 0.0007). In the final analysis of overall survival, the hazard ratio was 0.870 (95% confidence interval, 0.613-1.236; two-sided P = 0.4370). No significant differences were seen in the quality of life or symptom improvement rates between the two treatment groups. Gefitinib was well tolerated, was consistent with previous data and disease, and had fewer serious adverse events and fewer Common Terminology Criteria for Adverse Events grade 3 or 4 adverse events than docetaxel. The incidence of interstitial lung disease–type events was 3.7% (n = 3) with gefitinib and 3.9% (n = 3) with docetaxel.

Conclusions: The primary endpoint of progression-free survival was longer with gefitinib than docetaxel, and the secondary endpoints showed superior objective response rate, good tolerability, and similar quality of life improvement rates for gefitinib than docetaxel. Therefore, gefitinib is an important valid treatment option for second-line therapy for Korean NSCLC patients. Clin Cancer Res; 16(4); 1307–14
AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer
Authors: Hickinson D. Mark , Klinowska Teresa , Speake Georgina , Vincent John , Trigwell Cath , Anderton Judith , Beck Sarah , Marshall Gayle , Davenport Sara , Callis Rowena , Mills Elizabeth , Grosios Konstantina , Smith Paul , Barlaam Bernard , Wilkinson Robert W. , Ogilvie Donald
Published: February 2010

Purpose: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo.

Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors.

Results: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC50, 4 nmol/L), erbB2 (IC50, 3 nmol/L), and erbB3 (IC50, 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non–small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.

Conclusions: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2. Clin Cancer Res; 16(4); 1159–69