bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of mammographic masses based on level set segmentation with new image features and patient information
Authors: Shi Jiazheng , Sahiner Berkman , Chan Heang‐Ping , Ge Jun , Hadjiiski Lubomir , Helvie Mark A. , Nees Alexis , Wu Yi‐Ta , Wei Jun , Zhou Chuan , Zhang Yiheng , Cui Jing
Published: January 2008

Computer‐aided diagnosis (CAD) for characterization of mammographic masses as malignant or benign has the potential to assist radiologists in reducing the biopsy rate without increasing false negatives. The purpose of this study was to develop an automated method for mammographic mass segmentation and explore new image based features in combination with patient information in order to improve the performance of mass characterization. The authors’ previous CAD system, which used the active contour segmentation, and morphological, textural, and spiculation features, has achieved promising results in mass characterization. The new CAD system is based on the level set method and includes two new types of image features related to the presence of microcalcifications with the mass and abruptness of the mass margin, and patient age. A linear discriminant analysis (LDA) classifier with stepwise feature selection was used to merge the extracted features into a classification score. The classification accuracy was evaluated using the area under the receiver operating characteristic curve. The authors’ primary data set consisted of 427 biopsy‐proven masses (200 malignant and 227 benign) in 909 regions of interest (ROIs) (451 malignant and 458 benign) from multiple mammographic views. Leave‐one‐case‐out resampling was used for training and testing. The new CAD system based on the level set segmentation and the new mammographic feature space achieved a view‐based value of . The improvement compared to the previous CAD system was statistically significant . When patient age was included in the new CAD system, view‐based and case‐based values were and , respectively. The study also demonstrated the consistency of the newly developed CAD system by evaluating the statistics of the weights of the LDA classifiers in leave‐one‐case‐out classification. Finally, an independent test on the publicly available digital database for screening mammography with 132 benign and 197 malignant ROIs containing masses achieved a view‐based value of .
Endovascular image‐guided interventions (EIGIs)
Authors: Rudin Stephen , Bednarek Daniel R. , Hoffmann Kenneth R.
Published: January 2008

Minimally invasive interventions are rapidly replacing invasive surgical procedures for the most prevalent human disease conditions. X‐ray image‐guided interventions carried out using the insertion and navigation of catheters through the vasculature are increasing in number and sophistication. In this article, we offer our vision for the future of this dynamic field of endovascular image‐guided interventions in the form of predictions about (1) improvements in high‐resolution detectors for more accurate guidance, (2) the implementation of high‐resolution region of interest computed tomography for evaluation and planning, (3) the implementation of dose tracking systems to control patient radiation risk, (4) the development of increasingly sophisticated interventional devices, (5) the use of quantitative treatment planning with patient‐specific computer fluid dynamic simulations, and (6) the new expanding role of the medical physicist. We discuss how we envision our predictions will come to fruition and result in the universal goal of improved patient care.
Polymorphic Y Chromosomes Harbor Cryptic Variation with Manifold Functional Consequences
Authors: Lemos Bernardo , Araripe Luciana O. , Hartl Daniel L.
Published: January 2008

The paucity of polymorphisms in single-copy genes on the Y chromosome of
Drosophila
contrasts with data indicating that this chromosome has polymorphic phenotypic effects on sex ratio, temperature sensitivity, behavior, and fitness. We show that the Y chromosome of
D. melanogaster
harbors substantial genetic diversity in the form of polymorphisms for genetic elements that differentially affect the expression of hundreds of X-linked and autosomal genes. The affected genes are more highly expressed in males, more meagerly expressed in females, and more highly divergent between species. Functionally, they affect microtubule stability, lipid and mitochondrial metabolism, and the thermal sensitivity of spermatogenesis. Our findings provide a mechanism for adaptive phenotypic variation associated with the Y chromosome.
A Mosaic of Chemical Coevolution in a Large Blue Butterfly
Authors: Nash David R. , Als Thomas D. , Maile Roland , Jones Graeme R. , Boomsma Jacobus J.
Published: January 2008

Mechanisms of recognition are essential to the evolution of mutualistic and parasitic interactions between species. One such example is the larval mimicry that
Maculinea
butterfly caterpillars use to parasitize
Myrmica
ant colonies. We found that the greater the match between the surface chemistry of
Maculinea alcon
and two of its host
Myrmica
species, the more easily ant colonies were exploited. The geographic patterns of surface chemistry indicate an ongoing coevolutionary arms race between the butterflies and
Myrmica rubra
, which has significant genetic differentiation between populations, but not between the butterflies and a second, sympatric host,
Myrmica ruginodis
, which has panmictic populations. Alternative hosts may therefore provide an evolutionary refuge for a parasite during periods of counteradaptation by their preferred hosts.
Connecting Blazons and Neurons
Authors: Jones Caroline A.
Published: January 2008

Echo Objects
. The Cognitive Work of Images.
By Barbara Maria Stafford
. University of Chicago Press, Chicago, 2007. 307 pp. $45, £27. ISBN 9780226770512.

The author explores connections between the worlds of images and current neuroscience.
Identification of the Major Antigenic Protein of
Helicobacter cinaedi
and Its Immunogenicity in Humans with
H. cinaedi
Infections
Authors: Iwashita Hirofumi , Fujii Shigemoto , Kawamura Yoshiaki , Okamoto Tatsuya , Sawa Tomohiro , Masaki Takayuki , Nishizono Akira , Higashi Shuichi , Kitamura Toshio , Tamura Fumio , Sasaki Yutaka , Akaike Takaaki
Published: January 2008

Helicobacter cinaedi
infection is now recognized as an increasingly important emerging disease. Its pathogenesis and epidemiological features are not fully understood, however. Here, we investigated the antigenic protein of
H. cinaedi
and the immunological response to it in
H. cinaedi
-infected patients. We constructed a genomic library of
H. cinaedi
from an
H. cinaedi
clinical isolate, and various
H. cinaedi
recombinant proteins were expressed. We identified the 30-kDa protein, encoded in an 822-bp
H. cinaedi
genome, as a major antigen, which was specifically recognized by serum from an
H. cinaedi
-immunized rabbit and
H. cinaedi
-infected patients. The gene encoding this 30-kDa antigen had high sequence similarity with genes encoding putative membrane proteins of bacteria. To evaluate whether the 30-kDa protein can be applied in serological testing for
H. cinaedi
infections, the recombinant protein was expressed in
Escherichia coli
as a His-tagged fusion protein and purified by Ni
2+
affinity chromatography. Western blot analysis revealed strong immunoreactivity of the 31-kDa fusion protein with serum antibody from patients infected with
H. cinaedi
, but such an immunoreaction was absent or was very weak with uninfected control serum. An enzyme-linked immunosorbent assay using this
H. cinaedi
major antigen showed significantly high antibody titers for
H. cinaedi
-infected subjects compared with those of various control groups. We therefore conclude that the 30-kDa putative membrane protein is a major antigen of
H. cinaedi
and is useful for immunological and serological testing for clinical diagnosis and for further epidemiological study of
H. cinaedi
infection in humans.
Boron-Containing Functional Copolymers for Bioengineering Applications
Authors: Rzayev Zakir M. O. , Beşkardeş Oktay
Published: January 2008

This review summarizes the some advances and results of our recent investigations, outlining the synthesis, structural phenomena, unique properties and application areas of boron-containing bioengineering copolymers. Particular attention is paid to the effects of hydrogen bonding in copolymerization reactions of boron-containing monomers, and in formation of supramacromolecular structures, bioconjugates, physically and chemically crosslinkable copolymers, and other important bioengineering materials.
Application of Proteomics in Chinese Medicine Research
Authors: Cho William Chi-Shing
Published: January 2008

Proteomics technologies can be applied to simultaneously study the function, organization, diversity, and dynamic variety of a cell or a whole tissue. The integrative approach of proteomics is in line with the holistic concept and practices of traditional Chinese medicine (TCM). In this review, the technologies of proteomics, their adoption leverages the depth and breadth of TCM research are introduced. This article presents some examples to illustrate the use of proteomics technologies in the study of pharmacological effects and their action mechanisms relevant to TCM. Proteomics technologies could be used to screen the target molecules of the TCM actions, identify new bioactive components, and elucidate the underlying mechanisms of their effects. With proteomics approaches, it was found that the Siwu decoction could regulate the protein expression of the bone marrow of blood (Xue) deficient mice, including some proteins and enzymes involved in the hemopoiesis system. Ganoderma lucidum spores might promote the survival and axon regeneration of injured spinal motor neurons in rats by regulating the expression levels of proteins involved in the energy and tissue regeneration system. Polygonatum zanlanscianense Pamp exhibited cytotoxicity towards human myeloblast leukemia HL-60 cells through multiple apoptosis-including pathways. Panax ginseng might be beneficial to patients suffering from diabetes mellitus and its complications by alleviating inflammation. Taken together with a discussion on the challenges and perspectives, this paper provides an overview of the recent developments of proteomics technologies in TCM research, and contends that proteomics will play an important role in the modernization and internationalization of TCM.
Effects of Crude Rhubarb on Intestinal Permeability in Septic Patients
Authors: Fang Xue-Ling , Fang Qiang , Luo Jian-Jun , Zheng Xia
Published: January 2008

The therapeutic effect of crude rhubarb on intestinal permeability was investigated in septic patients. Forty septic patients were enrolled in this study and randomly divided into two groups: the crude rhubarb treatment group ( n = 18) and the control group ( n = 22). The same treatments were given to both groups except that the crude rhubarb treatment group was administrated with crude rhubarb powders (3 g, tid, p.o). The levels of procalcitonin, D-lactate in plasma and lactulose/mannitol (L/M) ratio in the urine were determined on the first day and the sixth day after treatment with or without crude rhubarb. There were no significant differences in procalcitonin, L/M ratio and D-lactate on the first day between the crude rhubarb treatment group and the control group ( p > 0.05). However, the ratio of L/M on the sixth day for the control group was 0.167 ± 0.036, while that of the crude rhubarb treatment group was 0.062 ± 0.013 ( p < 0.05). Moreover, the levels of procalcitonin and D-lactate in the crude rhubarb treatment group were obviously lower than those in the control group on the sixth day (procalcitonin: 4.11 ± 1.40 μg/L vs. 2.21 ± 0.61 μg/L ; D-lactate: 0.24 ± 0.06 ng/L vs. 0.09 ± 0.03 ng/L , p < 0.05, both). These data confirmed that crude rhubarb's effects on septic patients of ameliorating intestinal permeability.
CHEMICAL POTENTIAL AS A SOURCE OF STABILITY FOR GRAVITATING SKYRMIONS
Authors: LOEWE M. , MENDIZABAL S. , ROJAS J. C.
Published: January 2008

A discussion of the stability of self-gravitating Skyrmions, with a large winding number N, in a Schwarzschild type of metric, is presented for the case where an isospin chemical potential is introduced. It turns out that the chemical potential stabilizes the behavior of the Skyrmion discussed previously in the literature. This analysis is carried on in the framework of a variational approach using different ansatze for the radial profile of the Skyrmion. We found a divergent behavior for the size of the Skyrmion, associated to a certain critical value μc of the chemical potential. At this point, the mass of the Skyrmion vanishes. μc is essentially independent of gravitating effects. The stability of a large N skyrmion against decays into single particles is also discussed.
Entercation
Authors: Rey-Lopez Marta , Diaz-Redondo Rebeca P. , Fernandez-Vilas Ana , Pazos-Arias Jose J.
Published: January 2008

IDTV (interactive digital TV) opens new learning opportunities where new forms of education are needed. In order to gain the participation of viewers, and overcome their typical passivity, it is essential to combine education and entertainment. In this article we present a new concept in t-learning, called entercation experiences, where we use TV programs as a hook to engage users in education. The key element in this approach is an ontology for learning content based on the ADL SCORM (Sharable Content Object Reference Model) standard. We have developed this ontology so that we can choose the appropriate elements to construct entercation experiences, and thus provide learning personalization.
Web resources for language modeling in conversational speech recognition
Authors: Bulyko Ivan , Ostendorf Mari , Siu Manhung , Ng Tim , Stolcke Andreas , Çetin Özgür
Published: January 2008

This article describes a methodology for collecting text from the Web to match a target sublanguage both in style (register) and topic. Unlike other work that estimates n-gram statistics from page counts, the approach here is to select and filter documents, which provides more control over the type of material contributing to the n-gram counts. The data can be used in a variety of ways; here, the different sources are combined in two types of mixture models. Focusing on conversational speech where data collection can be quite costly, experiments demonstrate the positive impact of Web collections on several tasks with varying amounts of data, including Mandarin and English telephone conversations and English meetings and lectures.
Relation extraction and the influence of automatic named-entity recognition
Authors: Giuliano Claudio , Lavelli Alberto , Romano Lorenza
Published: January 2008

We present an approach for extracting relations between named entities from natural language documents. The approach is based solely on shallow linguistic processing, such as tokenization, sentence splitting, part-of-speech tagging, and lemmatization. It uses a combination of kernel functions to integrate two different information sources: (i) the whole sentence where the relation appears, and (ii) the local contexts around the interacting entities. We present the results of experiments on extracting five different types of relations from a dataset of newswire documents and show that each information source provides a useful contribution to the recognition task. Usually the combined kernel significantly increases the precision with respect to the basic kernels, sometimes at the cost of a slightly lower recall. Moreover, we performed a set of experiments to assess the influence of the accuracy of named-entity recognition on the performance of the relation-extraction algorithm. Such experiments were performed using both the correct named entities (i.e., those manually annotated in the corpus) and the noisy named entities (i.e., those produced by a machine learning-based named-entity recognizer). The results show that our approach significantly improves the previous results obtained on the same dataset.
Morph-based speech recognition and modeling of out-of-vocabulary words across languages
Authors: Creutz Mathias , Hirsimäki Teemu , Kurimo Mikko , Puurula Antti , Pylkkönen Janne , Siivola Vesa , Varjokallio Matti , Arisoy Ebru , Saraçlar Murat , Stolcke Andreas
Published: January 2008

We explore the use of morph-based language models in large-vocabulary continuous-speech recognition systems across four so-called morphologically rich languages: Finnish, Estonian, Turkish, and Egyptian Colloquial Arabic. The morphs are subword units discovered in an unsupervised, data-driven way using the
Morfessor
algorithm. By estimating
n
-gram language models over sequences of morphs instead of words, the quality of the language model is improved through better vocabulary coverage and reduced data sparsity. Standard word models suffer from high out-of-vocabulary (OOV) rates, whereas the morph models can recognize previously unseen word forms by concatenating morphs. It is shown that the morph models do perform fairly well on OOVs without compromising the recognition accuracy on in-vocabulary words. The Arabic experiment constitutes the only exception since here the standard word model outperforms the morph model. Differences in the datasets and the amount of data are discussed as a plausible explanation.
Using networked multimedia to improve educational access for deaf and hard of hearing students
Authors: Cavender Anna C.
Published: January 2008

Educational technology has the potential to better include deaf and hard of hearing students in the academic mainstream. This research involves development and testing of a classroom platform for deaf and hard of hearing students to access remote interpreters and captioners, avoid visual dispersion, and facilitate interaction in the classroom.
Enhancing accessibility through correction of speech recognition errors
Authors: Bell John-Mark
Published: January 2008

The learning within lectures of hearing-impaired students can be hindered by errors in captions generated by speech recognition. My research intends to address this problem by investigating ways of correcting these captions. I summarise approaches to automatic error correction and describe the preliminary studies that have been conducted. These studies show that human editors set a tough benchmark for automatic correction to meet and indicate that automatic correction is feasible. Finally, I summarise my intention to develop a correction framework that will permit quantitative and qualitative testing of correction methods.
Hard drive power consumption uncovered
Authors: Hylick Anthony , Rice Andrew , Jones Brian , Sohan Ripduman
Published: January 2008

Power consumption is a problem affecting all forms of computing, from server farms to mobile devices. Hard disks account for a significant percentage of a machine's power consumption due to the mechanical nature of drive operation and increasingly sophisticated electronics. Due to this fact, there has been much research conducted with aims at reducing the power consumption of hard drives; examples including adaptive spin-down policies [1] and probabilistic management approaches [4]. However, this work has been done without fine-grained measurements of drive power consumption to accurately characterize trends; a shortcoming observed by other authors [3].
Cellular Defenses against Superoxide and Hydrogen Peroxide
Authors: Imlay James A.
Published: January 2008

Life evolved in an anaerobic world; therefore, fundamental enzymatic mechanisms and biochemical pathways were refined and integrated into metabolism in the absence of any selective pressure to avoid reactivity with oxygen. After photosystem II appeared, environmental oxygen levels rose very slowly. During this time, microorganisms acquired oxygen tolerance by jettisoning enzymes that use glycyl radicals and exposed low-potential iron-sulfur clusters, which can be directly poisoned by oxygen. They also developed mechanisms to defend themselves against superoxide (O2−) and hydrogen peroxide, partially reduced oxygen species that are generated as inadvertent by-products of aerobic metabolism. Contemporary organisms have inherited both the vulnerabilities and the defenses of these ancestral microbes. Current research seeks to identify these, and bacteria comprise an exceptionally accessible experimental system that has provided many of the answers. This manuscript reviews recent developments and identifies remaining puzzles.
Spacecraft Observations of the Martian Atmosphere
Authors: Smith Michael D.
Published: January 2008

Recent spacecraft observations of the Martian atmosphere show that the current climate has a distinct and generally repeatable pattern of seasonal and spatial variations. The half of the year that Mars is closest to the Sun is characterized by warm, dusty conditions, whereas the opposite season is relatively cool, free of dust, and dominated by a low-latitude band of water ice clouds. Water vapor is most abundant at high latitudes in the summertime of both hemispheres, whereas a polar hood of clouds forms over the winter polar region. The greatest year-to-year variations are caused by intermittent large dust storms, which also affect atmospheric temperature and circulation patterns on a global scale.
Horizontal Convection
Authors: Hughes Graham O. , Griffiths Ross W.
Published: January 2008

Differential heating along one horizontal boundary of a fluid-filled volume establishes an overturning circulation (horizontal convection) in the volume. The governing dynamics in this type of convection are fundamentally different from those in other more commonly studied forms of convection in which the thermal forcing is applied at more than one level. The study of horizontal convection has been motivated largely by the need to understand the role of surface buoyancy forcing of the global oceans, and with this in mind we review a number of extensions to idealized convective flow in a simple box.
Some Applications of Magnetic Resonance Imaging in Fluid Mechanics: Complex Flows and Complex Fluids
Authors: Bonn Daniel , Rodts Stephane , Groenink Maarten , Rafaï Salima , Shahidzadeh-Bonn Noushine , Coussot Philippe
Published: January 2008

The review deals with applications of magnetic resonance imaging (MRI) techniques to study flow. We first briefly discuss the principles of flow measurement by MRI and give examples of some applications, such as multiphase flows, the MRI rheology of complex fluid flows, and blood flows in the human body.
Preparing the U.S. Health Community for Climate Change
Authors: Jackson Richard , Shields Kyra Naumoff
Published: January 2008

In society's effort to address and prepare for climate change, the health community itself must ensure that it is prepared. Health personnel will require flexible and iterative action plans to address climate change at the individual, hospital, local health department, state, and national levels. This requires that health workers analyze the impact of climate change with a view to human health, and then formulate robust policy and demonstrate authentic leadership. In this review, we summarize the status of the health community's preparation for climate change and provide specific recommendations for action at each level. Although preparation status and recommendations vary, our observation is that it is not enough for public health and medical care agencies and departments to develop policies and advocate change. They have a direct responsibility to demonstrate substantive leadership.
Comparison of hyperthermic hyperpnea elicited during rest and submaximal, moderate-intensity exercise
Authors: Fujii Naoto , Honda Yasushi , Hayashi Keiji , Soya Hideaki , Kondo Narihiko , Nishiyasu Takeshi
Published: January 2008

We tested the hypothesis that, in humans, hyperthermic hyperpnea elicited in resting subjects differs from that elicited during submaximal, moderate-intensity exercise. In the rest trial, hot-water legs-only immersion and a water-perfused suit were used to increase esophageal temperature (Tes) in 19 healthy male subjects; in the exercise trial, Tes was increased by prolonged submaximal cycling [50% peak O2 uptake (V̇o2)] in the heat (35°C). Minute ventilation (V̇e), ventilatory equivalent for V̇o2 (V̇e/V̇o2) and CO2 output (V̇e/V̇co2), tidal volume (Vt), and respiratory frequency (f) were plotted as functions of Tes. In the exercise trial, V̇e increased linearly with increases (from 37.0 to 38.7°C) in Tes in all subjects; in the rest trial, 14 of the 19 subjects showed a Tes threshold for hyperpnea (37.8 ± 0.5°C). Above the threshold for hyperpnea, the slope of the regression line relating V̇e and Tes was significantly greater for the rest than the exercise trial. Moreover, the slopes of the regression lines relating V̇e/V̇o2, V̇e/V̇co2, and Tes were significantly greater for the rest than the exercise trial. The increase in V̇e reflected increases in Vt and f in the rest trial, but only f in the exercise trial, after an initial increase in ventilation due to Vt. Finally, the slope of the regression line relating Tes and Vt or f was significantly greater for the rest than the exercise trial. These findings indicate that hyperthermic hyperpnea does indeed differ, depending on whether one is at rest or exercising at submaximal, moderate intensity.
A floxed allele of the androgen receptor gene causes hyperandrogenization in male mice
Authors: MacLean Helen E. , Chiu W. S. Maria , Ma Cathy , McManus Julie F. , Davey Rachel A. , Cameron Rhoda , Notini Amanda J. , Zajac Jeffrey D.
Published: January 2008

We previously generated a conditional floxed mouse line to study androgen action, in which exon 3 of the androgen receptor ( AR) gene is flanked by loxP sites, with the neomycin resistance gene present in intron 3. Deletion of exon 3 in global AR knockout mice causes androgen insensitivity syndrome, characterized by genotypic males lacking normal masculinization. We now report that male mice carrying the floxed allele (ARlox) have the reverse phenotype, termed hyperandrogenization. ARlox mice have increased mass of androgen-dependent tissues, including kidney, ( P < 0.001), seminal vesicle ( P < 0.001), levator ani muscle ( P = 0.001), and heart ( P < 0.05). Serum testosterone is not significantly different. Testis mass is normal, histology shows normal spermatogenesis, and ARlox males are fertile. ARlox males also have normal AR mRNA levels in kidney, brain, levator ani, liver, and testis. This study reaffirms the need to investigate the potential phenotypic effects of floxed alleles in the absence of cre in tissue-specific knockout studies. In addition, this androgen hypersensitivity model may be useful to further investigate the effects of subtle perturbations of androgen action in a range of androgen-responsive systems in the male.
A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment
Authors: Stearman Robert S. , Dwyer-Nield Lori , Grady Michael C. , Malkinson Alvin M. , Geraci Mark W.
Published: January 2008

One area of intensive investigation is to understand complex cellular and signaling interactions in the tumor microenvironment. Using a novel, although straightforward, microarray approach, we defined a gene expression signature from the lung tumor microenvironment in the murine A/J-urethane model of human lung adenocarcinoma. The tumor microenvironment is reflected by the composition of the cell types present and alterations in mRNA levels, resulting in a “Field Effect” around the tumor. The genes composing the Field Effect expression signature include proteases and their inhibitors, inflammation markers, and immune signaling molecules. By several criteria, the Field Effect expression signature can be attributed to the macrophage lineage, suggesting a qualitative change in the expression pattern of tumor-associated macrophages (TAM) observed in lung tumors. The protein expression levels for a number of Field Effect genes were verified by Western blot analysis of lung homogenates, and for their expression in macrophages and parenchymal cells outside of the tumors by immunohistochemistry. In addition, the Field Effect expression signature was used to classify bronchoalveolar lavage (BAL) cells from tumor-bearing or age-matched control mice. Using a variety of statistical measures, the Field Effect expression signature correctly classified the BAL cells >94% of the time. Finally, the protein levels for several Field Effect genes were higher in cell-free BAL fluid, indicating they may be secreted by the TAMs. This work suggests that TAMs generate a unique gene expression signature within the tumor microenvironment, and this signature could potentially be used for identifying lung cancer from BAL cells and/or fluid. [Cancer Res 2008;68(1):34–43]
Specific Genes Expressed in Association with Progesterone Receptors in Meningioma
Authors: Claus Elizabeth B. , Park Peter J. , Carroll Rona , Chan Jennifer , Black Peter M.
Published: January 2008

An association between hormones and meningioma has been postulated. No data exist that examine gene expression in meningioma by hormone receptor status. The data are surgical specimens from 31 meningioma patients undergoing neurosurgical resection at Brigham and Women's Hospital from March 15, 2004 to May 10, 2005. Progesterone and estrogen hormone receptors (PR and ER, respectively) were measured via immunohistochemistry and compared with gene expression profiling results. The sample is 77% female with a mean age of 55.7 years. Eighty percent were grade 1 and the mean MIB was 6.2, whereas 33% and 84% were ER+ and PR+, respectively. Gene expression seemed more strongly associated with PR status than with ER status. Genes on the long arm of chromosome 22 and near the neurofibromatosis type 2 (NF2) gene (22q12) were most frequently noted to have expression variation, with significant up-regulation in PR+ versus PR− lesions, suggesting a higher rate of 22q loss in PR− lesions. Pathway analyses indicated that genes in collagen and extracellular matrix pathways were most likely to be differentially expressed by PR status. These data, although preliminary, are the first to examine gene expression for meningioma cases by hormone receptor status and indicate a stronger association with PR than with ER status. PR status is related to the expression of genes near the NF2 gene, mutations in which have been identified as the initial event in many meningiomas. These findings suggest that PR status may be a clinical marker for genetic subgroups of meningioma and warrant further examination in a larger data set. [Cancer Res 2008;68(1):314–22]
CARM1 Regulates Estrogen-Stimulated Breast Cancer Growth through Up-regulation of E2F1
Authors: Frietze Seth , Lupien Mathieu , Silver Pamela A. , Brown Myles
Published: January 2008

Estrogen receptor α (ERα) mediates breast cancer proliferation through transcriptional mechanisms involving the recruitment of specific coregulator complexes to the promoters of cell cycle genes. The coactivator-associated arginine methyltransferase CARM1 is a positive regulator of ERα-mediated transcriptional activation. Here, we show that CARM1 is essential for estrogen-induced cell cycle progression in the MCF-7 breast cancer cell line. CARM1 is specifically required for the estrogen-induced expression of the critical cell cycle transcriptional regulator E2F1 whereas estrogen stimulation of cyclin D1 is CARM1 independent. Upon estrogen stimulation, the E2F1 promoter is subject to CARM1-dependent dimethylation on histone H3 arginine 17 (H3R17me2) in a process that parallels the recruitment of ERα. Additionally, we find that the recruitment of CARM1 and subsequent histone arginine dimethylation are dependent on the presence of the oncogenic coactivator AIB1. Thus, CARM1 is a critical factor in the pathway of estrogen-stimulated breast cancer growth downstream of ERα and AIB1 and upstream of the cell cycle regulatory transcription factor E2F1. These studies identify CARM1 as a potential new target in the treatment of estrogen-dependent breast cancer. [Cancer Res 2008;68(1):301–6]
Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion
Authors: Jagadeeswaran Ramasamy , Surawska Hanna , Krishnaswamy Soundararajan , Janamanchi Varalakshmi , Mackinnon A. Craig , Seiwert Tanguy Y. , Loganathan Sivakumar , Kanteti Rajani , Reichman Trevor , Nallasura Vidya , Schwartz Stuart , Faoro Leonardo , Wang Yi-Ching , Girard Luc , Tretiakova Maria S. , Ahmed Salman , Zumba Osvaldo , Soulii Lioubov , Bindokas Vytas P. , Szeto Livia L. , Gordon Gavin J. , Bueno Raphael , Sugarbaker David , Lingen Mark W. , Sattler Martin , Krausz Thomas , Vigneswaran Wickii , Natarajan Viswanathan , Minna John , Vokes Everett E. , Ferguson Mark K. , Husain Aliya N. , Salgia Ravi
Published: January 2008

Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer. [Cancer Res 2007;68(1):132–42]
Osteopontin Promotes Vascular Endothelial Growth Factor–Dependent Breast Tumor Growth and Angiogenesis via Autocrine and Paracrine Mechanisms
Authors: Chakraborty Goutam , Jain Shalini , Kundu Gopal C.
Published: January 2008

Angiogenesis is the hallmark of cancer, and development of aggressiveness of primary tumor depends on de novo angiogenesis. Here, using multiple in vitro and in vivo models, we report that osteopontin (OPN) triggers vascular endothelial growth factor (VEGF)–dependent tumor progression and angiogenesis by activating breast tumor kinase (Brk)/nuclear factor–inducing kinase/nuclear factor-κB (NF-κB)/activating transcription factor-4 (ATF-4) signaling cascades through autocrine and paracrine mechanisms in breast cancer system. Our results revealed that both exogenous and tumor-derived OPN play significant roles in VEGF-dependent tumor angiogenesis. Clinical specimen analysis showed that OPN and VEGF expressions correlate with levels of neuropilin-1, Brk, NF-κB, and ATF-4 in different grades of breast cancer. Consequently, OPN plays essential role in two key aspects of tumor progression: VEGF expression by tumor cells and VEGF-stimulated neovascularization. Thus, targeting OPN and its regulated signaling network could be a novel strategy to block tumor angiogenesis and may develop an effective therapeutic approach for the management of breast cancer. [Cancer Res 2008;68(1):152–61]
PAX5/TEL Acts as a Transcriptional Repressor Causing Down-modulation of CD19, Enhances Migration to CXCL12, and Confers Survival Advantage in pre-BI Cells
Authors: Fazio Grazia , Palmi Chiara , Rolink Antonius , Biondi Andrea , Cazzaniga Giovanni
Published: January 2008

PAX5 is a transcription factor essential for B-cell development. Recently, it has been found as a frequent target of aberrancies in childhood acute lymphoblastic leukemia (ALL; 30% of B cell ALL cases), showing monoallelic loss, point mutations, or chromosomal translocations. The role of these aberrancies is still poorly understood. We previously cloned the PAX5/TEL fusion gene in a patient affected by B-cell precursor ALL with a t(9;12) translocation. This is the first report investigating the molecular and functional roles of PAX5/TEL protein in vitro from murine wild-type pre-BI cells. We showed that PAX5/TEL protein acts as an aberrant transcription factor with repressor function, recruiting mSin3A, down-regulating B220, CD19, BLNK, MB-1, FLT3, and μ heavy chain expression, thus suggesting a block on B-cell differentiation. In a PAX5-deficient context, the presence of PAX5/TEL did not replace PAX5 functions. PAX5/TEL protein enhances cell migration towards CXCL12, with the overexpression of CXCR4. Moreover, the presence of the fusion gene overcomes interleukin-7 withdrawal and interferes with transforming growth factor-β1 pathway, inducing resistance and conferring cells an advantage in proliferation and survival. Thus, in vitro, the PAX5/TEL protein has a dominant effect on wild-type PAX5, interferes with the process of B-cell differentiation and migration, and induces resistance to apoptosis. Taken together, these phenomena likely represent key events in the process of B-cell transformation. [Cancer Res 2008;68(1):181–9]
Natriuretic Peptide Receptor A as a Novel Anticancer Target
Authors: Kong Xiaoyuan , Wang Xiaoqin , Xu Weidong , Behera Sumita , Hellermann Gary , Kumar Arun , Lockey Richard F. , Mohapatra Subhra , Mohapatra Shyam S.
Published: January 2008

The receptor for atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPRA), is expressed in cancer cells, and natriuretic peptides have been implicated in cancers. However, the direct role of NPRA signaling in tumorigenesis remains elusive. Here, we report that NPRA expression and signaling is important for tumor growth. NPRA-deficient mice showed significantly reduced antigen-induced pulmonary inflammation. NPRA deficiency also substantially protected C57BL/6 mice from lung, skin, and ovarian cancers. Furthermore, a nanoparticle-formulated interfering RNA for NPRA attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH2-terminal peptide of the ANP prohormone, which down-regulates NPRA expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. The antitumor activity of NP73-102 was in part attributed to apoptosis of tumor cells. Western blot and immunohistochemistry staining indicated that the transcription factor, nuclear factor-κB, was inactivated, whereas the level of tumor suppressor retinoblastoma protein was up-regulated in the lungs of NPRA-deficient mice. Furthermore, expression of vascular endothelial growth factor was down-regulated in the lungs of NPRA-deficient mice compared with that in wild-type mice. These results suggest that NPRA is involved in tumor angiogenesis and represents a new target for cancer therapy. [Cancer Res 2008;68(1):249–56]
Circulating Colony Stimulating Factor-1 and Breast Cancer Risk
Authors: Tamimi Rulla M. , Brugge Joan S. , Freedman Matthew L. , Miron Alexander , Iglehart J. Dirk , Colditz Graham A. , Hankinson Susan E.
Published: January 2008

Colony stimulating factor-1 (CSF1) and its receptor (CSF1-R) are important in mammary gland development and have been implicated in breast carcinogenesis. In a nested case-control study in the Nurses' Heath Study of 726 breast cancer cases diagnosed between June 1, 1992, and June 1, 1998, and 734 matched controls, we prospectively evaluated whether circulating levels of CSF1 (assessed in 1989–1990) are associated with breast cancer risk. The association varied by menopausal status (Pheterogeneity = 0.009). CSF1 levels in the highest quartile (versus lowest) were associated with an 85% reduced risk of premenopausal breast cancer [relative risk (RR), 0.15; 95% confidence interval (95% CI), 0.03–0.85; Ptrend = 0.02]. In contrast, CSF1 levels in the highest quartile conferred a 33% increased risk of postmenopausal breast cancer (RR, 1.33; 95% CI, 0.96–1.86; Ptrend = 0.11), with greatest risk for invasive (RR, 1.45; 95% CI, 1.02–2.07; Ptrend = 0.06) and ER+/PR+ tumors (RR, 1.72; 95% CI, 1.11–2.66; Ptrend = 0.04). Thus, the association of circulating CSF1 levels and breast cancer varies by menopausal status. [Cancer Res 2008;68(1):18–21]
Evaluation of Promoter Hypermethylation Detection in Body Fluids as a Screening/Diagnosis Tool for Head and Neck Squamous Cell Carcinoma
Authors: Carvalho André Lopes , Jeronimo Carmen , Kim Michael M. , Henrique Rui , Zhang Zhe , Hoque Mohammad O. , Chang Steve , Brait Mariana , Nayak Chetan S. , Jiang Wei-Wen , Claybourne Quia , Tokumaru Yutaka , Lee Juna , Goldenberg David , Garrett-Mayer Elizabeth , Goodman Steven , Moon Chul-so , Koch Wayne , Westra William H. , Sidransky David , Califano Joseph A.
Published: January 2008

Purpose: To evaluate aberrant promoter hypermethylation of candidate tumor suppressor genes as a means to detect epigenetic alterations specific to solid tumors, including head and neck squamous cell carcinoma (HNSCC).

Experimental Design: Using promoter regions identified via a candidate gene and discovery approach, we evaluated the ability of an expanded panel of CpG-rich promoters known to be differentially hypermethylated in HNSCC in detection of promoter hypermethylation in serum and salivary rinses associated with HNSCC. We did preliminary evaluation via quantitative methylation-specific PCR (Q-MSP) using a panel of 21 genes in a limited cohort of patients with HNSCC and normal controls. Using sensitivity and specificity for individual markers as criteria, we selected panels of eight and six genes, respectively, for use in salivary rinse and serum detection and tested these in an expanded cohort including up to 211 patients with HNSCC and 527 normal controls.

Results: Marker panels in salivary rinses showed improved detection when compared with single markers, including a panel with 35% sensitivity and 90% specificity and a panel with 85% sensitivity and 30% specificity. A similar pattern was noted in serum panels, including a panel with 84.5% specificity with 50.0% sensitivity and a panel with sensitivity of 81.0% with specificity of 43.5%. We also noted that serum and salivary rinse compartments showed a differential pattern of methylation in normal subjects that influenced the utility of individual markers.

Conclusions: Q-MSP detection of HNSCC in serum and salivary rinses using multiple targets offers improved performance when compared with single markers. Compartment-specific methylation in normal subjects affects the utility of Q-MSP detection strategies.
Phase I Pharmacokinetic/Pharmacodynamic Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Combination with Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in First-Line Treatment of Patients with Metastatic Colorectal Cancer
Authors: Folprecht Gunnar , Tabernero Josep , Köhne Claus-Henning , Zacharchuk Charles , Paz-Ares Luis , Rojo Federico , Quinn Susan , Casado Esther , Salazar Ramon , Abbas Richat , Lejeune Chantal , Marimón Irene , Andreu Jordi , Ubbelohde Ulrike , Cortes-Funes Hernan , Baselga Jose
Published: January 2008

Purpose: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC).

Methods: Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3). Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted.

Results: Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in >10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogen-activated protein kinase (MAPK) and induced p27 expression in the skin.

Conclusion: The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.
Combining Agents that Target the Tumor Microenvironment Improves the Efficacy of Anticancer Therapy
Authors: Blansfield Joseph A. , Caragacianu Diana , Alexander H. Richard , Tangrea Michael A. , Morita Shane Y. , Lorang Dominique , Schafer Peter , Muller George , Stirling David , Royal Richard E. , Libutti Steven K.
Published: January 2008

Purpose: Over the past 60 years, cytotoxic chemotherapy has targeted the cancer cell. Despite this, there have been few cancer cures. A new approach to cancer therapy is to target the multicellular biological entity of the tumor microenvironment.

Experimental Design: Lenalidomide, an immunomodulatory drug, sunitinib, a tyrosine kinase inhibitor, and low-dose metronomic cyclophosphamide, were tested alone and in combination for their abilities to inhibit endothelial cell tube formation, rat aortic ring outgrowth, tumor growth, and metastatic development in mice. In addition, ectopic tumor lysates were evaluated for the presence of proangiogenic proteins.

Results: The three agents alone were shown to significantly inhibit endothelial cells' ability to form tubes and significantly inhibit the multicellular microenvironment in the rat aortic ring assay (P < 0.01 and P < 0.001). This effect was also significantly augmented when the agents were combined. Furthermore, the three-drug combination was able halt the progression of tumor growth almost completely in xenograft models of ocular melanoma, colon cancer, pancreatic cancer, and cutaneous melanoma. These agents significantly decrease the number of proliferating cells in tumors, significantly increase the number of cells undergoing active cell death in tumors, and significantly decrease the number of blood vessels in treated tumors (P < 0.05). Combination therapy shows a decrease in the compensatory up-regulation of proangiogenic proteins after treatment when compared with single-agent therapy.

Conclusions: This combination of agents causes an inhospitable microenvironment for tumor cells and shows great promise for use in the clinic.