bluuebunny/crossref_metadata_2025 huggingface dataset:
RAMUS PUBIS INSUFFICIENCY FRACTURES AFTER TOTAL HIP ARTHROPLASTY: PHYSIOLOGICAL AND BIOMECHANICAL CONSIDERATIONS
Authors: Galit Nachoum , Tamar Brosh , Moshe Salai , Yehezkel Tytiun , Israel Dudkiewicz
Published: February 2009

Although uncommon, pubic ramus fractures are described in patients who have undergone total hip arthroplasty (THA). We describe two females with superior ramus pubis insufficiency fractures following THA. We consider the physiological and biomechanical aspects of those fractures, e.g. that the superior ramus pubis has the highest load stress on the pelvis (as has already been proved in a three-dimensional finite element model). Also being discussed are risk factors (intrinsic and extrinsic) for stress fractures and the management of insufficiency fractures. Both women suffered osteoporosis, obesity, and had a semisedentary lifestyle — all of which are known risks factors for insufficiency superior ramus pubis fracture to occur in a location which proved as a "weak link" zone after THA. Many of these fractures are undetected, mainly due to the lack of awareness of medical practitioners who attribute the clinical symptoms to other diseases; however, the differential diagnosis of groin pain within the first years following THA should include pubic ramus insufficiency fractures.
VALIDATION STUDY OF CADAVER RECTUS FEMORIS MUSCLE MEASUREMENT BY ULTRASONOGRAPHY AND ANATOMICAL PLANIMETRY
Authors: Weinrebe Wolfram , Stippler Dietmar , Doll Sara , Zahr Kurt , Jenetzky Ekkehart , Hader Claus , Füsgen Ingo , Adunsky Abraham
Published: February 2009

Ultrasonography is frequently used to measure the rectus femoris muscle cross-section area, and has been suggested to associate with poor health condition. However, no validation studies have been performed to compare rectus femoris muscle ultrasonography (RFMS) with anatomical planimetry when measuring the muscle cross-sectional area (CSA). This validation study compared the two methods of CSA measurement of unfixed (frozen) and fixed (unfrozen) rectus femoris muscle specimens obtained from elderly human cadavers. Agreement between tests was studied by Bland–Altman analysis. We found a significant difference between planimetry and RFMS of unfixed (frozen) muscle specimens (mean difference, -0.389 cm2; 95% CI, -0.144 to -0.634), p = 0.022. No significant difference was observed between the two methods when measuring fixed (unfrozen) muscle specimens (mean difference, 0.032 cm2, 95% CI, -0.007 to -0.070), p = 0.107. In fixed specimens, the 95% limit of agreement between the two methods ranged between 0.12 cm2 and -0.06 cm2 (<10% deviation); while in unfixed muscle specimens, the range was between 0.28 cm2 and -1.06 cm2 (~50% deviation). In light of the similar results obtained in fixed specimens, ultrasound is a safe and accurate method of rectus femoris muscle size assessment. In clinical practice, RFMS may be used to detect a decrease in rectus femoris muscle mass, typically associated with malnutrition of the elderly, and may therefore be a simple and practical tool for the screening of malnutrition.
RETENTION OF SCAFFOLD WITH STAPLE FIXATION FOR CARTILAGE REPAIR DURING CYCLIC MOTION OF HUMAN CADAVERIC KNEES
Authors: Zheng Naiquan , Lu Yiling , Boock Robert , Conrad Bryan , Binette Francois
Published: February 2009

Background: Adult articular cartilage has limited potential for healing. A new cell technology in which chondrocytes expanded in monolayer culture are transplanted into the cartilage defect of the knee has been introduced. A scaffold is used to hold tissue to the defect area while it heals. Methods: Sixteen paired, fresh-frozen cadaver knees were used. Full-thickness chondral defects of 2 cm × 3 cm were made on either medial or lateral femoral condyles. The scaffold, made of PGA/PLA foam reinforced by PDS mesh, was implanted into a prepared defect area using three or five PDS/PGA staples as the fixation approach. A custom-made fixation system was used to attach each knee to a material testing machine. Each knee was tested for 10 000 cycles at 1 Hz. Upon completion, knees were examined and rated on a semiquantitative scale for damage of the chondral and meniscal surfaces, and for wear and retention of the scaffold and staples. Findings: Implanted scaffolds were retained fully in defect spaces in all cases. No tearing or peeling of the scaffold was observed. The number of staples used for fixation did not influence the wear or retention of scaffolds and staples. Wearing to the adjacent cartilage or meniscal surfaces was undetectable. Results were similar, regardless of whether the scaffold was located in the medial or lateral condyle. No staple was found loose after 10 000 cycles. Interpretation: Three staples were adequate and five staples were feasible to hold the scaffold for a defect size of 2 cm × 3 cm during continuous passive motion.
LARGE DISPLACEMENT BEAM MODEL FOR CREEP BUCKLING ANALYSIS OF FRAMED STRUCTURES
Authors: TURKALJ GORAN , LANC DOMAGOJ , BRNIC JOSIP
Published: February 2009

In this work, a one-dimensional beam model for buckling analysis of framed structures under large displacement creep regimes is presented. The equilibrium equations of a prismatic and straight spatial beam element are formulated in the framework of corotational description, using the virtual work principle. Although the translations and rotations of the element are allowed to be large, the strains are assumed to be small. The material of a framed structure is assumed to be homogenous and isotropic. The bilinear elastic–plastic model with isotropic hardening and the power creep law are adopted for describing the inelastic behavior of the material. The numerical algorithm is implemented in a computer program called BMCA and its reliability is validated through test examples.
POSTBUCKLING OF LAMINATED SHELLS OF REVOLUTION WITH MERIDIONAL CURVATURE UNDER THERMAL AND MECHANICAL LOADS
Authors: SINGH S. , PATEL B. P. , Nath Y.
Published: February 2009

A study on the influence of meridional curvature on the buckling and postbuckling behavior of cross-ply laminated shells of revolution subjected to thermal and mechanical loads is carried out using the semianalytical finite element method. The nonlinear equations are solved using the Newton–Raphson iterative technique. The adaptive displacement control method is employed to trace the equilibrium path. Examined herein are the effects of positive and negative meridional curvature, the number of layers and the number of circumferential waves on the buckling/postbuckling behavior of cross-ply laminated, simply supported shells under thermal, external pressure, torsional and axial loadings. It is found that the critical load increases with the increase in the rise-to-radius ratio of positive meridional curvature shells for the loading cases considered. The critical temperature, torsional, axial loads decrease and the critical external pressure increases with increasing magnitude of the rise-to-radius ratio of negative meridional curvature shells. The postbuckling response of shells exposed to a uniform temperature rise is of a hardening nature for both positive and negative meridional curvature cases. Shells subjected to external pressure show a softening type of initial postbuckling response for positive meridional curvature, and a hardening type of postbuckling response for negative meridional curvature. The qualitative nature of postbuckling characteristics for torsional and axial loading cases may be softening, hardening or initially softening and later hardening, depending upon the combined influence of the rise-to-radius ratio, the number of circumferential waves and the number of layers.
FREQUENCIES OF A CIRCULAR PLATE WEAKENED ALONG AN INTERNAL CONCENTRIC CIRCLE
Authors: YU L. H.
Published: February 2009

A thin circular plate with a free or movable boundary, and weakened along an internal concentric circle, is considered. The frequencies of the circular plate varying with the radius of the weakened circle and the extent of the weakening represented by an elastic rotational restraint are determined. The results for the first four modes are tabulated. For the free plate, the internal weakening only slightly decreases the fundamental frequency of the plate, which is advantageous. For the plate with a movable edge, the internal weakening greatly decreases the fundamental frequency, especially for the purely hinged case.
CO-EXPRESSION AMONG CONSTITUENTS OF A MOTIF IN THE PROTEIN–PROTEIN INTERACTION NETWORK
Authors: BHARDWAJ NITIN , LU HUI
Published: February 2009

Almost all cellular functions are the results of well-coordinated interactions between various proteins. A more connected hub or motif in the interaction network is expected to be more important, and any perturbation in this motif would be more damaging to the smooth performance of the related functions. Thus, some coherent robustness of these hubs has to be derived. Here, we provide the global evidence that interaction hubs obtain their robustness against uneven protein concentrations through co-expression of the constituents, and that the degree of co-expression correlates strongly with the complexity of the embedded motif. We calculated the gene expression correlations between the proteins embedded in 3-, 4-, 5-, and 6-node interaction motifs of increasing complexities, and compared them to those between proteins from random motifs of similar complexities. We find that as the connectedness of these motifs increases, there is higher co-expression between the constituent proteins. For example, when the expression correlation is 0.7, the kernel density of the correlation increases from 0.152 for 4-node motifs with three edges to 0.403 for 4-node cliques. This implies that the robustness of the interaction system emerges from a proportionate synchronicity among the constituents of the motif via co-expression. We further show that such biological coherence via co-expression of component proteins can be reinforced by integrating conservation data in the analysis. For example, with addition of evolutionary information from other genomes, the ratio of kernel density for interaction and random data in the case of 5- and 6-node cliques in yeast increases from 37.8 to 123 and 98.4 to 1300, respectively, given that the expression correlation is 0.8. Our results show that genes whose products are involved in motifs have transcription and translation properties that minimize the noise in final protein concentrations, compared to random sets of genes.
ANALYZING MICROARRAY DATA WITH TRANSITIVE DIRECTED ACYCLIC GRAPHS
Authors: PHAN VINHTHUY , OLUSEGUN GEORGE E. , TRAN QUYNH T. , GOODWIN SHIRLEAN , BODREDDIGARI SRIDEVI , SUTTER THOMAS R.
Published: February 2009

Post hoc assignment of patterns determined by all pairwise comparisons in microarray experiments with multiple treatments has been proven to be useful in assessing treatment effects. We propose the usage of transitive directed acyclic graphs (tDAG) as the representation of these patterns and show that such representation can be useful in clustering treatment effects, annotating existing clustering methods, and analyzing sample sizes. Advantages of this approach include: (1) unique and descriptive meaning of each cluster in terms of how genes respond to all pairs of treatments; (2) insensitivity of the observed patterns to the number of genes analyzed; and (3) a combinatorial perspective to address the sample size problem by observing the rate of contractible tDAG as the number of replicates increases. The advantages and overall utility of the method in elaborating drug structure activity relationships are exemplified in a controlled study with real and simulated data.
CLUSTERING OF GENE EXPRESSION DATA AND END-POINT MEASUREMENTS BY SIMULATED ANNEALING
Authors: BUSHEL PIERRE R.
Published: February 2009

Most clustering techniques do not incorporate phenotypic data. Limited biological interpretation is garnered from the informal process of clustering biological samples and then labeling groups with the phenotypes of the samples. A more formal approach of clustering samples is presented. The method utilizes simulated annealing of the Modk-prototypes objective function. Separate weighting terms are used for microarray, clinical chemistry, and histopathology measurements to control the influence of each data domain on the clustering of the samples. The weights are adapted during the clustering process. A cluster's prototype is representative of the phenotype of the cluster members. Genes are extracted from phenotypic prototypes obtained from the livers of rats exposed to acetaminophen (an analgesic and antipyretic agent) that differed in the extent of centrilobular necrosis. Map kinase signaling and linoleic acid metabolism were significant biological processes influenced by the exposures of acetaminophen that manifested centrilobular necrosis.
TELEPORTATION OF AN ARBITRARY AND UNKNOWN JOSEPHSON CHARGE-QUBIT ENTANGLED STATE VIA A CLUSTER STATE
Authors: WU BO , LI DA-CHUANG , DAI HONG
Published: February 2009

An experimentally feasible scheme for teleporting an arbitrary and unknown entangled state is proposed. In this paper, we use a cluster state as the quantum channel, and we do not need any joint Bell-state measurement (BSM). Our scheme is based on Josephson charge qubits, and the successful probability and fidelity of teleportation can both reach unity. Moreover, the current scheme can be realized within the current experimental technology.
DIFFERENT CLASSES OF QUANTUM GATES ENTANGLERS FOR MULTIPARTITE STATES
Authors: HEYDARI HOSHANG
Published: February 2009

We construct quantum gates entanglers for different classes of multipartite states. In particular, we construct entangler operators for W and GHZ classes of multipartite states based on the construction of the concurrence classes. We also discuss in detail these two classes of the quantum gates entanglers for three-partite states.
TRIPARTITION OF ARBITRARY SINGLE-QUBIT QUANTUM INFORMATION BY USING ASYMMETRIC FOUR-QUBIT W STATE
Authors: LIU YI-MIN , YIN XIAO-FENG , ZHANG WEN , ZHANG ZHAN-JUN
Published: February 2009

In this paper we propose a four-party scheme for a sender to achieve the tripartition of his/her arbitrary single-qubit quantum information among three recipients via an asymmetric four-qubit W state as quantum channels. In the scheme, if and only if, the three recipients cooperate together, they can perfectly retrieve the sender's quantum information by performing first two 2-qubit collective unitary operations and then a single-qubit unitary operation. The scheme is symmetric with respect to the reconstruction for any recipient can conclusively recover the quantum information with the other two's helps.
SOME NEW HORIZONS IN RECORDING THE EEG
Authors: PRIBRAM KARL H.
Published: February 2009

The advent of multiple electrode recording, dense arrays and mathematical techniques such as non-linear dynamics has invigorated brain electrical recording techniques. Taking advantage of the excellent temporal resolution of the EEG, this summary review details several innovations, concentrating on (1) the rapid changes in electrical activity and a consequent stable complex pattern; and (2) the utilization of engineering techniques that have been applied across scales ranging upward from quantum physics. The implications for brain localization and for communication science are developed.
ATTRACTORS IN SONG
Authors: FRISTON KARL , KIEBEL STEFAN
Published: February 2009

This paper summarizes our recent attempts to integrate action and perception within a single optimization framework. We start with a statistical formulation of Helmholtz's ideas about neural energy to furnish a model of perceptual inference and learning that can explain a remarkable range of neurobiological facts. Using constructs from statistical physics it can be shown that the problems of inferring the causes of our sensory inputs and learning regularities in the sensorium can be resolved using exactly the same principles. Furthermore, inference and learning can proceed in a biologically plausible fashion. The ensuing scheme rests on Empirical Bayes and hierarchical models of how sensory information is generated. The use of hierarchical models enables the brain to construct prior expectations in a dynamic and context-sensitive fashion. This scheme provides a principled way to understand many aspects of the brain's organization and responses. We will demonstrate the brain-like dynamics that this scheme entails by using models of birdsongs that are based on chaotic attractors with autonomous dynamics. This provides a nice example of how non-linear dynamics can be exploited by the brain to represent and predict dynamics in the environment.
INDUCTION OF CLASSIFIERS THROUGH NON-PARAMETRIC METHODS FOR APPROXIMATE CLASSIFICATION AND RETRIEVAL WITH ONTOLOGIES
Authors: FANIZZI NICOLA , D'AMATO CLAUDIA , ESPOSITO FLORIANA
Published: February 2009

This work concerns non-parametric approaches for statistical learning applied to the standard knowledge representation languages adopted in the Semantic Web context. We present methods based on epistemic inference that are able to elicit and exploit the semantic similarity of individuals in OWL knowledge bases. Specifically, a totally semantic and language-independent semi-distance function is introduced, whence also an epistemic kernel function for Semantic Web representations is derived. Both the measure and the kernel function are embedded in non-parametric statistical learning algorithms customized for coping with Semantic Web representations. Particularly, the measure is embedded in a k-Nearest Neighbor algorithm and the kernel function is embedded in a Support Vector Machine. The implemented algorithms are used to perform inductive concept retrieval and query answering. An experimentation on real ontologies proves that the methods can be effectively employed for performing the target tasks, and moreover that it is possible to induce new assertions that are not logically derivable.
IMPROVING WORD SENSE DISAMBIGUATION WITH AUTOMATICALLY RETRIEVED SEMANTIC KNOWLEDGE
Authors: DLIGACH DMITRIY , PALMER MARTHA
Published: February 2009

Word Sense Disambiguation (WSD) is an important problem in Natural Language Processing. Supervised WSD involves assigning a sense from some sense inventory to each occurrence of an ambiguous word. Verb sense distinctions often depend on the distinctions in the semantics of the target verb's arguments. Therefore, some method of capturing their semantics is crucial to the success of a VSD system. In this paper we propose a novel approach to encoding the semantics of the noun arguments of a verb. This approach involves extracting various semantic properties of that verb from a large text corpus. We contrast our approach with the traditional methods and show that it performs better while the only resources it requires are a large corpus and a dependency parser.
DESIGN AND FABRICATION OF HIGH-PERFORMANCE INFRARED HOLLOW FIBER FOR MEDICAL LASER POWER DELIVERY
Authors: SHI YI-WEI , ZHU XIAO-SONG , SUI KE-RONG , TANG XIAO-LI
Published: February 2009

We proposed a method to evaluate the material dispersion of the dielectric film in dielectric-coated silver hollow fiber. By taking into consideration the derived material dispersion, the wavelengths of the loss peaks and valleys in the loss spectra of the hollow fiber can be predicted more accurately. Then, we fabricated the dielectric-coated silver hollow fiber according to the parameters obtained by using the improved design method. The measured data showed good agreement with the calculated results. The loss for medical laser of Er :YAG and CO 2 was less than 0.3 dB/m. The loss for green or red pilot beams was around 5 dB/m, which is sufficiently low for the purpose of pilot beam transmission. The derived material dispersion plays an important role in the design and fabrication of the hollow fiber for multiwavelength delivery.
Role of adipocyte-derived apoE in modulating adipocyte size, lipid metabolism, and gene expression in vivo
Authors: Huang Zhi Hua , Gu DeSheng , Mazzone Theodore
Published: February 2009

Adipocytes isolated from apolipoprotein E (apoE)-knockout (EKO) mice display alterations in triglyceride (TG) metabolism and gene expression. The present studies were undertaken to evaluate the impact of endogenously produced adipocyte apoE on these adipocyte parameters in vivo, independent of the profoundly disturbed metabolic milieu of EKO mice. Adipose tissue from wild-type (WT) or EKO mice was transplanted into WT recipients, which were then fed chow or high-fat diet for 8–10 wk. After a chow diet, freshly isolated transplanted EKO adipocytes were significantly ( P < 0.05) smaller (70%) than transplanted WT adipocytes and displayed significantly lower rates of TG synthesis and higher rates of TG hydrolysis. Transplanted EKO adipocytes also had higher mRNA levels for adiponectin, perilipin, and genes coding for enzymes in the fatty acid oxidation pathway and lower levels of caveolin. After a high-fat diet and consequent increase in circulating lipid and apoE levels, transplanted WT adipocyte size increased by 106 × 103μm3, whereas EKO adipocyte size increased only by 19 × 103μm3. Endogenous host adipose tissue harvested from WT recipients of transplanted WT or EKO adipose tissue did not demonstrate any difference in adipocyte size. Consistent with the in vivo observations, EKO adipocytes synthesized less TG when incubated with apoE-containing TG-rich lipoproteins than WT adipocytes. Our results establish a novel in vivo role for endogenously produced apoE, distinct from circulating apoE, in modulation of adipocyte TG metabolism and gene expression. They support a model in which endogenously produced adipocyte apoE facilitates adipocyte lipid acquisition from circulating TG-rich lipoproteins.
Area Spt in the Human Planum Temporale Supports Sensory-Motor Integration for Speech Processing
Authors: Hickok Gregory , Okada Kayoko , Serences John T.
Published: February 2009

Processing incoming sensory information and transforming this input into appropriate motor responses is a critical and ongoing aspect of our moment-to-moment interaction with the environment. While the neural mechanisms in the posterior parietal cortex (PPC) that support the transformation of sensory inputs into simple eye or limb movements has received a great deal of empirical attention—in part because these processes are easy to study in nonhuman primates—little work has been done on sensory-motor transformations in the domain of speech. Here we used functional magnetic resonance imaging and multivariate analysis techniques to demonstrate that a region of the planum temporale (Spt) shows distinct spatial activation patterns during sensory and motor aspects of a speech task. This result suggests that just as the PPC supports sensorimotor integration for eye and limb movements, area Spt forms part of a sensory-motor integration circuit for the vocal tract.
Neural Representations of Faces and Body Parts in Macaque and Human Cortex: A Comparative fMRI Study
Authors: Pinsk Mark A. , Arcaro Michael , Weiner Kevin S. , Kalkus Jan F. , Inati Souheil J. , Gross Charles G. , Kastner Sabine
Published: February 2009

Single-cell studies in the macaque have reported selective neural responses evoked by visual presentations of faces and bodies. Consistent with these findings, functional magnetic resonance imaging studies in humans and monkeys indicate that regions in temporal cortex respond preferentially to faces and bodies. However, it is not clear how these areas correspond across the two species. Here, we directly compared category-selective areas in macaques and humans using virtually identical techniques. In the macaque, several face- and body part–selective areas were found located along the superior temporal sulcus (STS) and middle temporal gyrus (MTG). In the human, similar to previous studies, face-selective areas were found in ventral occipital and temporal cortex and an additional face-selective area was found in the anterior temporal cortex. Face-selective areas were also found in lateral temporal cortex, including the previously reported posterior STS area. Body part–selective areas were identified in the human fusiform gyrus and lateral occipitotemporal cortex. In a first experiment, both monkey and human subjects were presented with pictures of faces, body parts, foods, scenes, and man-made objects, to examine the response profiles of each category-selective area to the five stimulus types. In a second experiment, face processing was examined by presenting upright and inverted faces. By comparing the responses and spatial relationships of the areas, we propose potential correspondences across species. Adjacent and overlapping areas in the macaque anterior STS/MTG responded strongly to both faces and body parts, similar to areas in the human fusiform gyrus and posterior STS. Furthermore, face-selective areas on the ventral bank of the STS/MTG discriminated both upright and inverted faces from objects, similar to areas in the human ventral temporal cortex. Overall, our findings demonstrate commonalities and differences in the wide-scale brain organization between the two species and provide an initial step toward establishing functionally homologous category-selective areas.
The Spatiotemporal Oscillations of Order Parameter for Isothermal Model of the Surface-Directed Spinodal Decomposition in Bounded Binary Mixtures
Authors: Krasnyuk Igor B. , Taranets Roman M.
Published: February 2009

The asymptotical behavior of order parameter in confined binary mixture is considered in one-dimensional geometry. The interaction between bulk and surface forces in the mixture is investigated. Its established conditions are when the bulk spinodal decomposition may be ignored and when the main role in the process of formation of the oscillating asymptotic periodic spatiotemporal structures plays the surface-directed spinodal decomposition which is modelled by nonlinear dynamical boundary conditions.
Novel Microtubule Polymerization Inhibitor with Potent Antiproliferative and Antitumor Activity
Authors: Arora Sonia , Wang Xin I. , Keenan Susan M. , Andaya Christina , Zhang Qiang , Peng Youyi , Welsh William J.
Published: February 2009

Microtubule-stabilizing and microtubule-destabilizing agents are commonly used as anticancer agents. Although highly effective, success with these agents has been limited due to their relative insolubility, cumbersome synthesis/purification, toxic side effects, and development of multidrug resistance. Hence, the identification of improved agents that circumvent one or more of these problems is warranted. We recently described the rational design of a series of triazole-based compounds as antimitotic agents. Members of this N-substituted 1,2,4-triazole family of compounds exhibit potent tubulin polymerization inhibition and broad spectrum cellular cytotoxicity. Here, we extensively characterize the in vitro and in vivo effects of our lead compound from the series 1-methyl-5-(3-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-4-yl)-1H-indole, designated T115. We show that T115 competes with colchicine for its binding pocket in tubulin, produces robust inhibition of tubulin polymerization, and disrupts the microtubule network system inside the cells. In addition, T115 arrests human cancer cells in the G2-M phase of cell cycling, a hallmark of microtubule destabilizing drugs. T115 also inhibits cell viability of several cancer cell lines, including multidrug-resistant cell lines, in the low nanomolar range. No cytotoxicity was observed by T115 against normal human skin fibroblasts cell lines, and acute toxicity studies in normal nontumor-bearing mice indicated that T115 is well-tolerated in vivo (maximum total tolerated dose, 400 mg/kg). In a mouse xenograft model using human colorectal (HT-29) and prostate (PC3) cancer cells, T115 significantly inhibited tumor growth when administered i.p. Taken together, our results suggest that T115 is a potential drug candidate for cancer chemotherapy. [Cancer Res 2009;69(5):1910–5]
The β-Catenin Axis Integrates Multiple Signals Downstream from RET/Papillary Thyroid Carcinoma Leading to Cell Proliferation
Authors: Castellone Maria Domenica , De Falco Valentina , Rao Deva Magendra , Bellelli Roberto , Muthu Magesh , Basolo Fulvio , Fusco Alfredo , Gutkind J. Silvio , Santoro Massimo
Published: February 2009

RET/papillary thyroid carcinoma (RET/PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC stimulates the β-catenin pathway. By stimulating PI3K/AKT and Ras/extracellular signal–regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3β (GSK3β) phosphorylation, thereby reducing GSK3β-mediated NH2-terminal β-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with β-catenin and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)β-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3β complex and activates the transcription factor T-cell factor/lymphoid enhancer factor. Moreover, through the ERK pathway, RET/PTC stimulates cyclic AMP–responsive element binding protein (CREB) phosphorylation and promotes the formation of a β-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing β-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC–expressing cells. Silencing of β-catenin by small interfering RNA inhibits proliferation of RET/PTC–transformed PC Cl3 thyrocytes, whereas a constitutively active form of β-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on β-catenin to stimulate cell proliferation. [Cancer Res 2009;69(5):1867–76]
Overexpression of the Cellular DEK Protein Promotes Epithelial Transformation In vitro and In vivo
Authors: Wise-Draper Trisha M. , Mintz-Cole Rachael A. , Morris Teresa A. , Simpson David S. , Wikenheiser-Brokamp Kathryn A. , Currier Mark A. , Cripe Timothy P. , Grosveld Gerard C. , Wells Susanne I.
Published: February 2009

High levels of expression of the human DEK gene have been correlated with numerous human malignancies. Intracellular DEK functions have been described in vitro and include DNA supercoiling, DNA replication, RNA splicing, and transcription. We have shown that DEK also suppresses cellular senescence, apoptosis, and differentiation, thus promoting cell growth and survival in monolayer and organotypic epithelial raft models. Such functions are likely to contribute to cancer, but direct evidence to implicate DEK as an oncogene has remained elusive. Here, we show that in line with an early role in tumorigenesis, murine papilloma formation in a classical chemical carcinogenesis model was reduced in DEK knockout mice. Additionally, human papillomavirus E6/E7, hRas, and DEK cooperated in the transformation of keratinocytes in soft agar and xenograft establishment, thus also implicating DEK in tumor promotion at later stages. Finally, adenoviral DEK depletion via short hairpin RNA expression resulted in cell death in human tumor cells in vitro and in vivo, but did not significantly affect differentiated epithelial cells. Taken together, our data uncover oncogenic DEK activities as postulated from its frequent up-regulation in human malignancies, and suggest that the targeted suppression of DEK may become a strategic approach to the treatment of cancer. [Cancer Res 2009;69(5):1792–9]
Silencing of TMS1/ASC Promotes Resistance to Anoikis in Breast Epithelial Cells
Authors: Parsons Melissa J. , Patel Pritty , Brat Daniel J. , Colbert Laronna , Vertino Paula M.
Published: February 2009

Ductal carcinoma in situ (DCIS) is characterized by ductal epithelial cells that have filled the luminal space of the breast duct and survive despite loss of extracellular matrix contact. In normal epithelial cells, the loss of such contact triggers a form of apoptosis known as detachment-induced apoptosis or “anoikis.” TMS1/ASC is a bipartite adaptor molecule that participates in inflammatory and apoptotic signaling pathways. Epigenetic silencing of TMS1 has been observed in a significant proportion of human breast and other cancers, but the mechanism by which TMS1 silencing contributes to carcinogenesis is unknown. Here, we examined the role of TMS1 in anoikis. We found that TMS1 expression is induced in response to loss of substratum interactions in breast epithelial cells. siRNA-mediated knockdown of TMS1 leads to anoikis resistance, due in part to the persistent activation of extracellular signal-regulated kinase and an impaired ability to up-regulate the BH3-only protein Bim. We further show that the detachment-induced cleavage of procaspase-8, a newly described mediator of cellular adhesion, is significantly inhibited in the absence of TMS1. These data show a novel upstream role for TMS1 in the promotion of anoikis, and suggest that silencing of TMS1 may contribute to the pathogenesis of breast cancer by allowing epithelial cells to bypass cell death in the early stages of breast cancer development. This conclusion is supported by in vivo data showing that TMS1 is selectively down-regulated in the aberrant epithelial cells filling the lumen of the breast duct in a subset of primary DCIS lesions. [Cancer Res 2009;69(5):1706–11]
Sulforaphane Inhibits Prostate Carcinogenesis and Pulmonary Metastasis in TRAMP Mice in Association with Increased Cytotoxicity of Natural Killer Cells
Authors: Singh Shivendra V. , Warin Renaud , Xiao Dong , Powolny Anna A. , Stan Silvia D. , Arlotti Julie A. , Zeng Yan , Hahm Eun-Ryeong , Marynowski Stanley W. , Bommareddy Ajay , Desai Dhimant , Amin Shantu , Parise Robert A. , Beumer Jan H. , Chambers William H.
Published: February 2009

The present study shows that oral gavage of 6 μmol d,l-sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L isomer, thrice per week beginning at 6 weeks of age, significantly inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice without causing any side effects. The incidence of the prostatic intraepithelial neoplasia and well-differentiated (WD) carcinoma were ∼23% to 28% lower (P < 0.05 compared with control by Mann-Whitney test) in the dorsolateral prostate (DLP) of SFN-treated mice compared with controls, which was not due to the suppression of T-antigen expression. The area occupied by the WD carcinoma was also ∼44% lower in the DLP of SFN-treated mice relative to that of control mice (P = 0.0011 by Mann Whitney test). Strikingly, the SFN-treated mice exhibited ∼50% and 63% decrease, respectively, in pulmonary metastasis incidence and multiplicity compared with control mice (P < 0.05 by t test). The DLP from SFN-treated mice showed decreased cellular proliferation and increased apoptosis when compared with that from control mice. Additionally, SFN administration enhanced cytotoxicity of cocultures of natural killer (NK) cells and dendritic cells (DC) against TRAMP-C1 target cells, which correlated with infiltration of T cells in the neoplastic lesions and increased levels of interleukin-12 production by the DC. In conclusion, the results of the present study indicate that SFN administration inhibits prostate cancer progression and pulmonary metastasis in TRAMP mice by reducing cell proliferation and augmenting NK cell lytic activity. [Cancer Res 2009;69(5):2117–25]
Polymorphisms in the Vitamin D Receptor and Risk of Ovarian Cancer in Four Studies
Authors: Tworoger Shelley S. , Gate Margaret A. , Lee I-Min , Buring Julie E. , Titus-Ernstoff Linda , Cramer Daniel , Hankinson Susan E.
Published: February 2009

Prior studies have suggested that vitamin D may reduce ovarian cancer risk. Thus, we examined whether three single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene (Fok1, Bsm1, Cdx2) were associated with risk of epithelial ovarian cancer in a retrospective case-control study (New England Case-Control study, NECC) and a nested case-control study of three prospective cohort studies: the Nurses' Health Study (NHS), NHSII, and the Women's Health Study. Data from the cohort studies were combined and analyzed using conditional logistic regression and pooled with the results from the NECC, which were analyzed using unconditional logistic regression, using a random effects model. We obtained genotype data for 1,473 cases and 2,006 controls. We observed a significant positive association between the number of Fok1 f alleles and ovarian cancer risk in the pooled analysis (Ptrend = 0.03). The odds ratio (OR) for the ff versus FF genotype was 1.26 [95% confidence interval (CI) = 1.01–1.57]. Neither the Bsm1 (Ptrend = 0.96) or Cdx2 (Ptrend = 0.13) SNPs were significantly associated with ovarian cancer risk. Among the prospective studies, the risk of ovarian cancer by plasma vitamin D levels did not clearly vary by any of the genotypes. For example, among women with the Fok1 FF genotype, the OR comparing plasma 25-hydroxyvitamin D ≥32 ng/mL versus <32 ng/mL was 0.66 (95% CI, 0.34–1.28), and among women with the Ff or ff genotype the OR was 0.71 (95% CI, 0.43–1.18). Our results of an association with the Fok1 VDR polymorphism further support a role of the vitamin D pathway in ovarian carcinogenesis. [Cancer Res 2009;69(5):1885–91]
Hepatocyte Growth Factor Activator Inhibitor Type 1 Regulates Epithelial to Mesenchymal Transition through Membrane-Bound Serine Proteinases
Authors: Cheng Haixia , Fukushima Tsuyoshi , Takahashi Nobuyasu , Tanaka Hiroyuki , Kataoka Hiroaki
Published: February 2009

Hepatocyte growth factor activator inhibitor-1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-associated proteinase inhibitor that potently inhibits a variety of serine proteinases, including those that are membrane bound. Although HAI-1/SPINT1 is widely expressed by epithelial cells and cancer cells, its functional role is still unclear, particularly in cancer. Here, we show that stable knockdown of HAI-1/SPINT1 in the human pancreatic cancer cell line SUIT-2 induces an elongated spindle-like morphology associated with accelerated invasion, thereby mimicking an epithelial to mesenchymal transition (EMT). We found that HAI-1/SPINT1 knockdown significantly reduced the expression of E-cadherin and was accompanied by up-regulation of Smad-interacting protein 1 (SIP1), an E-cadherin transcriptional repressor. In addition, matrix metalloproteinase-9 (MMP-9) was up-regulated. Similar results were obtained in the HLC-1 lung carcinoma cell line. Moreover, a metastatic variant of SUIT-2 (S2-CP8) that showed loss of E-cadherin expression also showed a significantly reduced level of HAI-1/SPINT1. Engineered overexpression of HAI-1/SPINT1 in S2-CP8 resulted in reversion of E-cadherin expression and SIP1 down-regulation, which accompanied reestablishment of epithelial morphology in culture. The EMT caused by HAI-1/SPINT1 knockdown seemed to be mediated, at least partly, by membrane-bound serine proteinases, matriptase/ST14 and TMPRSS4, as knockdown of matriptase/ST14 or TMPRSS4 in HAI-1/SPINT1 knockdown SUIT-2 cells and HLC-1 cells resulted in reversion of SIP1 and/or MMP-9 expression levels. We suggest that interactions between HAI-1/SPINT1 and membrane-bound serine proteinases contribute to transcriptional and functional changes involved in EMT in certain carcinoma cells. [Cancer Res 2009;69(5):1828–35]
Dysfunctional Microvasculature as a Consequence of Shb Gene Inactivation Causes Impaired Tumor Growth
Authors: Funa Nina S. , Kriz Vitezslav , Zang Guangxiang , Calounova Gabriela , Åkerblom Björn , Mares Jaroslav , Larsson Erik , Sun Ying , Betsholtz Christer , Welsh Michael
Published: February 2009

Shb (Src homology 2 protein B) is an adapter protein downstream of the vascular endothelial growth factor receptor receptor-2 (VEGFR-2). Previous experiments have suggested a role for Shb in endothelial cell function. Recently, the Shb gene was inactivated and Shb null mice were obtained on a mixed genetic background, but not on C57Bl6 mice. The present study was performed to address endothelial function in the Shb knockout mouse and its relevance for tumor angiogenesis. Tumor growth was retarded in Shb mutant mice, and this correlated with decreased angiogenesis both in tumors and in Matrigel plugs. Shb null mice display an abnormal endothelial ultrastructure in liver sinusoids and heart capillaries with cytoplasmic extensions projecting toward the lumen. Shb null heart VE-cadherin staining was less distinct than that of control heart, exhibiting in the former case a wavy and punctuate pattern. Experiments on isolated endothelial cells suggest that these changes could partly reflect cytoskeletal abnormalities. Vascular permeability was increased in Shb null mice in heart, kidney, and skin, whereas VEGF-stimulated vascular permeability was reduced in Shb null mice. It is concluded that Shb plays an important role in maintaining a functional vasculature in adult mice, and that interference with Shb signaling may provide novel means to regulate tumor angiogenesis. [Cancer Res 2009;69(5):2141–8]
Oral Cancer Diagnosis by Mechanical Phenotyping
Authors: Remmerbach Torsten W. , Wottawah Falk , Dietrich Julia , Lincoln Bryan , Wittekind Christian , Guck Jochen
Published: February 2009

Oral squamous cell carcinomas are among the 10 most common cancers and have a 50% lethality rate after 5 years. Despite easy access to the oral cavity for cancer screening, the main limitations to successful treatment are uncertain prognostic criteria for (pre-)malignant lesions. Identifying a functional cellular marker may represent a significant improvement for diagnosis and treatment. Toward this goal, mechanical phenotyping of individual cells is a novel approach to detect cytoskeletal changes, which are diagnostic for malignant change. The compliance of cells from cell lines and primary samples of healthy donors and cancer patients was measured using a microfluidic optical stretcher. Cancer cells showed significantly different mechanical behavior, with a higher mean deformability and increased variance. Cancer cells (n ≈ 30 cells measured from each patient) were on average 3.5 times more compliant than those of healthy donors [Dnormal = (4.43 ± 0.68) 10−3 Pa−1; Dcancer = (15.8 ± 1.5) 10−3 Pa−1; P < 0.01]. The diagnosis results of the patient samples were confirmed by standard histopathology. The generality of these findings was supported by measurements of two normal and four cancer oral epithelial cell lines. Our results indicate that mechanical phenotyping is a sensible, label-free approach for classifying cancer cells to enable broad screening of suspicious lesions in the oral cavity. It could in principle be applied to any cancer to aid conventional diagnostic procedures. [Cancer Res 2009;69(5):1728–32]
CpG Island Methylator Phenotype Predicts Progression of Malignant Melanoma
Authors: Tanemura Atsushi , Terando Alicia M. , Sim Myung-Shin , van Hoesel Anneke Q. , de Maat Michiel F.G. , Morton Donald L. , Hoon Dave S.B.
Published: February 2009

Purpose: The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci. These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression.

Experimental Design: The methylation status of the CpG island promoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARβ2, SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, and MINT31) in primary and metastatic tumors of different clinical stages (n = 122) was assessed.

Results: Here, we show an increase in hypermethylation of the TRGs WIF1, TFPI2, RASSF1A, and SOCS1 with advancing clinical tumor stage. Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31 is associated with disease outcome in stage III melanoma.

Conclusions: These findings show the significance of a CIMP pattern that is associated with advancing clinical stage of malignant melanoma. Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence.
Phospho-p70S6K/p85S6K and cdc2/cdk1 Are Novel Targets for Diffuse Large B-Cell Lymphoma Combination Therapy
Authors: Zhao Merry Y. , Auerbach Aaron , D'Costa Anisha M. , Rapoport Aaron P. , Burger Angelika M. , Sausville Edward A. , Stass Sanford A. , Jiang Feng , Sands Amy M. , Aguilera Nadine , Zhao X. Frank
Published: February 2009

Purpose: This study aimed to identify and evaluate molecular targets for the development of a novel combination chemotherapy to treat refractory and recurrent diffuse large B-cell lymphoma (DLBCL).

Experimental Design: Lymphoma samples from 38 cases of primary and recurrent DLBCL were analyzed using real-time quantitative PCR of the RPS6KB1 and CDC2 genes, and immunohistochemistry for their gene products p70S6K/p85S6K and cdc2/cdk1. The Farage, Karpas422, Pfeiffer, and Toledo DLBCL cell lines were subsequently treated with rapamycin and UCN-01 alone or in combination. Cell proliferation, apoptosis, and cell cycle progression were analyzed after the drug treatment. In addition, the levels of several key protein kinases involved in the phosphoinositide 3′-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, apoptosis, and cell cycle progression were analyzed in the presence and absence of the drugs.

Results: Amplification of the RPS6KB1 and CDC2 genes was found in both primary and recurrent DLBCL. Moreover, the vast majority of these lymphomas (∼94%) were strongly positive for phospho-p70S6K and cdc2/cdk1 proteins. The combination of rapamycin and UCN-01 synergistically inhibited the DLBCL cell proliferation by inducing G1 arrest as well as apoptosis by suppressing the phosphorylation of p70S6K/p85S6K and CDC2 expression.

Conclusion: RPS6KB1 and CDC2 overexpression is common in DLBCL. Simultaneously targeting the RPS6KB1 and CDC2 products phospho-p70S6K/p85S6K and cdc2/cdk1 is very effective in inhibiting DLBCL proliferation and overcoming drug resistance. This work suggests that multilevel inhibition of the PI3K/Akt/mTOR pathway and double-block of cell cycle progression are effective strategies for DLBCL therapy.