bluuebunny/crossref_metadata_2025 huggingface dataset:
MEDIAL AXIS APPROXIMATION AND UNSTABLE FLOW COMPLEX
Authors: GIESEN JOACHIM , RAMOS EDGAR A. , SADRI BARDIA
Published: December 2008

The medial axis of a shape is known to carry a lot of information about the shape. In particular, a recent result of Lieutier establishes that every bounded open subset of ℝn has the same homotopy type as its medial axis. In this paper we provide an algorithm that computes a structure we call the core for the approximation of the medial axis of a shape with smooth boundary from a discrete sample of its boundary. The core is a piecewise linear cell complex that is guaranteed to capture the topology of the medial axis of the shape provided the sample of its boundary is sufficiently dense but not necessarily uniform. We also present a natural method for augmenting the core in order to extend it geometrically while maintaining the topological guarantees. The definition of the core and its extension are based on the steepest ascent flow map that results from the distance function induced by the sample point set. We also provide a geometric guarantee on the closeness of the core and the actual medial axis.
Flow upscaling in highly heterogeneous reservoirs
Authors: Zhang P. , Pickup G. E. , Monfared H. , Christie M. A.
Published: December 2008

In the early stages of field development, there are many uncertainties and the current trend is to generate coarse-scale models so that many simulations can be run rapidly in order to determine the main sensitivities in a model. However, at a later stage, more data are available and there is less uncertainty in the model, so a more detailed modelling approach is desirable. In this paper, we discuss two modelling procedures which are suitable for different stages of the life of a field, and address the problem of upscaling at each stage. First, we consider a novel approach for generating coarse-scale models for evaluating uncertainty. When there is a large amount of uncertainty, the generation of fine-scale models is too time-consuming, and upscaling them by large factors may produce large errors. We demonstrate an alternative approach for modelling at a coarse scale, while preserving the heterogeneity of the fine-scale distribution, in such a way as to reproduce the fine-scale flow results. Secondly, we focus on more detailed geological models, generated at a later stage of field development. These models may comprise millions of grid cells, and may be highly heterogeneous. Such models require upscaling, but traditional methods may be very inaccurate. We have developed a method for upscaling using well-drive boundary conditions. Tests of this method show that it can reliably reproduce the fine-scale recovery in a range of models.
Scenario-based reservoir modelling: the need for more determinism and less anchoring
Authors: Bentley Mark , Smith Simon
Published: December 2008

The scenario-based reservoir modelling method places a strong emphasis on the deterministic control of the model design, contrasting with strongly probabilistic approaches in which effort is focused on the ‘richness’ of a geostatistical algorithm to derive multiple stochastic realizations. Scenario-based approaches also differ from traditional ‘rationalist’ modelling, which often involves the construction of only a single, best-guess or base-case model. The advantage of scenario modelling is that there is no requirement to anchor on a preferred, base-case model, and it is argued here that selection of a base case is detrimental to achieving appropriately wide uncertainty ranges. Multiple-deterministic scenario modelling also carries the advantage of maintaining explicit dependency between model parameters and the ultimate model outcome, such as a development plan. The approach has been applied widely to new fields, where multiple deterministic reservoir simulations of a suite of static models can be easily handled. The approach has also been extended to mature fields, in which practical approaches to multiple-history matching are required. Mature field scenario modelling, in particular, illustrates the weaknesses of base-case modelling, and delivers a strong statement on the non-uniqueness of modelling in general. Current issues are the need to develop better methodologies for multiple-history matching, and for linking discrete, deterministic, scenario-based outcomes to probabilistic reporting. Experimental design methods offer a solution to the latter issue, and a simple, practical workflow for its application is described.
A method for quantifying geological uncertainties in assessing remaining oil targets: a case study from the Glitne Field, North Sea
Authors: Keogh K. J. , Berg F. K. , Petek Glitne
Published: December 2008

Evaluating the static volume potential of a field from a single geological reservoir model can be a risky business. Each piece of input data used to build the model carries an uncertainty that is not expressed in a single deterministic realization. In evaluating the technical and economic feasibility of drilling a new production well on the StatoilHydro operated Glitne Field, a quantified assessment of the range in expected volumes was undertaken. A geological uncertainty study was initiated to identify and quantify the input parameters of greatest impact on static volumetric uncertainty in the reservoir model and to identify potential upsides or downsides that would strongly affect the economics of the potential well target areas. For each geological input parameter, a high-case and low-case scenario was established to capture the end members (approximating to P90–P10) in that parameter uncertainty. IRAP RMS was used in combination with an in-house Microsoft Excel macro together with @Risk to produce a quantitative analysis of the uncertainty range in STOIIP and a ranking of the parameters most affecting the uncertainty in this range. This study has contributed to making a better-informed decision for drilling a new production well on the Glitne Field and thus increasing ultimate recovery and field life further. The workflow used has its limitations but this study shows that a geological uncertainty study can be performed relatively simply using only a limited number of software applications. This study also hopes to highlight the importance of having these studies undertaken by company asset teams as part of their reservoir characterization routines.
The Schiehallion Field: lessons learned modelling a complex deepwater turbidite
Authors: Freeman Paul , Kelly Sean , Macdonald Chris , Millington John , Tothill Mike
Published: December 2008

The need for a new Schiehallion full field reservoir simulation model was driven by the requirement to re-evaluate the reserves in the field: the existing model indicated that the modelled volumes were potentially too conservative. This, coupled with a 50% increase in the wells database through ongoing development drilling, was the main reason for building the new model. An integrated multidisciplinary team consisting of BP and Shell staff was set up to build a new full-field reservoir simulation model for reserves re-evaluation. The paper outlines the workflow employed in building the new model, FFM2003, and describes elements of this workflow in more detail, concentrating on lessons learned during the process.
Using multiple-point statistics to build geologically realistic reservoir models: the MPS/FDM workflow
Authors: Strebelle Sebastien , Levy Marjorie
Published: December 2008

Building geologically realistic reservoir models that honour well data and seismic-derived information remains a major challenge. Conventional variogram-based modelling techniques typically fail to capture complex geological structures while object-based techniques are limited by the amount of conditioning data. This paper presents new reservoir facies modelling tools that improve both model quality and efficiency relative to traditional geostatistical techniques. Geostatistical simulation using Multiple-Point Statistics (MPS) is an innovative depositional facies modelling technique that uses conceptual geological models as training images to integrate geological information into reservoir models. Replacing the two-point statistic variogram with multiple-point statistics extracted from a training image enables to model non-linear facies geobody shapes such as sinuous channels, and to capture complex spatial relationships between multiple facies. In addition, because the MPS algorithm is pixel-based, it can handle a large amount of conditioning data, including many wells, seismic data, facies proportion maps and curves, variable azimuth maps, and interpreted geobodies, thus reducing the uncertainty in facies spatial distribution. Facies Distribution Modelling (FDM) is a new technique to generate facies probability cubes from user-digitized depositional maps and cross-sections, well data, and vertical facies proportion curves. Facies probability cubes generated by FDM are used as soft constraints in MPS geostatistical modelling. They are critical, especially with sparse well data, to ensure that the spatial distribution of the simulated facies is consistent with the depositional facies interpretation of the field. A workflow combining MPS and FDM has been successfully used in Chevron to model important oilfield assets in both shallow- and deep-water depositional environments. Sedimentary environments can be characterized by a succession of deposition of elements, or rock bodies, through time. These elements are traditionally grouped into classes, commonly named ‘depositional facies’, based on their lithology, petrophysical properties, and biological structures. For example, the typical depositional facies encountered in fluvial environments are high permeability sand channels, with levées and crevasse splays, having a more variable range of permeability and net-to-gross ratio, within a background of low permeability shaley facies.
Calibration and validation of reservoir models: the importance of high resolution, quantitative outcrop analogues
Authors: Jones Richard R. , Mccaffrey Kenneth J. W. , Imber Jonathan , Wightman Ruth , Smith Steven A. F. , Holdsworth Robert E. , Clegg Phillip , De Paola Nicola , Healy David , Wilson Robert W.
Published: December 2008

Rapidly developing methods of digital acquisition, visualization and analysis allow highly detailed outcrop models to be constructed, and used as analogues to provide quantitative information about sedimentological and structural architectures from reservoir to subseismic scales of observation. Terrestrial laser-scanning (lidar) and high precision Real-Time Kinematic GPS are key survey technologies for data acquisition. 3D visualization facilities are used when analysing the outcrop data. Analysis of laser-scan data involves picking of the point-cloud to derive interpolated stratigraphic and structural surfaces. The resultant data can be used as input for object-based models, or can be cellularized and upscaled for use in grid-based reservoir modelling. Outcrop data can also be used to calibrate numerical models of geological processes such as the development and growth of folds, and the initiation and propagation of fractures.
IκB Kinase-α Regulates Endothelial Cell Motility and Tumor Angiogenesis
Authors: DeBusk Laura M. , Massion Pierre P. , Lin P. Charles
Published: December 2008

The transcription factor nuclear factor-κB (NF-κB) is constitutively activated in many types of cancers and has been implicated in gene expression important for angiogenesis, tumor growth, progression, and metastasis. Here, we show that the NF-κB activator, IκB kinase-α (IKKα), but not IKKβ, promotes endothelial cell motility and tumor angiogenesis. IKKα is elevated in tumor vasculature compared with normal endothelium. Overexpression of IKKα in endothelial cells promoted cell motility and vascular tubule formation in a three-dimensional culture assay, and conversely, knockdown of IKKα in endothelial cells inhibited cell motility, compared with controls. Interestingly, blocking NF-κB activation totally abolished IKKα-induced angiogenic function. Furthermore, using a tumor and endothelial cell cotransplantation model, we show that overexpression of IKKα in endothelial cells significantly increased tumor vascular formation compared with controls, which contributed to increased tumor growth and tumor cell proliferation, and decreased tumor cell apoptosis. Collectively, these findings have identified a new function for IKKα through the canonical NF-κB pathway in tumor angiogenesis. [Cancer Res 2008;68(24):10223–8]
Coordinated Regulation of Cell Cycle Transcripts by p53-Inducible microRNAs, miR-192 and miR-215
Authors: Georges Sara A. , Biery Matthew C. , Kim Soo-yeon , Schelter Janell M. , Guo Jane , Chang Aaron N. , Jackson Aimee L. , Carleton Michael O. , Linsley Peter S. , Cleary Michele A. , Chau B. Nelson
Published: December 2008

Cell cycle arrest in response to DNA damage is an important antitumorigenic mechanism. MicroRNAs (miRNAs) were recently shown to play key regulatory roles in cell cycle progression. For example, miR-34a is induced in response to p53 activation and mediates G1 arrest by down-regulating multiple cell cycle–related transcripts. Here we show that genotoxic stress promotes the p53-dependent up-regulation of the homologous miRNAs miR-192 and miR-215. Like miR-34a, activation of miR-192/215 induces cell cycle arrest, suggesting that multiple miRNA families operate in the p53 network. Furthermore, we define a downstream gene expression signature for miR-192/215 expression, which includes a number of transcripts that regulate G1 and G2 checkpoints. Of these transcripts, 18 transcripts are direct targets of miR-192/215, and the observed cell cycle arrest likely results from a cooperative effect among the modulations of these genes by the miRNAs. Our results showing a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are underexpressed in primary cancers support the idea that miR-192 and miR-215 function as tumor suppressors. [Cancer Res 2008;68(24):10105–12]
Methylation of Polycomb Target Genes in Intestinal Cancer Is Mediated by Inflammation
Authors: Hahn Maria A. , Hahn Torsten , Lee Dong-Hyun , Esworthy R. Steven , Kim Byung-wook , Riggs Arthur D. , Chu Fong-Fong , Pfeifer Gerd P.
Published: December 2008

Epigenetic changes are strongly associated with cancer development. DNA hypermethylation is associated with gene silencing and is often observed in CpG islands. Recently, it was suggested that aberrant CpG island methylation in tumors is directed by Polycomb (PcG) proteins. However, specific mechanisms responsible for methylation of PcG target genes in cancer are not known. Chronic infection and inflammation contribute to up to 25% of all cancers worldwide. Using glutathione peroxidase, Gpx1 and Gpx2, double knockout (Gpx1/2-KO) mice as a model of inflammatory bowel disease predisposing to intestinal cancer, we analyzed genome-wide DNA methylation in the mouse ileum during chronic inflammation, aging, and cancer. We found that inflammation leads to aberrant DNA methylation in PcG target genes, with 70% of the ∼250 genes methylated in the inflamed tissue being PcG targets in embryonic stem cells and 59% of the methylated genes being marked by H3K27 trimethylation in the ileum of adult wild-type mice. Acquisition of DNA methylation at CpG islands in the ileum of Gpx1/2-KO mice frequently correlates with loss of H3K27 trimethylation at the same loci. Inflammation-associated DNA methylation occurs preferentially in tissue-specific silent genes and, importantly, is much more frequently represented in tumors than is age-dependent DNA methylation. Sixty percent of aberrant methylation found in tumors is also present in the inflamed tissue. In summary, inflammation creates a signature of aberrant DNA methylation, which is observed later in the malignant tissue and is directed by the PcG complex. [Cancer Res 2008;68(24):10280–9]
The Innate Immune Receptor Nod1 Protects the Intestine from Inflammation-Induced Tumorigenesis
Authors: Chen Grace Y. , Shaw Michael H. , Redondo Gloria , Núñez Gabriel
Published: December 2008

There is growing evidence that the host innate immune system has a critical role in regulating carcinogenesis, but the specific receptors involved and the importance of their interaction with commensal bacteria need to be elucidated. Two major classes of innate immune receptors, the Toll-like receptors and Nod-like receptors, many of which are upstream of nuclear factor-κB, are involved in the detection of intestinal bacteria. The Toll-like receptors have been implicated in promoting colon tumorigenesis, but the role of Nod-like receptors in regulating tumorigenesis remains unclear. Using an established mouse model system of colitis-associated colon tumorigenesis, we show that Nod1 deficiency results in the increased development of both colitis-associated and Apc tumor suppressor–related colon tumors. In the absence of Nod1 signaling, there is a greater disruption of the intestinal epithelial cell barrier due to chemically induced injury as manifested by increased surface epithelial apoptosis early on during chemically induced colitis and increased intestinal permeability. The increased intestinal permeability is associated with enhanced inflammatory cytokine production and epithelial cell proliferation in Nod1-deficient mice as compared with wild-type mice. Depletion of the gut microbiota suppressed tumor development in Nod1-deficient mice, thus highlighting a link between the commensal bacteria within the intestine and the host innate immune Nod1 signaling pathway in the regulation inflammation-mediated colon cancer development. [Cancer Res 2008;68(24):10060–7]
The High-Mobility Group A1a/Signal Transducer and Activator of Transcription-3 Axis: An Achilles Heel for Hematopoietic Malignancies?
Authors: Hillion Joelle , Dhara Surajit , Sumter Takita Felder , Mukherjee Mita , Di Cello Francescopaolo , Belton Amy , Turkson James , Jaganathan Souyma , Cheng Linzhao , Ye Zhaohui , Jove Richard , Aplan Peter , Lin Ying-Wei , Wertzler Kelsey , Reeves Ray , Elbahlouh Ossama , Kowalski Jeanne , Bhattacharya Raka , Resar Linda M. S.
Published: December 2008

Although HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis. Here, we show that the STAT3 gene, which encodes the signaling molecule signal transducer and activator of transcription 3 (STAT3), is a critical downstream target of HMGA1a. STAT3 mRNA and protein are up-regulated in fibroblasts overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a in fibroblasts. HMGA1a also binds directly to a conserved region of the STAT3 promoter in vivo in human leukemia cells by chromatin immunoprecipitation and activates transcription of the STAT3 promoter in transfection experiments. To determine if this pathway contributes to HMGA1-mediated transformation, we investigated STAT3 expression in our HMGA1a transgenic mice, all of which developed aggressive lymphoid malignancy. STAT3 expression was increased in the leukemia cells from our transgenics but not in control cells. Blocking STAT3 function induced apoptosis in the transgenic leukemia cells but not in controls. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Our results show that the HMGA1a–STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a. [Cancer Res 2008;68(24):10121–7]
Wnt5A Regulates Expression of Tumor-Associated Antigens in Melanoma via Changes in Signal Transducers and Activators of Transcription 3 Phosphorylation
Authors: Dissanayake Samudra K. , Olkhanud Purevdorj B. , O'Connell Michael P. , Carter Arnell , French Amanda D. , Camilli Tura C. , Emeche Chineye D. , Hewitt Kyle J. , Rosenthal Devin T. , Leotlela Poloko D. , Wade Michael S. , Yang Sherry W. , Brant Larry , Nickoloff Brian J. , Messina Jane L. , Biragyn Arya , Hoek Keith S. , Taub Dennis D. , Longo Dan L. , Sondak Vernon K. , Hewitt Stephen M. , Weeraratna Ashani T.
Published: December 2008

There are currently no effective therapies for metastatic melanoma and targeted immunotherapy results in the remission of only a very small percentage of tumors. In this study, we show that the noncanonical Wnt ligand, Wnt5A, can increase melanoma metastasis in vivo while down-regulating the expression of tumor-associated antigens important in eliciting CTL responses (e.g., MART-1, GP100, and tyrosinase). Melanosomal antigen expression is governed by MITF, PAX3, and SOX10 and is inhibited upon signal transducers and activators of transcription 3 (STAT3) activation, via decreases in PAX3 and subsequently MITF expression. Increasing Wnt5A in Wnt5A-low cells activated STAT3, and STAT3 was decreased upon Wnt5A knockdown. Downstream targets such as PAX3, MITF, and MART-1 were also affected by Wnt5A treatment or knockdown. Staining of a melanoma tissue array also highlighted the inverse relationship between MART-1 and Wnt5A expression. PKC activation by phorbol ester mimicked Wnt5A effects, and Wnt5A treatment in the presence of STAT3 or PKC inhibitors did not lower MART-1 levels. CTL activation studies showed that increases in Wnt5A correspond to decreased CTL activation and vice versa, suggesting that targeting Wnt5A before immunotherapy may lead to the enhancement of current targeted immunotherapy for patients with metastatic melanoma. [Cancer Res 2008;68(24):10205–14]
In vivo Dynamics of Stable Chronic Lymphocytic Leukemia Inversely Correlate with Somatic Hypermutation Levels and Suggest No Major Leukemic Turnover in Bone Marrow
Authors: van Gent Rogier , Kater Arnon P. , Otto Sigrid A. , Jaspers A. , Borghans José A.M. , Vrisekoop Nienke , Ackermans Mariëtte A.T. , Ruiter An F.C. , Wittebol Shulamiet , Eldering Eric , van Oers Marinus H.J. , Tesselaar Kiki , Kersten Marie José , Miedema Frank
Published: December 2008

Although accumulating evidence indicates that chronic lymphocytic leukemia (CLL) is a disease with appreciable cell dynamics, it remains uncertain whether this also applies to patients with stable disease. In this study, 2H2O was administered to a clinically homogeneous cohort of nine stable, untreated CLL patients. CLL dynamics in blood and bone marrow were determined and compared with normal B-cell dynamics in blood from five healthy individuals who underwent a similar 2H2O labeling protocol. Average CLL turnover rates (0.08–0.35% of the clone per day) were ∼2-fold lower than average B-cell turnover rates from healthy individuals (0.34–0.89%), whereas the rate at which labeled CLL cells in blood disappeared (0.00–0.39% of B cells per day) was ∼10-fold lower compared with labeled B cells from healthy individuals (1.57–4.24% per day). Leukemic cell turnover variables inversely correlated with the level of somatic hypermutation of the CLL clone (IgVH mutations). Although CLL cells in bone marrow had a higher level of label enrichment than CLL cells in blood, no difference between proliferation rates and proapoptotic and antiapoptotic profiles of CLL cells from these compartments was observed. These data suggest that, in stable disease, there is a biological relationship between the degree of somatic hypermutation of the CLL clone and its dynamics in vivo. Furthermore, in contrast to lymph nodes, the bone marrow does not seem to be a major CLL proliferation site. [Cancer Res 2008;68(24):10137–44]
Increased c-Jun-NH2-Kinase Signaling in Neurofibromatosis-1 Heterozygous Microglia Drives Microglia Activation and Promotes Optic Glioma Proliferation
Authors: Daginakatte Girish C. , Gianino Scott M. , Zhao Nina W. , Parsadanian Alexander S. , Gutmann David H.
Published: December 2008

Neurofibromatosis-1 (NF1) is a common tumor predisposition syndrome in which affected individuals develop benign and malignant tumors. Previous studies from our laboratory and others have shown that benign tumor formation in Nf1 genetically engineered mice (GEM) requires a permissive tumor microenvironment. In the central nervous system, Nf1 loss in glia is insufficient for glioma formation unless coupled with Nf1 heterozygosity in the brain. Our subsequent studies identified Nf1+/− microglia as a critical cellular determinant of optic glioma growth in Nf1 GEM. Using NF1 as an experimental paradigm to further characterize the role of microglia in glioma growth, we first examined the properties of Nf1+/− microglia in vitro and in vivo. Nf1+/− microglia exhibit increased proliferation and motility and express elevated levels of genes associated with microglia activation. We further show that Nf1+/− microglia harbor high levels of activated c-Jun-NH2-kinase (JNK) without any significant changes in Akt, mitogen-activated protein kinase (MAPK), or p38-MAPK activity. In contrast, Nf1−/− astrocytes do not exhibit increased JNK activation. SP600125 inhibition of JNK activity in Nf1+/− microglia results in amelioration of the increased proliferation and motility phenotypes and reduces the levels of expression of activated microglia-associated transcripts. Moreover, SP600125 treatment of Nf1 optic glioma–bearing GEM results in reduced optic glioma proliferation in vivo. Collectively, these findings suggest that Nf1+/− microglia represent a good model system to study the role of specialized microglia in brain tumorigenesis and identify a unique Nf1 deregulated pathway for therapeutic studies aimed at abrogating microenvironmental signals that promote brain tumor growth. [Cancer Res 2008;68(24):10358–66]
Genome-wide Allelic State Analysis on Flow-Sorted Tumor Fractions Provides an Accurate Measure of Chromosomal Aberrations
Authors: Corver Willem E. , Middeldorp Anneke , ter Haar Natalja T. , Jordanova Ekaterina S. , van Puijenbroek Marjo , van Eijk Ronald , Cornelisse Cees J. , Fleuren Gert Jan , Morreau Hans , Oosting Jan , van Wezel Tom
Published: December 2008

Chromosomal aberrations are a common characteristic of cancer and are associated with copy number abnormalities and loss of heterozygosity (LOH). Tumor heterogeneity, low tumor cell percentage, and lack of knowledge of the DNA content impair the identification of these alterations especially in aneuploid tumors. To accurately detect allelic changes in carcinomas, we combined flow-sorting and single nucleotide polymorphism arrays. Cells derived from archival cervical and colon cancers were flow-sorted based on differential vimentin and keratin expression and DNA content and analyzed on single nucleotide polymorphism arrays. A new algorithm, the lesser allele intensity ratio, was used to generate a molecular measure of chromosomal aberrations for each case. Flow-sorting significantly improved the detection of copy number abnormalities; 31.8% showed an increase in amplitude and 23.2% were missed in the unsorted fraction, whereas 15.9% were detected but interpreted differently. Integration of the DNA index in the analysis enabled the identification of the allelic state of chromosomal aberrations, such as LOH ([A]), copy-neutral LOH ([AA]), balanced amplifications ([AABB]), and allelic imbalances ([AAB] or [AAAB], etc.). Chromosomal segments were sharply defined. Fluorescence in situ hybridization copy numbers, as well as the high similarity between the DNA index and the allelic state index, which is the average of the allelic states across the genome, validated the method. This new approach provides an individual molecular measure of chromosomal aberrations and will likely have repercussions for preoperative molecular staging, classification, and prognostic profiling of tumors, particularly for heterogeneous aneuploid tumors, and allows the study of the underlying molecular genetic mechanisms and clonal evolution of tumor subpopulations. [Cancer Res 2008;68(24):10333–40]
Phosphorylated Insulin-Like Growth Factor-I/Insulin Receptor Is Present in All Breast Cancer Subtypes and Is Related to Poor Survival
Authors: Law Jennifer H. , Habibi Golareh , Hu Kaiji , Masoudi Hamid , Wang Michelle Y.C. , Stratford Anna L. , Park Eugene , Gee Julia M.W. , Finlay Pauline , Jones Helen E. , Nicholson Robert I. , Carboni Joan , Gottardis Marco , Pollak Michael , Dunn Sandra E.
Published: December 2008

Drugs that target the insulin-like growth factor-I receptor (IGF-IR) and/or insulin receptor (IR) are currently under investigation for a variety of malignancies including breast cancer. Although we have previously reported that IGF-IR expression in primary breast tumors is common, the activation status of this receptor has not been examined in relation to survival. Phosphorylated IGF-IR/IR (P-IGF-IR/IR) and its downstream signaling partner phospho-S6 (P-S6) were evaluated immunohistochemically in tumor tissue microarrays representing 438 cases of invasive breast cancer. P-IGF-IR/IR (n = 114; P = 0.046) and total levels of IR (n = 122; P = 0.009) were indicative of poor survival, whereas total IGF-IR (n = 112; P = 0.304) was not. P-IGF-IR/IR and P-S6 were coordinately expressed in primary breast tumors (likelihood ratio, 11.57; P = 6.70 × 10−4). Importantly, P-IGF-IR/IR was detected in all breast cancer subtypes (luminal, 48.1%; triple negative, 41.9%; and HER2, 64.3%). In vitro, the IGF-IR/IR inhibitor BMS-536924 decreased phospho-RSK and P-S6, and significantly suppressed the growth of breast cancer cell lines MCF-7, SUM149, and AU565 representing the luminal, triple negative, and HER2 subtypes, respectively, in monolayer and soft agar. BMS-536924 also inhibited growth in tamoxifen resistant MCF-7 Tam-R cells while having little effect on immortalized normal breast epithelial cells. Thus, we can determine which patients have the activated receptor and provide evidence that P-IGF-IR/IR is a prognostic factor for breast cancer. Beyond this, P-IGF-IR/IR could be a predictive marker for response to IGF-IR and/or IR-targeted therapies, as these inhibitors may be of benefit in all breast cancer subtypes including those with acquired resistance to tamoxifen. [Cancer Res 2008;68(24):10238–46]
Translating an Antagonist of Chemokine Receptor CXCR4: From Bench to Bedside
Authors: Wong Donald , Korz Walter
Published: December 2008

The majority of current cancer therapies focus on a primary tumor approach. However, it is metastases that cause the majority of cancer deaths. The metastatic process has been shown repeatedly to be greatly influenced by chemokines such as CXCL12 [stromal cell derived factor-1 (SDF-1)] and its receptor CXCR4. The activation of this pathway has been reported to modulate cell migration, survival, proliferation, and gene transcription through G proteins, phosphoinositide-3 kinase, Akt, extracellular signal-regulated kinase, arrestin, and Janus-activated kinase/signal transducers and activators of transcription. A wide variety of strategies, such as peptides, small molecules, antibodies, and small interfering RNA, have been used to target this pathway. Treatments in combination with current therapies seem to be especially promising in preclinical studies. A few compounds are advancing into early stages of clinical development. In this article, we will review the development of CXCR4 antagonists in oncology.
Reversal of Myeloid Cell–Mediated Immunosuppression in Patients with Metastatic Renal Cell Carcinoma
Authors: Kusmartsev Sergei , Su Zhen , Heiser Axel , Dannull Jens , Eruslanov Evgeniy , Kübler Hubert , Yancey Donna , Dahm Philip , Vieweg Johannes
Published: December 2008

Purpose: Tumor-induced immunosuppression remains a significant obstacle that limits the efficacy of biological therapy for renal cell carcinoma. Here we evaluate the role of CD33 myeloid-derived suppressor cells (MDSC) in the regulation of T-cell responses in renal cell carcinoma patients. We also examine effect of all-trans-retinoic acid (ATRA) on MDSC-mediated immune suppression.

Experimental Design: CD33-positive myeloid cells were isolated from the peripheral blood of renal cell carcinoma patients with magnetic beads and tested in vitro for their ability to inhibit T-cell responses. T-cell function was evaluated using ELISPOT and CTL assays.

Results: MDSC isolated from renal cell carcinoma patients, but not from healthy donors, were capable of suppressing antigen-specific T-cell responses in vitro through the secretion of reactive oxygen species and nitric oxide upon interaction with CTL. MDSC-mediated immune suppression and IFN-γ down-regulation was reversible in vitro by exposing cells to the reactive oxygen species inhibitors. Moreover, ATRA was capable of abrogating MDSC-mediated immunosuppression and improving T-cell function by direct differentiation into antigen-presenting cell precursors.

Conclusions: These results may have significant implications regarding the future design of active immunotherapy protocols that may include differentiation agents as part of a multimodal approach to renal cell carcinoma immunotherapy.
A Phase I and Pharmacokinetic Study of Ixabepilone in Combination with Carboplatin in Patients with Advanced Solid Malignancies
Authors: Plummer Ruth , Woll Penella , Fyfe David , Boddy Alan V. , Griffin Melanie , Hewitt Paula , Carmichael James , Namouni Fouad , Cohen Marvin , Verrill Mark
Published: December 2008

Purpose: To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety.

Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B).

Results: Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B).

Conclusions: Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin, with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle.
Cytosolic Phospholipase A2-α: A Potential Therapeutic Target for Prostate Cancer
Authors: Patel Manish I. , Singh Jaskirat , Niknami Marzieh , Kurek Caroline , Yao Mu , Lu Sasa , Maclean Fiona , King Nicholas J.C. , Gelb Michael H. , Scott Kieran F. , Russell Pamela J. , Boulas John , Dong Qihan
Published: December 2008

Purpose: Cytosolic phospholipase A2-α (cPLA2-α) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA2-α in prostate cancer cell lines and tissue and the effect of targeting cPLA2-α in vitro and in vivo.

Experimental Design: The expression of cPLA2-α was determined in prostate cancer cells by reverse transcription-PCR, Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA2-α activity were determined after inhibition with cPLA2-α small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA2-α inhibitor or vehicle was also administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA2-α was determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens.

Results: cPLA2-α is present in all prostate cancer cells lines, but increased in androgen-insensitive cells. Inhibition with small interfering RNA or Wyeth-1 results in significant reductions in prostate cancer cell numbers, as a result of reduced proliferation as well as increased apoptosis, and this was also associated with a reduction in cPLA2-α activity. Expression of cyclin D1 and phosphorylation of Akt were also observed to decrease. Wyeth-1 inhibited PC3 xenograft growth by ∼33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phosphorylated cPLA2-α is increased when hormone refractory is reached.

Conclusions: Expression and activation of cPLA2-α are increased in the androgen-insensitive cancer cell line and tissue. Inhibition of cPLA2-α results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory prostate cancer.
A Phase I Study of the Pan Bcl-2 Family Inhibitor Obatoclax Mesylate in Patients with Advanced Hematologic Malignancies
Authors: Schimmer Aaron D. , O'Brien Susan , Kantarjian Hagop , Brandwein Joseph , Cheson Bruce D. , Minden Mark D. , Yee Karen , Ravandi Farhad , Giles Francis , Schuh Andre , Gupta Vikas , Andreeff Michael , Koller Charles , Chang Hong , Kamel-Reid Suzanne , Berger Mark , Viallet Jean , Borthakur Gautam
Published: December 2008

Purpose: The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose.

Experimental Design: Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies.

Results: A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence.

Conclusions: Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
Advances in Breast Cancer: Pathways to Personalized Medicine
Authors: Olopade Olufunmilayo I. , Grushko Tatyana A. , Nanda Rita , Huo Dezheng
Published: December 2008

Breast cancer is a complex disease caused by the progressive accumulation of multiple gene mutations combined with epigenetic dysregulation of critical genes and protein pathways. There is substantial interindividual variability in both the age at diagnosis and phenotypic expression of the disease. With an estimated 1,152,161 new breast cancer cases diagnosed worldwide per year, cancer control efforts in the postgenome era should be focused at both population and individual levels to develop novel risk assessment and treatment strategies that will further reduce the morbidity and mortality associated with the disease. The discovery that mutations in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancers has radically transformed our understanding of the genetic basis of breast cancer, leading to improved management of high-risk women. A better understanding of tumor host biology has led to improvements in the multidisciplinary management of breast cancer, and traditional pathologic evaluation is being complemented by more sophisticated genomic approaches. A number of genomic biomarkers have been developed for clinical use, and increasingly, pharmacogenetic end points are being incorporated into clinical trial design. For women diagnosed with breast cancer, prognostic or predictive information is most useful when coupled with targeted therapeutic approaches, very few of which exist for women with triple-negative breast cancer or those with tumors resistant to chemotherapy. The immediate challenge is to learn how to use the molecular characteristics of an individual and their tumor to improve detection and treatment, and ultimately to prevent the development of breast cancer. The five articles in this edition of CCR Focus highlight recent advances and future directions on the pathway to individualized approaches for the early detection, treatment, and prevention of breast cancer.
DNA Copy-Number Alterations Underlie Gene Expression Differences between Microsatellite Stable and Unstable Colorectal Cancers
Authors: Jorissen Robert N. , Lipton Lara , Gibbs Peter , Chapman Matthew , Desai Jayesh , Jones Ian T. , Yeatman Timothy J. , East Philip , Tomlinson Ian P.M. , Verspaget Hein W. , Aaltonen Lauri A. , Kruhøffer Mogens , Ørntoft Torben F. , Andersen Claus Lindbjerg , Sieber Oliver M.
Published: December 2008

Purpose: About 15% of colorectal cancers harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in colorectal cancers, but little overlap exists between signatures hindering an assessment of overall consistency. Little is known about the causes and downstream effects of differential gene expression.

Experimental Design: DNA microarray data on 89 MSI and 140 microsatellite-stable (MSS) colorectal cancers from this study and 58 MSI and 77 MSS cases from three published reports were randomly divided into test and training sets. MSI-associated gene expression changes were assessed for cross-study consistency using training samples and validated as MSI classifier using test samples. Differences in biological pathways were identified by functional category analysis. Causation of differential gene expression was investigated by comparison to DNA copy-number data.

Results: MSI-associated gene expression changes in colorectal cancers were found to be highly consistent across multiple studies of primary tumors and cancer cell lines from patients of different ethnicities (P < 0.001). Clustering based on consistent changes separated additional test cases by MSI status, and classification of individual samples predicted MSI status with a sensitivity of 96% and specificity of 85%. Genes associated with immune response were up-regulated in MSI cancers, whereas genes associated with cell-cell adhesion, ion binding, and regulation of metabolism were down-regulated. Differential gene expression was shown to reflect systematic differences in DNA copy-number aberrations between MSI and MSS tumors (P < 0.001).

Conclusions: Our results show cross-study consistency of MSI-associated gene expression changes in colorectal cancers. DNA copy-number alterations partly cause the differences in gene expression between MSI and MSS cancers.
Nuclear Factor-κB p65/relA Silencing Induces Apoptosis and Increases Gemcitabine Effectiveness in a Subset of Pancreatic Cancer Cells
Authors: Pan Xue , Arumugam Thiruvengadam , Yamamoto Tameyoshi , Levin Pavel A. , Ramachandran Vijaya , Ji Baoan , Lopez-Berestein Gabriel , Vivas-Mejia Pablo E. , Sood Anil K. , McConkey David J. , Logsdon Craig D.
Published: December 2008

Purpose: Nuclear factor κB (NFκB) activity may increase survival and protect cancer cells from chemotherapy. Therefore, NFκB activity may be prognostic, and inhibition of NFκB may be useful for pancreatic cancer therapy. To test these hypotheses, we examined NFκB activity and the effects of inhibiting NFκB in several pancreatic cancer cell lines with differing sensitivities to gemcitabine.

Experimental Design: The gemcitabine sensitivity of pancreatic cancer cell lines BxPC-3, L3.6pl, CFPAC-1, MPanc-96, PANC-1, and MIA PaCa-2 were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and fluorescence-activated cell sorting assays. NFκB levels were determined by electrophoretic mobility shift assay and reporter assays. The effects of gemcitabine on NFκB activity were determined in vitro and in vivo. NFκB was inhibited by silencing of the p65/relA subunit using small interfering RNA in vitro and by neutral liposomal delivery of small interfering RNA in vivo, and the effects were evaluated on gemcitabine sensitivity.

Results: The cell lines L3.6pl, BxPC-3, and CFPAC-1 were sensitive, whereas MPanc-96, PANC-1, and MIA PaCa-2 were resistant to gemcitabine. No significant correlation was observed between basal NFκB activity and gemcitabine sensitivity. Gemcitabine treatment did not activate NFκB either in vitro or in vivo. Silencing of p65/relA induced apoptosis and increased gemcitabine killing of all gemcitabine-sensitive pancreatic cancer cells. No significant effects, however, were observed on gemcitabine-resistant pancreatic cancer cell lines either in vitro or in vivo.

Conclusions: NFκB activity did not correlate with sensitivity to gemcitabine. Silencing of p65/relA was effective alone and in combination with gemcitabine in gemcitabine-sensitive but not gemcitabine-resistant pancreatic cancer cells. Thus, NFκB may be a useful therapeutic target for a subset of pancreatic cancers.
Cyclooxygenase-2 Expression Is an Independent Predictor of Poor Prognosis in Colon Cancer
Authors: Ogino Shuji , Kirkner Gregory J. , Nosho Katsuhiko , Irahara Natsumi , Kure Shoko , Shima Kaori , Hazra Aditi , Chan Andrew T. , Dehari Reiko , Giovannucci Edward L. , Fuchs Charles S.
Published: December 2008

Purpose: Cyclooxygenase-2 (COX-2; PTGS2) is considered to play an important role in colorectal carcinogenesis and is often up-regulated in colon cancers. However, previous data on the influence of COX-2 expression on patient outcome have been conflicting.

Experimental Design: Using 662 colon cancers (stage I-IV) in two independent prospective cohorts (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected COX-2 overexpression in 548 (83%) tumors by immunohistochemistry. Cox proportional hazards models were used to compute hazard ratios (HR) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and related molecular events, including the CpG island methylation phenotype, microsatellite instability, and p53, CIMP, KRAS, and BRAF mutations.

Results: During follow-up of the 662 cases, there were 283 deaths, including 163 colon cancer-specific deaths. Patients with COX-2-positive tumors showed a trend towards an inferior colon cancer-specific mortality [HR, 1.37; 95% confidence interval (95% CI), 0.87-2.14], which became significant after adjusting for tumor stage and other predictors of clinical outcome (multivariate HR, 1.70; 95% CI, 1.06-2.74; P = 0.029). Notably, the prognostic effect of COX-2 expression might differ according to p53 status (Pinteraction = 0.04). Compared with tumors with both COX-2 and p53 negative, COX-2-positive tumors were significantly associated with an increased cancer-specific mortality (multivariate HR, 2.12; 95% CI, 1.23-3.65) regardless of p53 status. A similar trend was observed when overall mortality was used as an outcome.

Conclusion: COX-2 overexpression is associated with worse survival among colon cancer patients. The effect of COX-2 on clinical outcome may be modified by p53 status.