bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyphase development of the Falcón Basin in northwestern Venezuela: implications for oil generation
Authors: Baquero Marvin , Acosta Jorge , Kassabji Elías , Zamora José , Sousa Juan Carlos , Rodríguez Josmat , Grobas Jacqueline , Melo Luís , Schneider Frederic
Published: December 2009

A multi-event tectonic episode that affected the Caribbean and South American Plate boundaries as well as Cenozoic oil generation is based on new structural and geochemical data from the western Falcón Basin, Venezuela. It involves Late Cretaceous to Middle Eocene emplacement of the Lara Nappes followed by Late Eocene to Early Miocene tectonic collapse and graben formation, Middle Miocene inversion and out of sequence thrusting. Oil-source rock correlation of seeps in the northern part of the basin suggests a Cenozoic siliciclastic source rock deposited under suboxic to anoxic conditions. Potential Cenozoic source rocks and Late Cretaceous La Luna Formation were used to evaluate the generation conditions using one- and two-dimensional thermal modelling. A heat flow of
c
. 190 mW m
−2
was reached during the Oligocene–Early Miocene in the central part of the basin. As a result the Cretaceous source rock is overmature, while the primary Cenozoic source rocks are in the oil window. The thermal modelling also suggests that hydrocarbon accumulations are mainly located on the flanks of the graben, with small amounts possible in the centre, due to erosion during basin inversion. This modelling is highly consistent with the proposed polyphase tectonic model.
Clastic domains of sandstones in central/eastern Venezuela, Trinidad, and Barbados: heavy mineral and tectonic constraints on provenance and palaeogeography
Authors: Pindell James L. , Kennan Lorcan , Wright David , Erikson Johan
Published: December 2009

Current models for the tectonic evolution of northeastern South America invoke a Palaeogene phase of inter-American convergence, followed by diachronous dextral oblique collision with the Caribbean Plate, becoming strongly transcurrent in the Late Miocene. Heavy mineral analysis of Cretaceous to Pleistocene rocks from eastern Venezuela, Barbados and Trinidad allow us to define six primary clastic domains, refine our palaeogeographic maps, and relate them to distinct stages of tectonic development: (1) Cretaceous passive margin of northern South America; (2) Palaeogene clastics related to the dynamics of the Proto-Caribbean Inversion Zone before collision with the Caribbean Plate; (3) Late Eocene–Oligocene southward-transgressive clastic sediments fringing the Caribbean foredeep during initial collision; (4) Oligocene–Middle Miocene axial fill of the Caribbean foredeep; (5) Late Eocene–Middle Miocene northern proximal sedimentary fringe of the Caribbean thrustfront; and (6) Late Miocene–Recent deltaic sediments flowing parallel to the orogen during its post-collisional, mainly transcurrent stage. Domain 1–3 sediments are highly mature, comprising primary Guayana Shield-derived sediment or recycled sediment of shield origin eroded from regional Palaeogene unconformities. In Trinidad, palinspastic restoration of Neogene deformation indicates that facies changes once interpreted as north to south are in fact west to east, reflecting progradation from the Maturín Basin into central Trinidad across the NW–SE trending Bohordal marginal offset, distorted by about 70 km of dextral shear through Trinidad. There is no mineralogical indication of a northern or northwestern erosional sediment source until Oligocene onset of Domain 4 sedimentation. Paleocene–Middle Eocene rocks of the Scotland Formation sandstones in Barbados do show an immature orogenic signature, in contrast to Venezuela–Trinidad Domain 2 sediments, this requires: (1) at least a bathymetric difference, if not a tectonic barrier, between them; and (2) that the Barbados deep-water depocentre was within turbidite transport distance of the Early Palaeogene orogenic source areas of western Venezuela and/or Colombia. Domains 4–6 (from Late Oligocene) show a strong direct or recycled influence of Caribbean Orogen igneous and metamorphic terranes in addition to substantial input from the shield areas to the south. The delay in the appearance of common Caribbean detritus in the east, relative to the Paleocene and Eocene appearance of Caribbean-influenced sands in the west, reflects the diachronous, eastward migration of Caribbean foredeep subsidence and sedimentation as a response to eastward-younging collision of the Caribbean Plate and the South American margin.
Submarine volcanic stratigraphy and the Caribbean LIP's formational environment
Authors: Diebold John
Published: December 2009

In 1995, R/V
Maurice Ewing
cruise EW9501 collected 5200 km of high-quality multichannel reflection profiles and 104 wide angle sonobuoy profiles in the Venezuelan Basin and over the Beata Ridge. These data provide images of the entire Caribbean crust, from seafloor to Moho, and verify earlier models of a two-‘layer’ crust. The EW9501 data also image the internal structure of these layers, revealing previously unseen features. The upper crustal ‘layer’ is actually a complex sequence, whose stratigraphy is analysed to show that the thickest part of the Caribbean volcanic plateau was experiencing east–west compressional deformation during the last stages of its emplacement.
Magma source evolution beneath the Caribbean oceanic plateau: new insights from elemental and Sr-Nd-Pb-Hf isotopic studies of ODP Leg 165 Site 1001 basalts
Authors: Kerr Andrew C. , Pearson D. Graham , Nowell Geoff M.
Published: December 2009

Ocean Drilling Project Leg 165 sampled 38 m of the basaltic basement of the Caribbean Plate at Site 1001 on the Hess Escarpment. The recovered section consists of 12 basaltic flow units which yield a weighted mean Ar/Ar age of 80.9±0.9 Ma. The basalts (6.4–8.5 wt% MgO) are remarkably homogeneous in composition and are more depleted in incompatible trace elements than N-MORB. Depleted initial radiogenic isotope ratios (ε
Nd
+11.1 to +11.9; ε
Hf
+15.2 to +16.9;
87
Sr/
86
Sr 0.7025–0.7028;
206
Pb/
204
Pb 18.34–18.50;
207
Pb/
204
Pb 15.42–15.51;
208
Pb/
204
Pb 37.64–37.90) reveal a long-term history of depletion. Although the Site 1001 basalts are superficially similar to N-MORB, radiogenic isotopes in conjunction with incompatible trace element ratios show that the basalts have more similarity to the depleted basalts and komatiites of Gorgona Island. This chemical composition strongly implies that the Site 1001 basalts are derived from a mantle plume-depleted component and not from depleted ambient upper mantle. Therefore the Site 1001 basalts are, both compositionally and tectonically, a constituent part of the Caribbean oceanic plateau. Mantle melt modelling suggests that the Site 1001 lavas have a composition which is consistent with second-stage melting of compositionally heterogeneous mantle plume source material which had already been melted, most likely to form the 90 Ma basalts of the plateau. The prolonged residence (>10 Ma) of residual mantle plume source material below the region confirms computational model predictions and places significant constraints on tectonic models of Caribbean evolution in the Late Cretaceous.
The Caribbean: an oroclinal basin?
Authors: Milsom John
Published: December 2009

Tightly curved mountain belts are prominent features of global topography. Typically, these ‘oroclines’ occur in areas of regional compression but enclose basins where extension has been contemporaneous with outward directed thrusting in the orogens. Examples of such basin–orogen pairs include the Alboran Sea–Gibraltar Arc, Tyrrhenian Sea–Aeolian Arc, Aegean Sea–Hellenic Arc and Pannonian Basin–Carpathian Arc, all in the western Tethys but matched in the eastern Tethys by the Banda Sea and Outer Banda Arc. The development of the basins has been variously explained by gravitational collapse of rapidly elevated mountain blocks and by extrusion prompted by asthenopheric flows, but it is not even universally agreed that similar processes have operated in all cases. Critics have cited gross differences in volcanic activity (absent from the Gibraltar Arc, modest in the Carpathians but intense in other examples) and in the presence or absence of recognizable Wadati–Benioff Zones. The superficial similarities between the Caribbean Sea–Antilles Arcs and typical oroclinal basin–orocline pairs have recently been invoked in support of an
in situ
Caribbean evolutionary model, even though the disputed origins of oroclines limit their reliability as analogues. The Caribbean's considerably greater area further emphasizes the need for caution, while the most obvious objection to identifying it as a member of the oroclinal group is its very long history. Oroclinal basins typically pass from initiation to effective stabilization in a few tens of millions of years, whereas the original Caribbean oceanic crust, which is now bounded to the east and west by active subduction zones, was probably formed in the Jurassic. Rather than invoking an overall common origin for the Caribbean and the Tethyan basins, it is more useful to look for shared causes of specific individual similarities. The impact of a rigid block might be as effective in imposing curvature on a mountain belt as rapid expansion in an adjacent area. However, it does seem that the case for the crust of the Caribbean being typical of oceanic large igneous provinces (LIPs) may have been overstated and, in the light of oroclinal analogues, that some features of the still poorly understood Beata Ridge and Lower Nicaragua Rise may be most easily explained by east–west extension promoted by the convergence between North and South America.
Emerging role of neuregulin as a modulator of muscle metabolism
Authors: Gumà Anna , Martínez-Redondo Vicente , López-Soldado Iliana , Cantó Carles , Zorzano Antonio
Published: December 2009

Neuregulin was described initially as a neurotrophic factor involved in the formation of the neuromuscular junction in skeletal muscle. However, in recent years, neuregulin has been reported to be a myokine that exerts relevant effects on myogenesis and the regulation of muscle metabolism. In this new context, the rapid and chronic metabolic effects of neuregulin appear to be related to muscle contraction. Indeed, the effects of neuregulin resemble those of exercise, which are accompanied by an improvement in insulin sensitivity. In this review, we challenge the classical role assigned to neuregulin in muscle and propound the emerging concept of its involvement in the regulation of energetic metabolism and insulin responsiveness.
Executioners of apoptosis in pancreatic β-cells: not just for cell death
Authors: Choi Diana , Woo Minna
Published: December 2009

Pancreatic β-cell mass is dynamic and is regulated by β-cell proliferation, neogenesis, and apoptosis. Under physiological conditions, apoptosis is tightly regulated with a slow, net rise in β-cell mass over time. Excessive β-cell apoptosis is an important contributor to both type 1 and type 2 diabetes development. Therefore, much effort has been given recently to better understand the mechanisms of apoptosis that occur both during physiological homeostasis and during the course of both types of diabetes. Caspases are the executioners of apoptosis that ultimately result in cell suicide. In mammals, there are 14 caspases, of which many participate in the apoptotic pathways. Genetic mouse models have been important tools for elucidation of the specific apoptotic pathways that play an essential role in β-cell apoptosis under physiological and pathological conditions. This review focuses on the diverse roles of each of the specific caspases and their regulators, unveiling both the classical apoptotic roles as well as emerging nonapoptotic roles.
Expression of transporters involved in urine concentration recovers differently after cessation of lithium treatment
Authors: Blount Mitsi A. , Sim Jae H. , Zhou Rong , Martin Christopher F. , Lu Wei , Sands Jeff M. , Klein Janet D.
Published: December 2009

Patients receiving lithium therapy, an effective treatment for bipolar disorder, often present with acquired nephrogenic diabetes insipidus. The nephrotoxic effects of lithium can be detected 3 wk after the start of treatment and many of these symptoms may disappear in a few weeks after lithium use is stopped. Most patients, however, still have a urine-concentrating defect years after ending treatment. This prompted an investigation of the transporters involved in the urine concentration mechanism, UT-A1, UT-A3, aquaporin-2 (AQP2), and NKCC2, after discontinuing lithium therapy. Sprague-Dawley rats fed a Li2CO3-supplemented diet produced large volumes of dilute urine after 14 days. After lithium treatment was discontinued, urine osmolality returned to normal within 14 days but urine volume and urine urea failed to reach basal levels. Western blot and immunohistochemical analyses revealed that both urea transporters UT-A1 and UT-A3 were reduced at 7 and 14 days of lithium treatment and both transporters recovered to basal levels 14 days after discontinuing lithium administration. Similar analyses demonstrated a decrease in AQP2 expression after 7 and 14 days of lithium therapy. AQP2 expression increased over the 7 and 14 days following the cessation of lithium but failed to recover to normal levels. NKCC2 expression was unaltered during the 14-day lithium regimen but did increase 14 days after the treatment was stopped. In summary, the rapid restoration of UT-A1 and UT-A3 as well as the increased expression of NKCC2 are critical components to the reestablishment of urine concentration after lithium treatment.
Neural Representation of Subjective Value Under Risk and Ambiguity
Authors: Levy Ifat , Snell Jason , Nelson Amy J. , Rustichini Aldo , Glimcher Paul W.
Published: December 2009

Risk and ambiguity are two conditions in which the consequences of possible outcomes are not certain. Under risk, the probabilities of different outcomes can be estimated, whereas under ambiguity, even these probabilities are not known. Although most people exhibit at least some aversion to both risk and ambiguity, the degree of these aversions is largely uncorrelated across subjects, suggesting that risk aversion and ambiguity aversion are distinct phenomena. Previous studies have shown differences in brain activations for risky and ambiguous choices and have identified neural mechanisms that may mediate transitions from conditions of ambiguity to conditions of risk. Unknown, however, is whether the value of risky and ambiguous options is necessarily represented by two distinct systems or whether a common mechanism can be identified. To answer this question, we compared the neural representation of subjective value under risk and ambiguity. fMRI was used to track brain activation while subjects made choices regarding options that varied systematically in the amount of money offered and in either the probability of obtaining that amount or the level of ambiguity around that probability. A common system, consisting of at least the striatum and the medial prefrontal cortex, was found to represent subjective value under both conditions.
Interaction between SNPs in the NRF2 gene and elite endurance performance
Authors: Eynon Nir , Alves Alberto Jorge , Sagiv Moran , Yamin Chen , Sagiv Michael , Meckel Yoav
Published: December 2009

Nuclear respiratory factor 2 (NRF2), a member of the Cap-N-Collar family of transcription factors, plays an important role in the mitochondrial biogenesis, and variants of NRF2 gene have been associated with endurance performance. The aims of the present study were 1) to compare NRF2 A/C (rs12594956) and NRF2 C/T (rs8031031) genotype and allele frequencies between athletes of sports with different demands (endurance vs. sprinters) as well as between competitive levels (elite level vs. national level) and 2) to analyze the interaction of these two polymorphisms and its influence on the level of endurance performance. One hundred and fifty-five track and field athletes (74 endurance athletes and 81 sprinters) and 240 nonathletic healthy individuals participated in this study. Endurance athletes presented a higher frequency of the AA (rs12594956) and CT (rs8031031) genotypes than sprinters and the control group, as well as higher A and T alleles, respectively. These differences did not appear between the sprinters and control subjects. The odds ratio for harboring the “optimal genotype” ( NRF2 AA+ NRF2 CT) was 4.53 (95% confidence interval 1.23–16.6) in the whole cohort of endurance athletes and 6.55 (95% confidence interval 1.12–38.25) in elite-level endurance athletes, compared with control subjects and both levels of sprinters. In conclusion, our data indicate that the NRF2 A/C and NRF2 C/T single nucleotide polymorphisms (SNPs) are associated, separately and in combination, with elite endurance athletes, which supports the notion that these specific gene variants might belong to a growing group of SNPs that are associated with endurance performance.
New Results on Passivity Analysis of Delayed Discrete‐Time Stochastic Neural Networks
Authors: Yu Jianjiang
Published: December 2009

The problem of passivity analysis for a class of discrete‐time stochastic neural networks (DSNNs) with time‐varying interval delay is investigated. The delay‐dependent sufficient criteria are derived in terms of linear matrix inequalities (LMIs). The results are shown to be generalization of some previous results and are less conservative than the existing works. Meanwhile, the computational complexity of the obtained stability conditions is reduced because less variables are involved. Two numerical examples are given to show the effectiveness and the benefits of the proposed method.
A Targeted Parathyroidectomy Using Guide Wire Technique in a Pregnant Patient with Primary Hyperparathyroidism
Authors: Kandil E. , Faruqui S. , Alharash J. , Alabbas H. , Rodgers B. , Blank B. , Jaffe B. M.
Published: December 2009

Primary hyperparathyroidism may cause fetal demise in pregnant patients if prompt diagnosis and treatment is not initiated. The paper describes a novel guide wire technique for a targeted parathyroidectomy, which may reduce the risk to mother and fetus and be useful in other related circumstances.
Existence of Solutions for Integrodifferential Equations of Fractional Order with Antiperiodic Boundary Conditions
Authors: Alsaedi Ahmed
Published: December 2009

We discuss the existence of solutions for a nonlinear antiperiodic boundary value problem of integrodifferential equations of fractional
order q ∈ (1, 2]. The contraction mapping principle and Krasnoselskii′s fixed point theorem are applied to establish the results.
Antivascular Therapy for Epithelial Ovarian Cancer
Authors: Duhoux Francois P. , Machiels Jean-Pascal
Published: December 2009

Ovarian cancer is the fifth largest cancer killer in women. Improved understanding of the molecular pathways implicated in the pathogenesis of ovarian cancer has led to the investigation of novel targeted therapies. Ovarian cancer is characterized by an imbalance between pro- and antiangiogenic factors in favor of angiogenesis activation. Various antivascular strategies are currently under investigation in ovarian cancer. They can schematically be divided into antiangiogenic and vascular-disrupting therapies. This paper provides a comprehensive review of these new treatments targeting the tumor vasculature in this disease. Promising activities have been detected in phase II trials, and results of phase III clinical trials are awaited eagerly.
Proapoptotic Activity of Bortezomib in Gastrointestinal Stromal Tumor Cells
Authors: Bauer Sebastian , Parry Joshua A. , Mühlenberg Thomas , Brown Matthew F. , Seneviratne Danushka , Chatterjee Payel , Chin Anna , Rubin Brian P. , Kuan Shih-Fan , Fletcher Jonathan A. , Duensing Stefan , Duensing Anette
Published: December 2009

Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes. Although >85% of GIST patients treated with the small-molecule inhibitor imatinib mesylate (Gleevec) achieve disease stabilization, complete remissions are rare and a substantial proportion of patients develop resistance to imatinib over time. Upregulation of soluble, non–chromatin-bound histone H2AX has an important role in imatinib-induced apoptosis of GIST cells. Additionally, H2AX levels in untreated GIST are maintained at low levels by a pathway that involves KIT, phosphoinositide 3-kinase, and the ubiquitin-proteasome system. In this study, we asked whether bortezomib-mediated inhibition of the ubiquitin-proteasome machinery could lead to upregulation of histone H2AX and GIST cell death. We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of KIT protein expression. Downregulation of KIT transcription was an underlying mechanism for bortezomib-mediated inhibition of KIT expression. In contrast, the nuclear factor-κB signaling pathway did not seem to play a major role in bortezomib-induced GIST cell death. Significantly, we found that bortezomib would induce apoptosis in two imatinib-resistant GIST cell lines as well as a short-term culture established from a primary imatinib-resistant GIST. Collectively, our results provide a rationale to test the efficacy of bortezomib in GIST patients with imatinib-sensitive or -resistant tumors. Cancer Res; 70(1); 150–9
Prolyl Hydroxylases 2 and 3 Act in Gliomas as Protective Negative Feedback Regulators of Hypoxia-Inducible Factors
Authors: Henze Anne-Theres , Riedel Johanna , Diem Tanja , Wenner Julia , Flamme Ingo , Pouyseggur Jacques , Plate Karl H. , Acker Till
Published: December 2009

Adaptive responses to hypoxia in tumors are transcriptionally regulated by the hypoxia inducible factors (HIF-1α/HIF-2α), which are tightly controlled by the HIF-prolyl hydroxylases (PHD). Hypoxia induces expression of the PHD2 and PHD3 proteins in tumors but the pathobiological significance of these events is uncertain. Here, we show that PHD2 and PHD3 induction acts within a negative feedback loop to limit the hypoxic HIF response. In glioblastomas, PHD2 and PHD3 are hypoxia-inducible in vitro and expressed in hypoxic areas of tumors in vivo. Comparison with other PHDs revealed distinct cytoplasmatic and nuclear localization patterns of PHD2 and PHD3. Gain and loss of function experiments defined PHD2 and PHD3 as HIF target genes that remained operative even at low oxygen concentrations. We found that increased PHD levels could compensate for reduced oxygen availability to regulate the HIF response. This negative feedback loop protected tumor cells against hypoxia-induced cell death, functionally implicating this pathway in the control of the tumor-suppressive components of the HIF system in glioblastoma. Moreover, PHD inhibition facilitated cell death induction by staurosporine or tumor necrosis factor–related apoptosis-inducing ligand, hinting at a more general protective role of PHD in the regulation of cell viability. In summary, our findings recognize the PHD/HIF regulatory axis as a novel therapeutic target to disable a tumor's ability to adjust to hypoxic conditions and control cell survival, helping to potentially overcome therapeutic cell death resistance in glioblastomas. Cancer Res; 70(1); 357–66
Obesity and Breast Cancer: Progress to Understanding the Relationship
Authors: Brown Kristy A. , Simpson Evan R.
Published: December 2009

Epidemiological evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase (AMPK) is recognized to be a master regulator of energy homeostasis. One of its actions is to phosphorylate and inhibit the actions of cAMP-responsive element binding protein (CREB)-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the CREB-dependent regulation of aromatase is a crucial determinant of breast tumor formation through local production of estrogens. We report here that the regulation of aromatase expression in the breast by AMPK and CRTC2, in response to the altered adipokine milieu associated with obesity, provides an important link between obesity and breast cancer risk. Cancer Res; 70(1); 4–7
The Nicotinamide Phosphoribosyltransferase: A Molecular Link between Metabolism, Inflammation, and Cancer
Authors: Gallí Mara , Van Gool Frédéric , Rongvaux Anthony , Andris Fabienne , Leo Oberdan
Published: December 2009

Beyond its well-described role in cellular metabolism, intracellular nicotinamide adenine dinucleotide (NAD) levels have been shown to affect the enzymatic activity of a series of NAD-dependent enzymes, influencing biological responses such as cell survival and inflammation. Nicotinamide phosphoribosyl transferase activity has been shown to be essential for maintaining adequate intracellular NAD levels, suggesting that this enzyme may in fact play a central role in modulating the activity of a wide range of NAD-dependent enzymes. Several recent observations concur with this hypothesis and suggest that by regulating NAD availability, Nampt is able to control both cell viability and the inflammatory response. Nampt may thus represent a novel pharmacological target with valuable anti-inflammatory and antitumor properties. Cancer Res; 70(1); 8–11
Diagnosing Cervical Cancer and High-Grade Precursors by HPV16 Transcription Patterns
Authors: Schmitt Markus , Dalstein Véronique , Waterboer Tim , Clavel Christine , Gissmann Lutz , Pawlita Michael
Published: December 2009

Infections with high-risk human papillomaviruses (HPV), mainly HPV type 16, can cause malignant transformation of the human cervical epithelium and the development of cervical cancer (CxCa). A rapid and precise diagnosis of the precancerous lesions by conventional cytology or HPV DNA tests remains difficult and often leads to overtreatment. We quantitatively analyzed the HPV16 transcriptome of 80 HPV16 DNA-positive cervical scrapes classified as mild cytologic grade, including no intraepithelial lesion or malignancy (NIL/M; normal, n = 25) and low-grade squamous intraepithelial lesion (LSIL; n = 24), and severe cytologic grade, including high-grade squamous intraepithelial lesion (HSIL; n = 24) and CxCa (n = 7), with novel nucleic acid sequence-based amplification–Luminex assays. In severe lesions, HPV16 E6*II and E1C encoding transcripts were strongly upregulated, whereas spliced E1^E4 and L1 encoding transcripts were markedly downregulated. Using a combination of the four marker transcripts, 100% of CxCa and 67% of HSIL cases were correctly identified as severe, and 74% of LSIL and 92% of NIL/M samples as mild cytologic grade. Compared with a commercially available HPV E6/E7 mRNA assay, the specificity of the marker combination for discriminating severe and mild cytologic lesions increased from 23% to 83%. In conclusion, we identified a novel HPV16 RNA pattern for grading of cervical lesions with a potentially high diagnostic value for the primary screening of CxCa precursors and the triage of cervical lesions. Cancer Res; 70(1); 249–56
Systems Biologists Seek Fuller Integration of Systems Biology Approaches in New Cancer Research Programs
Authors: Wolkenhauer Olaf , Auffray Charles , Baltrusch Simone , Blüthgen Nils , Byrne Helen , Cascante Marta , Ciliberto Andrea , Dale Trevor , Drasdo Dirk , Fell David , Ferrell James E. , Gallahan Daniel , Gatenby Robert , Günther Ulrich , Harms Brian D. , Herzel Hanspeter , Junghanss Christian , Kunz Manfred , van Leeuwen Ingeborg , Lenormand Philippe , Levi Francis , Linnebacher Michael , Lowengrub John , Maini Philip K. , Malik Arif , Rateitschak Katja , Sansom Owen , Schäfer Reinhold , Schürrle Karsten , Sers Christine , Schnell Santiago , Shibata Darryl , Tyson John , Vera Julio , White Michael , Zhivotovsky Boris , Jaster Robert
Published: December 2009

Systems biology takes an interdisciplinary approach to the systematic study of complex interactions in biological systems. This approach seeks to decipher the emergent behaviors of complex systems rather than focusing only on their constituent properties. As an increasing number of examples illustrate the value of systems biology approaches to understand the initiation, progression, and treatment of cancer, systems biologists from across Europe and the United States hope for changes in the way their field is currently perceived among cancer researchers. In a recent EU-US workshop, supported by the European Commission, the German Federal Ministry for Education and Research, and the National Cancer Institute of the NIH, the participants discussed the strengths, weaknesses, hurdles, and opportunities in cancer systems biology. Cancer Res; 70(1); 12–3
Imaging the Unfolded Protein Response in Primary Tumors Reveals Microenvironments with Metabolic Variations that Predict Tumor Growth
Authors: Spiotto Michael T. , Banh Alice , Papandreou Ioanna , Cao Hongbin , Galvez Michael G. , Gurtner Geoffrey C. , Denko Nicholas C. , Le Quynh Thu , Koong Albert C.
Published: December 2009

Cancer cells exist in harsh microenvironments that are governed by various factors, including hypoxia and nutrient deprivation. These microenvironmental stressors activate signaling pathways that affect cancer cell survival. While others have previously measured microenvironmental stressors in tumors, it remains difficult to detect the real-time activation of these downstream signaling pathways in primary tumors. In this study, we developed transgenic mice expressing an X-box binding protein 1 (XBP1)-luciferase construct that served as a reporter for endoplasmic reticulum (ER) stress and as a downstream response for the tumor microenvironment. Primary mammary tumors arising in these mice exhibited luciferase activity in vivo. Multiple tumors arising in the same mouse had distinct XBP1-luciferase signatures, reflecting either higher or lower levels of ER stress. Furthermore, variations in ER stress reflected metabolic and hypoxic differences between tumors. Finally, XBP1-luciferase activity correlated with tumor growth rates. Visualizing distinct signaling pathways in primary tumors reveals unique tumor microenvironments with distinct metabolic signatures that can predict for tumor growth. Cancer Res; 70(1); 78–88
Central Role of IFNγ–Indoleamine 2,3-Dioxygenase Axis in Regulation of Interleukin-12–Mediated Antitumor Immunity
Authors: Gu Tao , Rowswell-Turner Rachael B. , Kilinc Mehmet O. , Egilmez Nejat K.
Published: December 2009

Sustained intratumoral delivery of interleukin-12 (IL-12) and granulocyte macrophage colony-stimulating factor induces tumor regression via restoration of tumor-resident CD8+ T-effector/memory cell cytotoxicity and subsequent repriming of a secondary CD8+ T-effector cell response in tumor-draining lymph nodes (TDLN). However, treatment-induced T-effector activity is transient and is accompanied with a CD4+ CD25+ Foxp3+ T-suppressor cell rebound. Molecular and cellular changes in posttherapy tumor microenvironment and TDLN were monitored to elucidate the mechanism of counterregulation. Real-time PCR analysis revealed a 5-fold enhancement of indoleamine 2,3-dioxygenase (IDO) expression in the tumor and the TDLN after treatment. IDO induction required IFNγ and persisted for up to 7 days. Administration of the IDO inhibitor d-1-methyl tryptophan concurrent with treatment resulted in a dramatic enhancement of tumor regression. Enhanced efficacy was associated with a diminished T-suppressor cell rebound, revealing a link between IDO activity and posttherapy regulation. Further analysis established that abrogation of the regulatory counterresponse resulted in a 10-fold increase in the intratumoral CD8+ T-cell to CD4+ Foxp3+ T-cell ratio. The ratio of proliferating CD8+ T-effector to CD4+ Foxp3+ T-suppressor cells was prognostic for efficacy of tumor suppression in individual mice. IFNγ-dependent IDO induction and T-suppressor cell expansion were primarily driven by IL-12. These findings show a critical role for IDO in the regulation of IL-12–mediated antitumor immune responses. Cancer Res; 70(1); 129–38.
Expression of Interleukin-1 Receptor–Associated Kinase-1 in Non–Small Cell Lung Carcinoma and Preneoplastic Lesions
Authors: Behrens Carmen , Feng Lei , Kadara Humam , Kim Hyun-Jung , Lee J. Jack , Mehran Reza , Hong Waun Ki , Lotan Reuben , Wistuba Ignacio I.
Published: December 2009

Purpose: To identify the pattern of interleukin-1 receptor–associated kinase (IRAK-1) protein expression in non–small cell lung carcinoma (NSCLC) and corresponding preneoplastic lesions.

Experimental Design: Archived tissue from NSCLC (adenocarcinoma and squamous cell carcinoma; n = 306) and adjacent bronchial epithelial specimens (n = 315) were analyzed for the immunohistochemical expression of IRAK-1, and the findings were correlated with patients' clinicopathologic features. Furthermore, we investigated the correlation between IRAK-1 expression and expression of NF-κB and IL-1α in tumor specimens.

Results: NSCLC tumors showed significantly higher cytoplasmic and lower nuclear IRAK-1 expression than normal epithelium. Squamous dysplasias had significantly higher cytoplasmic IRAK-1 expression than normal epithelium. In tumors, a significant positive correlation was detected between IRAK-1 expression (nuclear and cytoplasmic; P = 0.011) and IL-1α cytoplasmic expression (P < 0.0001). The correlation between the expression of the markers and patients' clinicopathologic features varied according to tumor histologic type and sex. High IRAK-1 cytoplasmic expression correlated with worse recurrence-free survival in women with NSCLC [hazard ratio (HR), 2.204; P = 0.033], but not in men. In adenocarcinoma, combined low level of expression of nuclear IRAK-1 and NF-κB correlated significantly with worse overall (HR, 2.485; P = 0.007) and recurrence-free (HR, 3.058; P = 0.006) survivals in stage I/II patients.

Conclusions: IRAK-1 is frequently expressed in NSCLC tissue specimens, and this expression is an early phenomenon in the sequential development of lung cancer. IRAK-1 is a novel inflammation-related marker and a potential target for lung cancer chemopreventive strategies. Clin Cancer Res; 16(1); 34–44
Phase I Study of the Angiogenesis Inhibitor BIBF 1120 in Patients with Advanced Solid Tumors
Authors: Mross Klaus , Stefanic Martin , Gmehling Daniela , Frost Annette , Baas Franziska , Unger Clemens , Strecker Ralph , Henning Jürgen , Gaschler-Markefski Birgit , Stopfer Peter , de Rossi Lothar , Kaiser Rolf
Published: December 2009

Purpose: BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120.

Patients and Methods: Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients.

Results: Most frequent BIBF 1120–related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (tmax = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients.

Conclusions: BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile, and first efficacy signals were observed. Twice daily dosing permitted increased drug exposure without additional toxicity. Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies. Clin Cancer Res; 16(1); 311–9
A Group of Genome-Based Biomarkers That Add to a Kattan Nomogram for Predicting Progression in Men with High-Risk Prostate Cancer
Authors: Paris Pamela L. , Weinberg Vivian , Albo Giancarlo , Roy Ritu , Burke Catherine , Simko Jeffry , Carroll Peter , Collins Colin
Published: December 2009

Purpose: The three main treatment options for primary prostate cancer are surgery, radiation, and active surveillance. Surgical and radiation intervention for prostate cancer can be associated with significant morbidity. Therefore, accurate stratification predictive of outcome for prostate cancer patients is essential for appropriate treatment decisions. Nomograms that use clinical and pathologic variables are often used for risk prediction. Favorable outcomes exist even among men classified by nomograms as being at high risk of recurrence.

Experimental Design: Previously, we identified a set of DNA-based biomarkers termed Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) and have shown that they can predict risk of recurrence with 80% accuracy. Here, we examined the risk prediction ability of GEMCaP in a high-risk cohort and compared it to a Kattan nomogram.

Results: We determined that the GEMCaP genotype alone is comparable with the nomogram, and that for a subset of cases with negative lymph nodes improves upon it.

Conclusion: Thus, GEMCaP shows promise for predicting unfavorable outcomes for negative lymph node high-risk cases, where the nomogram falls short, and suggests that addition of GEMCaP to nomograms may be warranted. Clin Cancer Res; 16(1); 195–202
Targeting of Bone-Derived Insulin-Like Growth Factor-II by a Human Neutralizing Antibody Suppresses the Growth of Prostate Cancer Cells in a Human Bone Environment
Authors: Kimura Taichi , Kuwata Takeshi , Ashimine Satoshi , Yamazaki Manabu , Yamauchi Chisako , Nagai Kanji , Ikehara Akashi , Feng Yang , Dimitrov Dimiter S. , Saito Seiichi , Ochiai Atsushi
Published: December 2009

Purpose: Advanced prostate cancer frequently involves the bone, where the insulin-like growth factor (IGF)-II is abundant. However, the importance of IGF-II in bone metastasis from prostate cancer is uncertain. The present study was aimed at examining the therapeutic importance of targeting IGF-II in bone metastases from prostate cancer.

Experimental Design: We investigated whether inhibiting IGF-II using a human neutralizing antibody (m610) suppresses the growth of prostate cancer cells in a human bone environment. Human MDA PCa 2b prostate cancer cells were inoculated into human adult bone implanted into mammary fat pad of nonobese diabetic/severe combined immunodeficient mice or inoculated into mammary fat pad of the mice without human bone implantation. The mice were treated with m610 or a control antibody (m102.4) once weekly for 4 weeks immediately after inoculation with MDA PCa 2b cells.

Results: Histomorphologic examination indicated that m610 treatment significantly decreased the MDA PCa 2b tumor area in the human bone compared with the control. Ki-67 immunostaining revealed that the percentage of proliferating cancer cells in the m610-treated bone tumor sections was significantly lower than that in the control. m610 had no effect on MDA PCa 2b tumor growth in the absence of implanted human bone. m610 prevented the in vitro IGF-II–induced proliferation of MDA PCa 2b cells.

Conclusions: Our results indicate that IGF-II plays an important role in the prostate cancer cell growth in human bone, suggesting that targeting it by neutralizing antibodies offers a new therapeutic strategy for bone metastasis from prostate cancer. Clin Cancer Res; 16(1); 121–29
Rap1 Stabilizes β-Catenin and Enhances β-Catenin–Dependent Transcription and Invasion in Squamous Cell Carcinoma of the Head and Neck
Authors: Goto Mitsuo , Mitra Raj S. , Liu Min , Lee Julia , Henson Bradley S. , Carey Thomas , Bradford Carol , Prince Mark , Wang Cun-Yu , Fearon Eric R. , D'Silva Nisha J.
Published: December 2009

Purpose: In head and neck squamous cell carcinoma (HNSCC) cells, Rap1 shuttles between the nucleus and cytoplasm. Prior findings suggested that Rap1 may modulate the β-catenin–independent Wnt pathway in some settings, but the role of Rap1 in β-catenin–dependent Wnt signaling remains undefined.

Experimental Design and Results: We observed that β-catenin bound to active Rap1 in vitro and Rap1 activated β-catenin/T-cell factor (TCF)–dependent transcription. Immunofluorescence studies showed that ectopic expression of Rap1 increased nuclear translocation of β-catenin. Overexpression of active Rap1 facilitated an increase in β-catenin–mediated transcription that was abrogated by dominant-negative TCF4. Conversely, small interfering RNA–mediated inhibition of endogenous Rap1 expression inhibited β-catenin/TCF–mediated transcription as well as invasion of HNSCC. Furthermore, inhibition of Rap1 expression downregulated the expression of matrix metalloproteinase 7, a transcriptional target of β-catenin/TCF. In HNSCC cells stably transfected with β-catenin or treated with lithium chloride or Wnt3A to stabilize endogenous β-catenin, inhibition of Rap1 expression led to decreases in the free pool of β-catenin. Immunohistochemical studies of tissue from HNSCC patients revealed that increased β-catenin intensity correlated with higher tumor stage. Furthermore, the prognostic effect of active Rap1 on tumor N stage was found to depend on cytosolic β-catenin expression (P < 0.013). When β-catenin is high, higher Rap1GTP intensity is associated with more advanced N stage.

Conclusions: The findings suggest that Rap1 enhances β-catenin stability and nuclear localization. In addition to indicating that Rap1 has a significant role in regulating β-catenin and β-catenin–dependent progression to more advanced N-stage lesions, these data highlight Rap1 as a potential therapeutic target in HNSCC. Clin Cancer Res; 16(1); 65–76
Association of Epidermal Growth Factor Receptor Polymorphism, Skin Toxicity, and Outcome in Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab-Docetaxel Treatment
Authors: Klinghammer Konrad , Knödler Maren , Schmittel Alexander , Budach Volker , Keilholz Ulrich , Tinhofer Ingeborg
Published: December 2009

Purpose: Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), has shown clinical efficacy in squamous cell carcinoma of the head and neck with prolonged progression-free (PFS) and overall survival (OS). In this study, we analyzed whether cetuximab-induced skin rash was correlated with distinct polymorphisms within the EGFR gene known to modulate EGFR expression, ligand binding, or signaling activity.

Experimental Design: Fifty-one patients enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with cetuximab/docetaxel were genotyped for two genetic variations in the EGFR gene, a point substitution G→A in exon 13 resulting in an amino acid substitution in position 521 (EGFR-R521K) and a CA repeat (CA-SSR) polymorphism in intron 1. Association between genotypes and incidence/grade of skin rash was determined by Fisher's exact test. The predictive value of genotypes for PFS and OS was determined using the log-rank test.

Results: Overall, 21 patients (41%) developed skin rash with grade >1 within 6 weeks of treatment. The common EGFR-R521K genotype (G/G) was significantly associated with increased skin toxicity (P = 0.024) and showed a trend toward reduced risk of tumor progression (hazard ratio, 0.55; 95% confidence interval, 0.27-1.08; P = 0.08), whereas no correlation of the EGFR-R521K genotype with OS could be observed (P = 0.20). No significant interaction between CA-SSR polymorphism and skin toxicity, PFS, or OS could be detected.

Conclusions: Our study revealed an influence of the EGFR-R521K genotype on skin toxicity and suggested its relation to clinical activity of cetuximab/docetaxel treatment. Clin Cancer Res; 16(1); 304–10
Bevacizumab Safety in Patients with Central Nervous System Metastases
Authors: Besse Benjamin , Lasserre Susan F. , Compton Peter , Huang Jane , Augustus Stella , Rohr Ulrich-Peter
Published: December 2009

Purpose: Patients with central nervous system (CNS) metastases were excluded from bevacizumab trials following a case of fatal cerebral hemorrhage in a patient with hepatocellular carcinoma in 1997. Safety information for bevacizumab-treated patients with CNS metastases was reviewed to determine whether general exclusion of these patients from bevacizumab treatment is still justified.

Experimental Design: A retrospective exploratory analysis was conducted using datasets from 13 randomized controlled phase II/III trials (dataset A), two open-label single-arm safety trials (dataset B), and two prospective studies including patients with treated CNS metastases (dataset C). In datasets A and B, known CNS metastasis was an exclusion criterion; patients with CNS metastasis had unrecognized CNS metastases at study entry or developed them during the trial. All reported cerebral hemorrhage grades in patients with CNS metastases were quantified.

Results: In dataset A, occult brain metastases were identified in 187 of 8,443 patients (91 in bevacizumab arms and 96 in non-bevacizumab arms). Three bevacizumab-treated patients (3.3%) developed grade 4 cerebral hemorrhage, whereas one control-arm patient (1.0%) developed grade 5 cerebral hemorrhage. In dataset B, 321 of 4,382 patients had initially occult CNS metastases, in whom two grade 1 and one grade 3 cerebral hemorrhage (0.9%) were reported. In 131 patients with treated CNS metastases in dataset C, one bevacizumab-treated patient (0.8%) developed grade 2 cerebral hemorrhage.

Conclusions: In this selected population, patients with CNS metastases are at similar risk of developing cerebral hemorrhage, independent of bevacizumab therapy. Consequently, such patients with CNS metastases from advanced/metastatic breast cancer, non–small cell lung carcinoma, and renal and colorectal cancer should not be generally excluded from bevacizumab therapy or clinical trials. Clin Cancer Res; 16(1); 269–78
A Systematic Review on Intrapyloric Botulinum Toxin Injection for Gastroparesis
Authors: Bai Yu , Xu Mao-Jin , Yang Xia , Xu Can , Gao Jun , Zou Duo-Wu , Li Zhao-Shen
Published: December 2009

Background: Though trials evaluating the effect of intrapyloric botulinum toxin injection on gastroparesis have been reported, there is no agreement whether botulinum toxin can effectively relieve the symptoms and improve the results of gastric emptying study in patients with gastroparesis. We performed a systematic literature review to address this issue. Methods: Databases including PubMed, EMBASE, and the Cochrane Library and Science Citation Index were searched. Two reviewers independently identified relevant trials. Outcome measures were the improvement of subjective symptoms and objective measurement. Results: 15 reports were included; only 2 randomized controlled trials were available. Almost all the non-randomized trials reported significant improvement in subjective symptoms and objective gastric emptying study after botulinum toxin injection. While the 2 randomized controlled trials did not confirm the efficacy of botulinum toxin injection, none of the individual trials showed that there was statistically significant subjective and objective improvement in the active patients when compared with patients receiving placebo. Conclusions: Available high-quality trials showed that intrapyloric botulinum toxin injection could not significantly relieve subjective symptoms and improve objective measurement in patients with gastroparesis, and there is no evidence to recommend botulinum toxin injection for the treatment of gastroparesis.