bluuebunny/crossref_metadata_2025 huggingface dataset:
Palaeozoic palaeogeography of Mexico: constraints from detrital zircon age data
Authors: Nance R. Damian , Keppie J. Duncan , Miller Brent V. , Murphy J. Brendan , Dostal Jaroslav
Published: December 2009

Detrital zircon age populations from Palaeozoic sedimentary and metasedimentary rocks in Mexico support palinspastic linkages to the northwestern margin of Gondwana (Amazonia) during the late Proterozoic–Palaeozoic. Age data from: (1) the latest Cambrian-Pennsylvanian cover of the
c
. 1 Ga Oaxacan Complex of southern Mexico; (2) the ?Cambro-Ordovician to Triassic Acatlán Complex of southern Mexico's Mixteca terrane; and (3) the ?Silurian Granjeno Schist of northeastern Mexico's Sierra Madre terrane, collectively suggest Precambrian provenances in: (1) the
c
. 500–650 Ma Brasiliano orogens and
c
. 600–950 Ma Goias magmatic arc of South America, the Pan-African Maya terrane of the Yucatan Peninsula, and/or the
c
. 550–600 Ma basement that potentially underlies parts of the Acatlán Complex; (2) the Oaxaquia terrane or other
c
. 1 Ga basement complexes of the northern Andes; and (3)
c
. 1.4–3.0 Ga cratonic provinces that most closely match those of Amazonia. Exhumation within the Acatlán Complex of
c
. 440–480 Ma granitoids prior to the Late Devonian–early Mississippian, and
c
. 290 Ma granitoids in the early Permian, likely provided additional sources in the Palaeozoic. The detrital age data support the broad correlation of Palaeozoic strata in the Mixteca and Sierra Madre terranes, and suggest that, rather than representing vestiges of Iapetus or earlier oceanic tracts as has previously been proposed, both were deposited along the southern, Gondwanan (Oaxaquia) margin of the Rheic Ocean and were accreted to Laurentia during the assembly of Pangaea in the late Palaeozoic.
Rheic Ocean mafic complexes: overview and synthesis
Authors: Murphy J. Brendan , Gutiérrez-Alonso Gabriel , Nance R. Damian , Fernández-Suárez Javier , Keppie J. Duncan , Quesada Cecilio , Dostal Jaroslav , Braid James A.
Published: December 2009

The Rheic Ocean formed during the Late Cambrian–Early Ordovician when peri-Gondwanan terranes (e.g. Avalonia) drifted from the northern margin of Gondwana, and was consumed during the collision between Laurussia and Gondwana and the amalgamation of Pangaea. Several mafic complexes, from the Acatlán Complex in Mexico to the Bohemian Massif in eastern Europe, have been interpreted to represent vestiges of the Rheic Ocean. Most of these complexes are either Late Cambrian–Early Ordovician or Late Palaeozoic in age. Late Cambrian–Early Ordovician complexes are predominantly rift-related continental tholeiites, derived from an enriched
c.
1.0 Ga subcontinental lithospheric mantle, and are associated with crustally-derived felsic volcanic rocks. These complexes are widespread and virtually coeval along the length of the Gondwanan margin. They reflect magmatism that accompanied the early stages of rifting and the formation of the Rheic Ocean, and they remained along the Gondwanan margin to form part of a passive margin succession as Avalonia and other peri-Gondwanan terranes drifted northward. True ophiolitic complexes of this age are rare, a notable exception occurring in NW Iberia where they display ensimatic arc geochemical affinities. These complexes were thrust over, or extruded into, the Gondwanan margin during the Late Devonian–Carboniferous collision between Gondwana and Laurussia (Variscan orogeny). The Late Palaeozoic mafic complexes (Devonian and Carboniferous) preserve many of the lithotectonic and/or chemical characteristics of ophiolites. They are characterized by derivation from an anomalous mantle which displays time-integrated depletion in Nd relative to Sm. Devonian ophiolites pre-date closure of the Rheic Ocean. Although their tectonic setting is controversial, there is a consensus that most of them reflect narrow tracts of oceanic crust that originated along the Laurussian margin, but were thrust over Gondwana during Variscan orogenesis. The relationship of the Carboniferous ophiolites to the Rheic Ocean
sensu stricto
is unclear, but some of them apparently formed in a strike-slip regimes within a collisional setting directly related to the final stages of the closure of the Rheic Ocean.
Neoproterozoic reworking of the Palaeoproterozoic Capricorn Orogen of Western Australia and implications for the amalgamation of Rodinia
Authors: Occhipinti Sandra A. , Reddy Steven M.
Published: December 2009

Argon isotopic data from mica from the southern Capricorn region of Western Australia record complex intra- and inter-grain systematics that reflect modification due to a range of processes. However,
40
Ar/
39
Ar age distributions, though complex, generally show early Neoproterozoic ages in the west, increasing to Mesoproterozoic ages in the east. Palaeoproterozoic ages associated with cooling after the
c.
1.8 Ga Capricorn Orogen or
c.
1.6 Ga Mangaroon Orogen are not preserved. These data reflect cooling from a
c
. 300 °C thermal overprint that took place prior to 960 Ma that is related to the enigmatic Edmundian Orogeny. These data, combined with sediment provenance data from the Early Neoproterozoic Officer Basin and U–Pb age data from the nearby Pinjarra Orogen, indicate that the late Mesoproterozoic–Neoproterozoic Pinjarra and Edmundian events are dynamically linked and reflect tectonic activity on the western margin of the amalgamated West Australian Craton. The temporal framework for this event suggest a link to the evolving Rodinian supercontinent and reflect the oblique collision of either Greater India or Kalahari cratons with the West Australian Craton. These results illustrate that the temporal evolution of poorly preserved orogens can be constrained by low-temperature thermochronology in the adjacent cratons.
The Palaeoproterozoic Trans-Hudson Orogen: a prototype of modern accretionary processes
Authors: Corrigan D. , Pehrsson S. , Wodicka N. , de Kemp E.
Published: December 2009

The Trans-Hudson Orogen (THO) of North America is one of the earliest orogens in Earth's history that evolved through a complete Wilson Cycle. It represents
c
. 150 Ma of opening of the Manikewan Ocean, from
c
. 2.07–1.92 Ga, followed by its demise in the interval 1.92–1.80 Ga, during the final phase of growth of the Supercontinent Columbia (Nuna). It is characterized by three lithotectonic divisions: (i) Churchill margin (or peri-Churchill); (ii) Reindeer Zone; and (iii) Superior margin (or peri-Superior). The peri-Churchill realm records progressive outward continental growth by accretion of Archaean to Palaeoproterozoic micro-continents (Hearne, Meta Incognita/Core Zone, Sugluk) and eventually arc terranes (La Ronge–Lynn Lake) to the Slave-Rae nuclei, with attendant development of orogenies and basin inversions related to the specific accretion events (1.92–1.89 Ga Snowbird; 1.88–1.865 Ga Foxe; 1.87–1.865 Ga Reindeer orogenies). The Reindeer Zone is characterized by primitive to evolved oceanic arcs, back-arc basins, oceanic crust and ocean plateaus that formed during closure of the Manikewan Ocean, and accretion of a micro-continent (Sask Craton) and smaller Archaean crustal fragments. The terminal phase of the Trans–Hudson orogeny represents collision between the Superior craton, the Reindeer Zone and the composite western Churchill Province during the interval 1.83–1.80 Ga.
Middle Miocene Chiapas fold and thrust belt of Mexico: a result of collision of the Tehuantepec Transform/Ridge with the Middle America Trench
Authors: Mandujano-Velazquez J. J. , Keppie J. Duncan
Published: December 2009

The Middle Miocene, thin-skinned, Chiapas fold-and-thrust belt (Gulf of Mexico–southeastern Mexico–Belize) consists of WNW-trending folds and thrusts, and East–West sinistral transcurrent faults resulting from N60°E shortening. Balanced cross-sections indicate that shortening varies from 48% (SW) to
c
. 8% (NE) with a total shortening of 106 km, and that thrusts merge into a basal décollement in the Callovian salt horizon. The Middle Miocene age of the deformation is synchronous with collision of the Tehuantepec Transform/Ridge with the Middle America Trench off Chiapas. The presently exposed Tehuantepec Transform/Ridge varies from a transform fault across which the age of the oceanic crust changes producing a step (down to the east) to a ridge resulting from compression following a change in plate motion and a series of seamounts. On the other hand, the earthquake data show that the part of the Tehuantepec Transform/Ridge subducted during the past 5 Ma is a step with no accompanying ridge. Whereas collision of a ridge segment with the trench is inferred to be responsible for the 13–11 Ma deformation in the upper plate, its termination at 11 Ma suggests an along-strike transition to a step. Collision of the Tehuantepec Transform/Ridge also appears to have terminated arc magmatism along the Pacific coast of Chiapas. The similarity between the petroleum-producing, Cantarell structure in the Sonda de Campeche and the buried foldbelt in the Sierra de Chiapas suggests there is considerable further hydrocarbon potential.
Rebuilding for eternity
Authors: Geller Tom
Published: December 2009

Researchers use computer vision techniques to preserve culturally significant sites as high-resolution 3D models.
The business of softwareIn praise of bad programmers
Authors: Armour Phillip G.
Published: December 2009

A tale illustrating the difference between individual and team skills.
Other people's data
Authors: Petschulat Stephen
Published: December 2009

Companies have access to more types of external data than ever before. How can they integrate it most effectively?
MapReduce
Authors: Dean Jeffrey , Ghemawat Sanjay
Published: December 2009

MapReduce advantages over parallel databases include storage-system independence and fine-grain fault tolerance for large jobs.
Information retrieval and advertising
Authors: Bilenko Mikhail , Gabrilovich Evgeniy , Richardson Matthew , Zhang Yi
Published: December 2009

The Information Retrieval and Advertising Workshop (IRA 2009) was held on July 23, 2009 in Boston, Massachusetts, in conjunction with the 32nd Annual ACM SIGIR Conference. The workshop covered theoretical and empirical issues in several research areas that span the intersection of computational advertising, information retrieval, and economics. The workshop consisted of 3 invited talks, 6 refereed paper presentations, 2 positions statement presentations and several discussion sessions.
Water Dynamics in Semi-IPN Porous Membrane for Fuel Cells
Authors: Chu Peter P. , Wu Chien-Shun , Liu Bo-Cheng , Wang J. S. , Pan Jin-Ping
Published: December 2009

Water diffusion and dynamic motion within the confined sPEEK channel are examined. To produce materials with different channel dimension, sPEEK/hyper branch mBMI membrane are prepared by in-situ polymerization. NMR T1 and T2 relaxation time measurements are employed to understand the dynamic behavior of water at low (λ=2-3) medium (λ=4-8) and high (λ=14-20) water uptake in these membranes. At fully saturated extreme, the activation energy is found to be higher (30 to 40 kJ/mole) than that of the bulk water (20 to 30 kJ/mole). This is due to the fact that water diffuse in the constraint channel, thus experiencing higher viscousity. On the other hand, at low water uptake, the water migration activation energy is lower than that of the bulk or in the fully saturated sample. This suggested proton migration involves the relay motion of interconnected hydrogen boding network formed between the sulfonated/amine group of mBMI with the residue water.
Life Threatening Complication during Treatment of Erysipelas due to Undiagnosed Ischemia of the Calf
Authors: Brzeziński Tomasz , Ostrowski Tomasz , Skórski Maciej
Published: December 2009

Erysipelas is a superficial skin infection due to streptococci strains, which usually responds well to conservative treatment. Coexisting undiagnosed ischemia of the extremity may lead to severe complications. 57-year-old man developed large, circumflex ulceration of his right calf within two weeks before the admission after three-month treatment of erysipelas. Computer angiography showed chronic occlusion of the superficial femoral artery and the above knee popliteal artery. Rapid debridement of the wound took control over the infection. Patient required complex vascular procedure which allowed to prepare the ulcer for meshed skin grafts. Patient was discharged home on 64th hospital day with completely healed ulcer.
Permanence of Periodic Predator‐Prey System with General Nonlinear Functional Response and Stage Structure for Both Predator and Prey
Authors: Huang Xuming , Kong Xiangzeng , Yang Wensheng
Published: December 2009

We study the permanence of periodic predator‐prey system with general nonlinear functional responses and stage structure for both predator and prey and obtain that the predator and the prey species are permanent.
Interactive Data Mining for Molecular Graphs
Authors: Yılmaz Burcu , Göktürk Mehmet
Published: December 2009

Designing new medical drugs for a specific disease requires extensive analysis of many molecules that have an activity for the disease. The main goal of these extensive analyses is to discover substructures (fragments) that account for the activity of these molecules. Once they are discovered, these fragments are used to understand the structure of new drugs and design new medicines for the disease. In this paper, we propose an interactive approach for visual molecule mining to discover fragments of molecules that are responsible for the desired activity with respect to a specific disease. Our approach visualizes molecular data in a form that can be interpreted by a human expert. Using a pipelining structure, it enables experts to contribute to the solution with their expertise at different levels. In order to derive desired fragments, it combines histogram‐based filtering and clustering methods in a novel way. This combination enables a flexible determination of frequent fragments that repeat in molecules exactly or with some variations.
Painless Obstructive Jaundice Secondary to a Common Bile Duct Abscess: A Delayed Sequela of Cholecystectomy
Authors: Fairhurst Katherine , Strickland Andrew , Bridgewater Franklin H. G. , Maddern Guy J.
Published: December 2009

Complications related to cholecystectomy are well described. Most occur in the early postoperative period and are recognised either at the time of, or shortly after surgery. Clinical sequelae occurring years following cholecystectomy are rare and infrequently reported. In addition, most delayed complications are related to the continuing presence or new formation of gallstones. In this paper we present a unique case of an abscess of the common bile duct wall, presenting with painless obstructive jaundice more than 30 years following an open cholecystectomy, without the presence of gallstones. The clinical presentation, investigations, and treatment are discussed with a review of other relevant reported cases in the literature.
Use of Hydrophilic Insoluble Polymers in the Restoration of Metal-Contaminated Soils
Authors: Qu Guiwei , de Varennes Amarilis
Published: December 2009

To develop cost-effective techniques that contribute to phytostabilization of severely metal-contaminated soils is a necessary task in environmental research. Hydrophilic insoluble polymers have been used for some time in diapers and other hygienic products and to increase the water-holding capacity of coarse-textured soils. These polymers contain groups, such as carboxyl groups, that are capable of forming bonds with metallic cations, thereby decreasing their bioavailability in soils. The use of polyacrylate polymers as soil amendments to restore metal-contaminated soils has been investigated in the Technical University of Lisbon since the late nineties. Plant growth and plant nutrients concentrations, extractable levels of metals in soil, and soil enzyme activities were used to monitor the improvement in soil quality following the application of these polymers. In contaminated soils, hydrophilic insoluble polymers can create microcosms that are rich in water and nutrients (counterions) but only contain small concentrations of toxic elements; the conditions of these microenvironments are favorable to roots and microorganisms. In this paper we described the most relevant information available about this topic.
Immunological and Therapeutic Strategies against Salmonid Cryptobiosis
Authors: Woo Patrick T. K.
Published: December 2009

Salmonid cryptobiosis is caused by the haemoflagellate,Cryptobia salmositica. Clinical signs of the disease in salmon (Oncorhynchusspp.) include exophthalmia, general oedema, abdominal distension with ascites, anaemia, and anorexia. The disease-causing factor is a metalloprotease and the monoclonal antibody (mAb-001) against it is therapeutic. MAb-001 does not fix complement but agglutinates the parasite. Some brook charr,Salvelinus fontinaliscannot be infected (Cryptobia-resistant); this resistance is controlled by a dominant Mendelian locus and is inherited. InCryptobia-resistant charr the pathogen is lysed via the Alternative Pathway of Complement Activation. However, some charr can be infected and they have high parasitaemias with no disease (Cryptobia-tolerant). In infectedCryptobia-tolerant charr the metalloprotease is neutralized by a natural antiprotease,α2 macroglobulin. Two vaccines have been developed. A single dose of the attenuated vaccine protects 100% of salmonids (juveniles and adults) for at least 24 months. Complement fixing antibody production and cell-mediated response in vaccinated fish rise significantly after challenge. Fish injected with the DNA vaccine initially have slight anaemias but they recover and have agglutinating antibodies. On challenge, DNA-vaccinated fish have lower parasitaemias, delayed peak parasitaemias and faster recoveries. Isometamidium chloride is therapeutic against the pathogen and its effectiveness is increased after conjugation to antibodies.
Histone Deacetylase Inhibitor Therapy in Epithelial Ovarian Cancer
Authors: Takai Noriyuki , Narahara Hisashi
Published: December 2009

Since epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in ovarian cancers, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs) in treating ovarian cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and expression of genes related to the malignant phenotype in a variety of ovarian cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of thep21WAF1gene in human ovarian carcinoma cells. In xenograft models, some of HDACIs have demonstrated antitumor activity with only few side effects. Some clinical trials demonstrate that HDACI drugs provide an important class of new mechanism-based therapeutics for ovarian cancer. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating ovarian cancer, especially focusing on preclinical studies and clinical trials.
AnnaBot: A Static Verifier for Java Annotation Usage
Authors: Darwin Ian
Published: December 2009

This paper describes AnnaBot, one of the first tools to verify correct use of Annotation-based metadata in the Java
programming language. These Annotations are a standard Java 5 mechanism used to attach metadata to types, methods, or fields without using an external configuration file. A binary representation of the Annotation becomes part of the compiled “.class” file,
for inspection by another component or library at runtime. Java Annotations were introduced into the Java language in 2004 and have become widely used in recent years due to their introduction in the Java Enterprise Edition 5, the Hibernate object-relational mapping API, the Spring Framework, and elsewhere. Despite that, mainstream development tools have not yet produced a widely-used verification tool to confirm correct configuration and placement of annotations external to the particular runtime component. While most of the examples in this paper use the Java Persistence API, AnnaBot is capable of verifying anyannotation-based API for which “claims”—description of annotation
usage—are available. These claims can be written in Java or using a proposed Domain-Specific Language, which has been designed and a parser (but not the code generator) have been written.
Correctness of Protein Identifications ofBacillus subtilisProteome with the Indication on Potential False Positive Peptides Supported by Predictions of Their Retention Times
Authors: Macur Katarzyna , Bączek Tomasz , Kaliszan Roman , Temporini Caterina , Corana Federica , Massolini Gabriella , Grzenkowicz-Wydra Jolanta , Obuchowski Michał
Published: December 2009

The predictive capability of the retention time prediction model based on quantitative structure-retention relationships (QSRR) was tested. QSRR model was derived with the use of set of peptides identified with the highest scores and originated from 8 known proteins annotated as model ones. The predictive ability of the QSRR model was verified with the use of aBacillus subtilisproteome digest after separation and identification of the peptides by LC-ESI-MS/MS. That ability was tested with three sets of testing peptides assigned to the proteins identified with different levels of confidence. First, the set of peptides identified with the highest scores achieved in the search were considered. Hence, proteins identified on the basis of more than one peptide were taken into account. Furthermore, proteins identified on the basis of just one peptide were also considered and, depending on the possessed scores, both above and below the assumed threshold, were analyzed in two separated sets. The QSRR approach was applied as the additional constraint in proteomic research verifying results of MS/MS ion search and confirming the correctness of the peptides identifications along with the indication of the potential false positives.
Is Classical Energy Equation Adequate for Convective Heat Transfer in Nanofluids?
Authors: Fan Jing , Wang Liqiu
Published: December 2009

To address whether the heat transfer in nanofluids still satisfies the classical energy equation, we theoretically examine the macroscale manifestation of the microscale physics in nanofluids. The microscale interaction between nanoparticles and base fluids manifests itself as thermal waves/resonance at the macroscale. The energy equation that governs the heat transfer in nanofluids is of a dual-phase-lagging type instead of the postulated and commonly-used classical energy equation. The interplays among diffusion, convection, and thermal waves/resonance enrich the heat transfer in nanofluids considerably.
Small-Molecule Inhibitors of Phosphatidylinositol 3-Kinase/Akt Signaling Inhibit Wnt/β-Catenin Pathway Cross-Talk and Suppress Medulloblastoma Growth
Authors: Baryawno Ninib , Sveinbjörnsson Baldur , Eksborg Staffan , Chen Ching-Shih , Kogner Per , Johnsen John Inge
Published: December 2009

Activation of the β-catenin and receptor kinase pathways occurs often in medulloblastoma, the most common pediatric malignant brain tumor. In this study, we show that molecular cross-talk between the β-catenin and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways is crucial to sustain medulloblastoma pathophysiology. Constitutive activation of phosphoinositide-dependent protein kinase 1 (PDK1), Akt, and glycogen synthase kinase 3β (GSK-3β) was detected by immunohistochemistry in all primary medulloblastomas examined (n = 41). Small-molecule inhibitors targeting the PI3K/Akt signaling pathway affected β-catenin signaling by inhibition of GSK-3β activity, resulting in cytoplasmic retention of β-catenin and reduced expression of its target genes cyclin D1 and c-Myc. The PDK1 inhibitor OSU03012 induced mitochondrial-dependent apoptosis of medulloblastoma cells and enhanced the cytotoxic effects of chemotherapeutic drugs in a synergistic or additive manner. In vivo, OSU03012 inhibited the growth of established medulloblastoma xenograft tumors in a dose-dependent manner and augmented the antitumor effects of mammalian target of rapamycin inhibitor CCI-779. These findings demonstrate the importance of cross-talk between the PI3K/Akt and β-catenin pathways in medulloblastoma and rationalize the PI3K/Akt signaling pathway as a therapeutic target in treatment of this disease. Cancer Res; 70(1); 266–76
Definition of microRNAs That Repress Expression of the Tumor Suppressor Gene FOXO1 in Endometrial Cancer
Authors: Myatt Stephen S. , Wang Jun , Monteiro Lara J. , Christian Mark , Ho Ka-Kei , Fusi Luca , Dina Roberto E. , Brosens Jan J. , Ghaem-Maghami Sadaf , Lam Eric W-F.
Published: December 2009

Endometrial cancer is the most common malignancy of the lower female reproductive tract. The tumor suppressor FOXO1 is downregulated in endometrial cancer compared with normal endometrium but the underlying mechanisms are not well understood. Using microRNA (miR) target prediction algorithms, we identified several miRs that potentially bind the 3′-untranslated region of FOXO1 transcripts. Expression profiling of normal and malignant endometrial samples by quantitative real-time PCR and Northern blot analysis revealed an inverse correlation between the levels of FOXO1 protein and the abundance of several of the in silico–predicted miRs, suggesting that loss of FOXO1 expression in endometrial cancer may be mediated by miRs. To determine the role of candidate miRs, we used the endometrial cancer cell lines HEC-1B and Ishikawa, which express FOXO1 at high and low levels, respectively. Expression of miR-9, miR-27, miR-96, miR-153, miR-182, miR-183, or miR-186, but not miR-29a, miR-128, miR-152, or miR-486 mimetics in HEC-1B cells was sufficient to significantly reduce the abundance of FOXO1. Conversely, FOXO1 expression was efficiently restored in the Ishikawa cell line upon simultaneous inhibition of miR-9, miR-27, miR-96, miR-153, miR-183, and miR-186. Moreover, induction of FOXO1 in Ishikawa cells by miR inhibitors was accompanied by G1 cell cycle arrest and cell death, and was attenuated by the small interfering RNA–mediated downregulation of FOXO1 expression. Our findings identify several miRs overexpressed in endometrial cancer that function in concert to repress FOXO1 expression. Further, aberrant miR expression results in deregulated cell cycle control and impaired apoptotic responses, and thus, may be central to endometrial tumorigenesis. Cancer Res; 70(1); 367–77
c-Jun-NH2-kinase-1 Inhibition Leads to Antitumor Activity in Ovarian Cancer
Authors: Vivas-Mejia Pablo , Benito Juliana Maria , Fernandez Ariel , Han Hee-Dong , Mangala Lingegowda , Rodriguez-Aguayo Cristian , Chavez-Reyes Arturo , Lin Yvonne G. , Carey Mark S. , Nick Alpa M. , Stone Rebecca L. , Kim Hye Sun , Claret Francois-Xavier , Bornmann William , Hennessy Bryan T.J. , Sanguino Angela , Peng Zhengong , Sood Anil K. , Lopez-Berestein Gabriel
Published: December 2009

Purpose: To show the functional, clinical, and biological significance of c-Jun-NH2-kinase (JNK)-1 in ovarian carcinoma.

Experimental Design: Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK in vitro and in experimental models of ovarian cancer was assessed. We studied the role of N-5-[4-(4-methyl piperazine methyl)-benzoylamido]-2-methylphenyl-4-[3-(4-methyl)-pyridyl]-2-pyrimidine amine (WBZ_4), a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer.

Results: We found a significant association of pJNK with progression-free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose-dependent fashion in four ovarian cancer cell lines. In vivo, whereas imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The antitumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights compared with nonsilencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition.

Conclusions: These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the redesigned WBZ_4 compound should be considered for further clinical development. Clin Cancer Res; 16(1); 184–94
Somatic EGFR Mutation and Gene Copy Gain as Predictive Biomarkers for Response to Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer
Authors: Dahabreh Issa J. , Linardou Helena , Siannis Fotios , Kosmidis Paris , Bafaloukos Dimitrios , Murray Samuel
Published: December 2009

Purpose: The aim of this systematic review and meta-analysis was to characterize common EGFR molecular aberrations as potential predictive biomarkers for response to monotherapy with tyrosine kinase inhibitors (TKI) in non–small cell lung cancer (NSCLC).

Experimental Design: We systematically identified articles investigating EGFR status [somatic mutational and gene copy aberrations (copy number)] in patients with NSCLC treated with TKIs. Eligible studies had to report complete and partial response rates stratified by EGFR status. We used random effects models for bivariable meta-analysis of sensitivity and specificity; positive and negative likelihood ratios (+LR and −LR, respectively) were also calculated and were considered as secondary end points.

Results: Among 222 retrieved articles, 59 were considered eligible for the somatic EGFR mutation meta-analysis (1,020 mutations among 3,101 patients) and 21 were considered eligible for the EGFR gene copy number meta-analysis (542 gene gain among 1,539 patients). EGFR mutations were predictive of response to single-agent TKIs [sensitivity, 0.78; 95% confidence interval (95% CI), 0.74-0.82; specificity, 0.86; 95% CI, 0.82-0.89; +LR, 5.6; −LR, 0.25]. EGFR gene gain was also associated with response to TKIs, albeit with lower sensitivity and specificity. In subgroup analysis, the only recognized trend was for a higher predictive value in Whites compared with East Asians for both mutation and gene copy number.

Conclusion: This analysis provides empirical evidence that EGFR mutations are sensitive and specific predictors of response to single-agent epidermal growth factor receptor TKIs in advanced NSCLC. The diagnostic performance of mutations seems better than that of EGFR gene gain. Clin Cancer Res; 16(1); 291–303
The –928 G/C and –362 G/C Single-Nucleotide Polymorphisms in the Promoter of MCP-1: Increased Transcriptional Activity and Novel Binding Sites
Authors: Nyquist Paul , Zhang Jianhua , De Graba Thomas J.
Published: December 2009

Background: The –928 guanine (G)/cytosine (C) and –362 G/C single-nucleotide polymorphisms (SNPs) in the proximal promoter region of the monocyte chemoattractant protein 1 gene have been associated with an increased risk for intimal medial thickness and carotid atherosclerosis, respectively. We characterized the transcriptional activity of these two SNPs in vitro and identified transcription factors that bind to them. Methods: The proximal promoter region spanning bases –2746 to +440 was sequenced in subjects with carotid atherosclerosis. Two SNPs consisting of C-for-G substitution at bases –928 and –362 were characterized. Each observed haplotype was inserted into a luciferase reporter and transfected into mammalian cells. Results: Stimulation with 12-O-tetradecanoylphorbol 13-acetate increased transcriptional activity of the –928 C plasmid (p = 0.005). The basal transcription activities of the plasmids containing –928 C and –362 C were also increased (p < 0.001 and p < 0.0001, respectively). Electrophoretic mobility shift assay (EMSA) and DNA footprinting identified an Ah receptor nuclear translocator protein (ARNT) binding site at the –928 C SNP. EMSA data indicated signal transducers and activators of transcription (STAT) binding at the –362 G SNP. A nuclear binding protein, poly(ADP-ribose) polymerase (PARP) 1, was purified from the –928 C SNP site and identified by mass spectroscopy. Conclusion: The –928 C SNP and the –362 C SNP are associated with increased transcriptional activity in vitro, but the –362 G site is not. The –928 C SNP is associated with PARP-1 and ARNT binding, and the –362 G is associated with a STAT binding site.
Predictors of One-Year Disability and Death in Chinese Hospitalized Women after Ischemic Stroke
Authors: Kong Fan-Yi , Tao Wen-Dan , Hao Zi-Long , Liu Ming
Published: December 2009

Background and Purpose: Women have a worse functional outcome after stroke, but the specific factors associated with a poor outcome in women are rarely reported. This study was designed to investigate the clinical predictors of 1-year disability and death in women after ischemic stroke. Methods: Patients with ischemic stroke consecutively registered from March 2002 to July 2007 were followed prospectively for 1 year. Multivariate regression models were employed to analyze predictors of disability (defined as modified Rankin scale score, mRS, 3–5 ) and death. Results: A total of 2,774 ischemic stroke patients were included with 1,119 (40.3%) females (mean age 65 ± 13.5 years). Among female patients, disability (mRS 3–5) is 1.68-fold higher and case fatality is 1.23-fold higher than in men at the 1-year follow-up. Diabetes is an independent predictor of 1-year disability among women (odds ratio, 1.56; 95% confidence interval, CI, 1.01–2.39). In-hospital acute renal failure (hazard ratio, HR, 7.26; 95% CI, 3.47–5.19), suboptimal antiplatelets (HR, 0.55; 95% CI, 0.37–0.83) and antihypertensive therapy (HR, 0.61; 95% CI, 0.42–0.90) are associated with death at 1 year after stroke among women. Conclusions: The present study indicates that diabetes, in-hospital acute renal failure, suboptimal antiplatelets and antihypertensive therapy are the possible explanations for the poor 1-year outcome of women hospitalized with ischemic stroke.
Rank Transformation in Haseman-Elston Regression Using Scores for Location-Scale Alternatives
Authors: Gerhard Daniel , Hothorn Ludwig A.
Published: December 2009

The Haseman-Elston method is a simple regression approach for detecting genetic linkage to quantitative traits in sib-pair studies. Although this method and especially the new extended Haseman-Elston approach are quite robust, there might be some loss of power for non-normally distributed traits. We propose using rank transformation techniques, which either combine the information on a trend in locations and in scales or detect a trend only for a subset of the trait variables for genetically different sibs under linkage. As this rank transformation is based on linear regression, no exact grouping of identity by descent proportions has to be assumed. Simulation results indicate a gain in power compared to recently suggested nonparametric methods.
Multiple Subsampling of Dense SNP Data Localizes Disease Genes with Increased Precision
Authors: Stewart William C.L. , Peljto Anna L. , Greenberg David A.
Published: December 2009

Background/Aims: Current linkage studies detect and localize trait loci using genotypes sampled at hundreds of thousands of single nucleotide polymorphisms (SNPs). Such data should provide precise estimates of trait location once linkage has been established. However, correlations between nearby SNPs can distort the information about trait location. Traditionally, when faced with this dilemma, three approaches have been used: (1) ignore the correlation; (2) approximate the correlation; or, (3) analyze a single, approximately uncorrelated subset of the original dense data. Methods: Here, we examine and test a simple and efficient estimator of trait location that averages location estimates across random subsamples of the original dense data. Based on pairwise estimates of correlation, we ensure that the SNPs within each subsample are approximately uncorrelated. In addition, we use the nonparametric bootstrap procedure to compute narrow, high-resolution candidate gene regions (i.e. confidence intervals for the true trait location). Results: Using simulated data, we show that the three existing approaches to dense SNP linkage analysis (described above) can yield biased and/or inefficient estimation depending on the underlying correlation structure. With respect to mean squared error, our estimator outperforms the third approach, and is as good as, but usually better than the first and second approaches. Relative to the third approach, our estimator led to a 47.5% reduction in the candidate gene region length based on the analysis of 15 hypertension families genotyped at ∼500,000 SNPs. Conclusion: The method we developed will be an important tool for constructing high-resolution candidate gene regions that could ultimately aid in targeting regions for sequencing projects.
A Double-Blind Study of Zaltoprofen for the Treatment of Upper Respiratory Tract Infection
Authors: Azuma Arata , Kudoh Shoji , Nakashima Mitsuyoshi , Nagatake Tsuyoshi
Published: December 2009

We conducted a double-blind study to evaluate the antipyretic and analgesic effects of a single administration of zaltoprofen, a nonsteroidal anti-inflammatory drug, in patients with acute upper respiratory tract infection. 170 patients were assigned to one of the 3 treatment groups (80, 160 mg, placebo). Changes over time of body temperature and the visual analog scale score of pain were measured under the supervision of the study staff at the participating medical institutions. A significant decrease in body temperature from the baseline value was noted at all measurement points from 0.5 to 6 h after drug administration in the zaltoprofen groups. The lowest temperature during the observation period was recorded between 3 and 4 h, and the body temperature tended to rise at 6 h. No significant decrease in body temperature was noted at any time during the observation period in the placebo group. A significant decrease in pain scores from the baseline was noted at all measurement points in the zaltoprofen groups, and the decrease was maintained even at 6 h. An analgesic effect but no antipyretic effect was observed in the placebo group.
Prevalence and Factors Related to Substance Use among Adolescents with Eating Disorders
Authors: Castro-Fornieles Josefina , Díaz Rosa , Goti Javier , Calvo Rosa , Gonzalez Laura , Serrano Lourdes , Gual Antoni
Published: December 2009

Objective: Very few studies have assessed substance use in clinical samples of adolescents with eating disorders (ED). This paper reports the prevalence of regular or risky substance use (RRSU) and substance use disorder (SUD) in adolescents with ED. Methods: The Teen-Addiction Severity Index (T-ASI), the Youth Self-Report (YSR) scale and substance use questionnaires were administered to 95 adolescent patients aged 12–17 years who fulfilled the DSM-IV-TR diagnostic criteria for anorexia nervosa, bulimia nervosa and ED not otherwise specified. All patients were consecutively attended at an Eating Disorders Unit. Results: 14.7% presented SUD related to tobacco, 3.2% to cannabis, 1.1% to alcohol, and 1.1% to other substances. Patients with RRSU-SUD of any substance except tobacco were 34.7%. Patients with RRSU-SUD failed more subjects, repeated more school years and had higher scores on T-ASI scales of problems at school, family function and social relationships, and on YSR scales of delinquent behavior and externalizing problems. Conclusions: Substance use problems in ED adolescents are frequent and formal screening of them as well as a specific therapeutic approach are necessary.
Management of Chronic Childhood Immune Thrombocytopenic Purpura: AIEOP Consensus Guidelines
Authors: De Mattia Domenico , Del Vecchio Giovanni Carlo , Russo Giovanna , De Santis Attilio , Ramenghi Ugo , Notarangelo Lucia , Jankovic Momcilo , Molinari Angelo Claudio , Zecca Marco , Nobili Bruno , Giordano Paola
Published: December 2009

Background/Objective: The management of chronic childhood idiopathic thrombocytopenic purpura (ITP) is distinct from acute ITP. Similar to the publication on acute ITP guidelines, the AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) considered it appropriate to develop consensus guidelines for chronic childhood ITP to provide useful and shared information for physicians, healthcare professionals, parents and patients. Design/Methods: A preliminary, evidence-based document issued by a select group of AIEOP pediatric hematologists was discussed, modified and approved during a Consensus Conference according to procedures previously validated by the AIEOP Board. Results: The guidelines give prominence to the periodical reevaluation of all the etiological hypotheses of thrombocytopenia in relation to its clinical condition. The majority of chronic ITP children do not require treatment, especially if bleeding is absent or minimal. The treatment decision depends on several factors other than the platelet count, and treatment options are suggested in relation to the therapeutic scenarios. Recommendations are given regarding support for surgery, particular hemorrhagic conditions, daily activities/sports, as well as for vaccines and drugs. Experimental treatments are also discussed.
Coupling Aging Immunity with a Sedentary Lifestyle: Has the Damage Already Been Done? – A Mini-Review
Authors: Simpson Richard J. , Guy Keith
Published: December 2009

The elderly population is at an unprecedented risk of infectious diseases and malignancy due to apparently inevitable age-related declines in immunity. The ‘immune risk profile’ (IRP) is an array of biomarkers that has been used to predict morbidity and mortality in older adults. As it is generally accepted that middle-aged and elderly individuals who habitually participate in moderate-intensity exercise are less likely to incur an infection than their sedentary counterparts, this review addresses current knowledge on the effects of regular exercise on aspects of adaptive immunity as they relate to the IRP. Findings from cross-sectional studies mostly show enhanced immunity in physically active compared to sedentary older adults. These include greater T-cell responsiveness to mitogens in vitro, a reduced frequency of antigen-experienced and senescent T-cells (i.e. CD45RO+/KLRG1+/CD57+/CD28–), enhanced IL-2 production and T-lymphocyte expression of the IL-2 receptor, longer chromosome telomere lengths in blood leukocytes and in vivo immune responses to vaccines and recall antigens. In contrast, the evidence from the available longitudinal studies that have used an exercise training intervention in previously sedentary elderly to improve similar immune responses is less compelling. Although this might indicate that exercise has limited immune restorative properties in previously sedentary elderly, there are still relatively few studies that have addressed specific IRP criteria and the large variation in experimental design among the longitudinal studies complicates the juxtaposition of these results. It is clear that a more substantial and focused research approach is required before physical exercise can be used in earnest as an effective immune restorative strategy in the elderly. This mini-review summarizes the major findings of these studies and proposes future avenues of research to investigate the effects of regular exercise on aspects of adaptive immunity in the elderly as they relate to the IRP.
No Miniatures, not even Decoration, yet Extraordinarily Fascinating New Hypotheses Concerning the Lancelot Compilation and Related Manuscripts
Authors: Biemans Jos
Published: December 2009

This essay sheds new light on the controversial fourteenth-century poet and compiler Lodewijk van Velthem. Specifically, the article considers the possible relationships between The Hague, Koninklijke Bibliotheek, MS 129 A 10, the manuscript containing the famous Lancelot Compilation, and Leiden, University Library, MS BPL 14 E, the only extant manuscript with Velthem's entire Fifth Part of the Spiegel historiael. A note written at the end of the manuscript in The Hague naming Velthem has been interpreted in different ways, either as a note of the manuscript's ownership, or as the attribution of the compilation to Velthem. Other scholars have considered Velthem the 'corrector' of the manuscript. The relatively low quality of these two manuscripts, as well as the types of annotations made in the margins of MS 129 A 10, however, can be explained when we consider both books as the poet's working copies, as manuscripts which formed part of Velthem's own literary archive.
A Modest Manuscript Within an Impressive Oeuvre: The Hague, Koninklijke Bibliotheek, MS 135 J 9, and the Master of the Guise Hours
Authors: Clark Gregory
Published: December 2009

MS 135 J 9, a French manuscript in the Koninklijke Bibliotheek [Royal Library] in The Hague, Netherlands, is placed in the framework of the career and oeuvre of the Master of the Guise Hours.
The Bout Psalter-Hours, Dated 1453
Authors: Marrow James
Published: December 2009

Just before Anne Korteweg retired, she purchased for the Koninklijke Bibliotheek one final spectacular illuminated manuscript, known as the Bout Psalter-Hours, a manuscript containing miniatures made by several artists who worked in several different Northern Netherlandish cities. For his contribution, James H. Marrow analyzes this manuscript, which is a capstone of Dr Korteweg's career.
Some Observations on Clement of Alexandria, Stromata, Book Five
Authors: Havrda Matyáš
Published: December 2009

The article is a collection of comments to various passages of Clement of Alexandria’s Stromata V (1,1-2; 2,5-6; 3,2; 6,3; 8,6; 18,3; 23,2-24,2; 38,5; 71,2-3; 83,5; 90,2; 98,4; 133,7; 141,3). Its aim is to complement earlier research by re-examining the syntactic structure or the meaning of terms, by adducing new parallels or by proposing fresh explanations of difficult segments of the text.
Phases of Black Theology in South Africa: A Historical Review
Authors: Motlhabi Mokgethi
Published: December 2009

This essay examines the development of Black Theology in South Africa. It structures this overview of the development into two related parts and according to five evolutionary phases. After a brief general introduction, the first part discusses each of the five phases in some detail and briefly describes the kinds of groups and individuals who were involved in each phase. It is argued that these phases do not represent a smooth transition from one to the other, but that at least two extended lulls were experienced during this development. So far there has been no recovery from the latest lull, which is attributed mainly to the need for a new paradigm. In the second part the relationships that Black Theology in South Africa had with other theologies, such as American Black Theology and African Theology are discussed.