bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Inhibitor of c-Met and VEGF Receptor Tyrosine Kinases with a Broad Spectrum of In Vivo Antitumor Activities
Authors: Awazu Yoshiko , Nakamura Kazuhide , Mizutani Akio , Kakoi Yuichi , Iwata Hidehisa , Yamasaki Seiji , Miyamoto Naoki , Imamura Shinichi , Miki Hiroshi , Hori Akira 
Published: April 2013

Abstract
The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are dysregulated in a wide variety of human cancers and are linked with tumorigenesis and metastatic progression. VEGF also plays a key role in tumor angiogenesis and progression by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor tyrosine kinases (VEGFR). Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of tumors. Toward this goal, we generated and characterized T-1840383, a small-molecule kinase inhibitor that targets both c-Met and VEGFRs. T-1840383 inhibited HGF-induced c-Met phosphorylation and VEGF-induced VEGFR-2 phosphorylation in cancer epithelial cells and vascular endothelial cells, respectively. It also inhibited constitutively activated c-Met phosphorylation in c-met–amplified cancer cells, leading to suppression of cell proliferation. In addition, T-1840383 potently blocked VEGF-dependent proliferation and capillary tube formation of endothelial cells. Following oral administration, T-1840383 showed potent antitumor efficacy in a wide variety of human tumor xenograft mouse models, along with reduction of c-Met phosphorylation levels and microvessel density within tumor xenografts. These results suggest that the efficacy of T-1840383 is produced by direct effects on tumor cell growth and by an antiangiogenic mechanism. Furthermore, T-1840383 showed profound antitumor activity in a gastric tumor peritoneal dissemination model. Collectively, our findings indicate the therapeutic potential of targeting both c-Met and VEGFRs simultaneously with a single small-molecule inhibitor for the treatment of human cancers. Mol Cancer Ther; 12(6); 913–24. ©2013 AACR.
Abstract A26: DNA copy number alterations deregulate expression of miRNAs in lung adenocarcinoma
Authors: Stewart Greg L. , Enfield Katey SS , Lam Stephen , Lam Wan 
Published: April 2013

Abstract
Background: Lung cancer represents an enormous health burden, representing the most common cause of cancer death worldwide, with a five-year survival of less than 15%. microRNAs (miRNAs) have emerged as major players in lung cancer oncogenesis, displaying both oncogenic and tumor suppressive functions. DNA copy number (CN) amplification of oncogenes is a major molecular mechanism driving cancer, and like protein coding genes, CN alterations can influence miRNA expression levels. We hypothesize that DNA copy number gain modulates the expression of miRNAs important to cancer cell growth, and that integrative analysis can identify these cancer driving miRNAs.
Methods: Global gene dosage profiles for 46 lung adenocarcinoma and paired adjacent non-malignant tissues were generated by array comparative genomic hybridization. miRNA sequencing analysis was performed on this same panel of tumors and matched non-malignant tissues using Illumina GAXII small RNA sequencing technologies. CN and expression were correlated for each miRNA (Spearman's correlation &gt;0.3, p&lt;0.05) and expression of each significant miRNA was compared between tumors with and without CN gain (U-test p&lt;0.05). To select for miRNAs that most likely play a role in cancer we compared the expression between tumor and matched normal and selected for miRNAs with a fold change of at least 2 in tumors as compared to normal tissues.
Results: We identified a panel of miRNAs in lung adenocarcinoma whose expression deregulation was associated with CN alteration. These miRNAs were found to be gained in &gt;15% of tumors and underwent at least a 2 fold greater increase in expression in tumors compared to matched normal tissues. This study identified several miRNAs known to play a role in cancer including miR-141, known to be highly upregulated in lung and ovarian cancer, and miR-301a, upregulated in invasive early cervical cancer. In addition we identified several novel miRNAs that have not yet been implicated in cancer.
Conclusion: Here we identify a panel of miRNAs that are selectively gained at the genomic level to alter expression in lung adenocarcinoma. Several of these miRNAs have been previously shown to have oncogenic properties in many cancer types including lung cancer and may be potentially useful as therapeutic targets. In addition we identify several miRNAs that have not been previously reported in lung cancer. Future characterization of these miRNAs may lead to increased knowledge of adenocarcinoma oncogenesis.
Citation Format: Greg L. Stewart, Katey SS Enfield, Stephen Lam, Wan Lam. DNA copy number alterations deregulate expression of miRNAs in lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A26.
Abstract B28: MicroRNA-641 activates MAPK by targeting NF1 and cooperates with its host gene AKT2 in human cancer
Authors: Richards Edward J. , Coppola Marc , Guo Jianping , Kong William , Cheng Jin Q. 
Published: April 2013

Abstract
AKT2 is frequently up-regulated in human cancer. MiR-641 is an uncharacterized microRNA that locates at intron-1 of the AKT2 gene. We hypothesize that miR-641 and AKT2 are co-regulated, and cooperate to promote tumor development. Here we demonstrated that the transcription factors which induce AKT2 also increase miR-641 expression. Further, we identified miR-641 activation of the MAPK pathway by targeting tumor suppressor NF1, a GTPase-activating protein that inhibits RAS. Upon ectopic expression of miR-641, NF1 expression was reduced. As a result, pERK was elevated. Whereas knockdown of miR-641 exhibits opposite effects. In addition, depletion of miR-641 sensitizes tumor cells to cisplatin-induced apoptosis. Knockdown of miR-641 synergized with AKT2 inhibition to induce cell death. These data suggest that miR-641 functions as an oncomiR that co-regulates and cooperates with AKT2 in human cancer.
Citation Format: Edward J. Richards, Marc Coppola, Jianping Guo, William Kong, Jin Q. Cheng. MicroRNA-641 activates MAPK by targeting NF1 and cooperates with its host gene AKT2 in human cancer [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B28.
Abstract IA1: Physiological and pathological functions of microRNAs
Authors: Baltimore David 
Published: April 2013

Abstract
microRNAs have emerged as major regulators of the functions of genes in multicellular organisms. They generally and perhaps always act as reducers of the protein output from a given mRNA allotment generated from a particular gene. However, when acting on mRNAs that function in a regulated pathway, they can either inhibit or augment the output from that pathway depending on whether they act on inhibitory gene transcripts or activating gene transcripts. We have concentrated on miRs that function within the circuitry of the hematopoietic system, focusing on those that impinge on innate and adaptive immune responses. We have found that miR-146a acts as a classic negative regulator of inflammation while miR-155 acts as a positive regulator by targeting inhibitory proteins. A miR that has particularly interested us recently is miR125b, which both acts during the development of hematopoietic cells from the hematopoietic stem cell and modulates the function of myeloid cells. In all of this work, we have relied on mouse knockouts, siRNA knockouts and overproducing constructs to probe miR function and have been impressed by the ease with which these genetic manipulations can lead to hyperproliferation and cancer. Overexpression of miR-125b leads to particularly rapid induction of very aggressive tumor cells that can be of either the myeloid or lymphoid lineage. The developmental origin of these tumors is under investigation.
microRNAs have been seen as modulators of gene expression. Because it is becoming clear that they are so powerful in their physiological and pathological properties, it seems more appropriate to now consider them as co-regulators of gene expression, partners with transcription factors in determining the functional outcome of developmental and regulatory pathways.
Citation Format: David Baltimore. Physiological and pathological functions of microRNAs [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA1.
Abstract IA5: Epigenetic genome control by heterochromatin machinery and non-coding RNAs
Authors: Grewal Shiv 
Published: April 2013

Abstract
Heterochromatin assembly involving posttranslational modifications of histones is critical for various chromosomal processes including the regulation of gene expression and the maintenance of genomic integrity. Defective heterochromatin formation has been linked to cancer. Our previous work has shown that non-coding RNAs and the RNAi machinery, involved in the processing of non-coding RNAs, play prominent roles in the assembly of heterochromatin structures. Indeed, the loss of factors involved in RNAi such as Argonaute, Dicer and RNA-dependent RNA polymerase cause severe defects in centromeric heterochromatin formation, leading to missegregation of chromosomes during cell division. An Argonaute-containing RNAi effector complex named RITS has been identified that facilitates the loading of a conserved histone methyltransferase Clr4/Suv39h, which is essential for heterochromatin assembly. We have recently discovered an unexpected role for heterochromatin factors in the RNA quality control. Heterochromatin factors localize broadly across the genome and collaborate with RNAi machinery to suppress potentially deleterious RNAs, the uncontrolled accumulation of which can cause DNA damage and modify epigenetic genomic profiles. I will present our recent findings showing that non-coding RNAs and heterochromatin play important roles in dynamic regulation of genomes, which has important implications for human health and disease.
Citation Format: Shiv Grewal. Epigenetic genome control by heterochromatin machinery and non-coding RNAs [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA5.
Abstract IA9: Small RNA pathways in germline
Authors: Aravin Alexei A. 
Published: April 2013

Abstract
In animals, a discrete class of small RNAs, the piwi-interacting RNAs (piRNAs), guard germ cell genomes against the activity of mobile genetic elements.
piRNAs are generated, via an unknown mechanism, from apparently single-stranded precursors that arise from discrete genomic loci, termed piRNA clusters. Presently, little is known about the signals that distinguish a locus as a source of piRNAs. It is also unknown how individual piRNAs are selected from long precursor transcripts. To address these questions, we inserted new artificial sequence information into piRNA clusters and introduced these marked clusters as transgenes into heterologous genomic positions in mice and flies. Profiling of piRNA from transgenic animals demonstrated that artificial sequences were incorporated into the piRNA repertoire. Transgenic piRNA clusters are functional in non-native genomic contexts in both mice and flies, indicating that the signals that define piRNA generative loci must lie within the clusters themselves rather than being implicit in their genomic position. We found that both local and long-range sequence environments inform the generation of individual piRNAs from precursor transcripts.
Citation Format: Alexei A. Aravin. Small RNA pathways in germline [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA9.
Cost-Effectiveness of Apixaban, Dabigatran, Rivaroxaban, and Warfarin for Stroke Prevention in Atrial Fibrillation
Authors: Harrington Amanda R. , Armstrong Edward P. , Nolan Paul E. , Malone Daniel C. 
Published: April 2013

Background and Purpose—
To estimate the cost-effectiveness of stroke prevention in patients with nonvalvular atrial fibrillation by using novel oral anticoagulants apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg compared with warfarin.

Methods—

A Markov decision-analysis model was constructed using data from clinical trials to evaluate lifetime costs and quality-adjusted life-years of novel oral anticoagulants compared with warfarin. The modeled population was a hypothetical cohort of 70-year-old patients with nonvalvular atrial fibrillation, increased risk for stroke (CHADS
2
≥1), renal creatinine clearance ≥50 mL/min, and no previous contraindications to anticoagulation. The willingness-to-pay threshold was $50 000/quality-adjusted life-years gained.

Results—
In the base case, warfarin had the lowest cost of $77 813 (SD, $2223), followed by rivaroxaban 20 mg ($78 738±$1852), dabigatran 150 mg ($82 719±$1959), and apixaban 5 mg ($85 326±$1512). Apixaban 5 mg had the highest quality-adjusted life-years estimate at 8.47 (SD, 0.06), followed by dabigatran 150 mg (8.41±0.07), rivaroxaban 20 mg (8.26±0.06), and warfarin (7.97±0.04). In a Monte Carlo probabilistic sensitivity analysis, apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg, and warfarin were cost-effective in 45.1%, 40%, 14.9%, 0% of the simulations, respectively.

Conclusions—
In patients with nonvalvular atrial fibrillation and an increased risk of stroke prophylaxis, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg were all cost-effective alternatives to warfarin. The cost-effectiveness of novel oral anticoagulantss was dependent on therapy pricing in the United States and neurological events associated with rivaroxaban 20 mg.
Has ICT Polarized Skill Demand? Evidence from Eleven Countries over Twenty-Five Years
Authors: Michaels Guy , Natraj Ashwini , Van Reenen John 
Published: April 2013

Abstract
We test the hypothesis that information and communication technologies (ICT) polarize labor markets by increasing demand for the highly educated at the expense of the middle educated, with little effect on low-educated workers. Using data on the United States, Japan, and nine European countries from 1980 to 2004, we find that industries with faster ICT growth shifted demand from middle-educated workers to highly educated workers, consistent with ICT-based polarization. Trade openness is also associated with polarization, but this is not robust to controlling for R&D. Technologies account for up to a quarter of the growth in demand for highly educated workers.
Sharp bounds for Hardy type operators on higher-dimensional product spaces
Authors: Lu Shanzhen , Yan Dunyan , Zhao Fayou 
Published: April 2013

Abstract
A new class of Hardy type operator defined on a higher-dimensional product space is discussed. It includes two different kinds of the classical Hardy operators. In addition, we also consider the fractional Hardy operator

H
β

. The bound of operator

H
β

from

L
p

to

L
q

is explicitly worked out. Especially, the bound of operator

H
β

from

L
1

to

L

n

n
−
β

,
∞

is sharp.

MSC:26D10, 26D15, 42B99.
Characterization of a new high copy Stowaway family MITE, BRAMI-1 in Brassica genome
Authors: Sampath Perumal , Lee Sang-Choon , Lee Jonghoon , Izzah Nur Kholilatul , Choi Beom-Soon , Jin Mina , Park Beom-Seok , Yang Tae-Jin 
Published: April 2013

AbstractBackgroundMiniature inverted-repeat transposable elements (MITEs) are expected to play important roles in evolution of genes and genome in plants, especially in the highly duplicated plant genomes. Various MITE families and their roles in plants have been characterized. However, there have been fewer studies of MITE families and their potential roles in evolution of the recently triplicatedBrassicagenome.ResultsWe identified a new MITE family,BRAMI-1,belonging to theStowawaysuper-family in theBrassicagenome.In silicomapping revealed that 697 members are dispersed throughout the euchromatic regions of theB. rapapseudo-chromosomes. Among them, 548 members (78.6%) are located in gene-rich regions, less than 3 kb from genes. In addition, we identified 516 and 15 members in the 470 Mb and 15 Mb genomic shotgun sequences currently available forB. oleraceaandB. napus, respectively. The resulting estimated copy numbers for the entire genomes were 1440, 1464 and 2490 inB. rapa, B. oleraceaandB. napus,respectively. Concurrently, only 70 members of the relatedArabidopsis ATTIRTA-1 MITE family were identified in theArabidopsisgenome. Phylogenetic analysis revealed thatBRAMI-1 elements proliferated in theBrassicagenus after divergence from theArabidopsislineage. MITE insertion polymorphism (MIP) was inspected for 50BRAMI-1 members, revealing high levels of insertion polymorphism between and within species ofBrassicathat clarifyBRAMI-1 activation periods up to the present. Comparative analysis of the 71 genes harbouring theBRAMI-1 elements with their non-insertion paralogs (NIPs) showed that theBRAMI-1 insertions mainly reside in non-coding sequences and that the expression levels of genes with the elements differ from those of their NIPs.ConclusionAStowawayfamily MITE, named asBRAMI-1, was gradually amplified and remained present in over than 1400 copies in each of threeBrassicaspecies. Overall, 78% of the members were identified in gene-rich regions, and it is assumed that they may contribute to the evolution of duplicated genes in the highly duplicatedBrassicagenome. The resulting MIPs can serve as a good source of DNA markers forBrassicacrops because the insertions are highly dispersed in the gene-rich euchromatin region and are polymorphic between or within species.
The effect of dams and seasons on malaria incidence and anopheles abundance in Ethiopia
Authors: Yewhalaw Delenasaw , Getachew Yehenew , Tushune Kora , W/Michael Kifle , Kassahun Wondwossen , Duchateau Luc , Speybroeck Niko 
Published: April 2013

Abstract

Background
Reservoirs created by damming rivers are often believed to increase malaria incidence risk and/or stretch the period of malaria transmission. In this paper, we report the effects of a mega hydropower dam on P. falciparum malaria incidence in Ethiopia.

Methods
A longitudinal cohort study was conducted over a period of 2 years to determine Plasmodium falciparum malaria incidence among children less than 10 years of age living near a mega hydropower dam in Ethiopia. A total of 2080 children from 16 villages located at different distances from a hydropower dam were followed up from 2008 to 2010 using active detection of cases based on weekly house to house visits. Of this cohort of children, 951 (48.09%) were females and 1059 (51.91%) were males, with a median age of 5 years. Malaria vectors were simultaneously surveyed in all the 16 study villages. Frailty models were used to explore associations between time-to-malaria and potential risk factors, whereas, mixed-effects Poisson regression models were used to assess the effect of different covariates on anopheline abundance.

Results
Overall, 548 (26.86%) children experienced at least one clinical malaria episode during the follow up period with mean incidence rate of 14.26 cases/1000 child-months at risk (95% CI: 12.16 - 16.36). P. falciparum malaria incidence showed no statistically significant association with distance from the dam reservoir (p = 0.32). However, P. falciparum incidence varied significantly between seasons (p < 0.01). The malaria vector, Anopheles arabiensis, was however more abundant in villages nearer to the dam reservoir.

Conclusions

P. falciparum malaria incidence dynamics were more influenced by seasonal drivers than by the dam reservoir itself. The findings could have implications in timing optimal malaria control interventions and in developing an early warning system in Ethiopia.
Impact of non-dialysis chronic kidney disease on survival in patients with septic shock
Authors: Maizel Julien , Deransy Romain , Dehedin Benedicte , Secq Edouard , Zogheib Elie , Lewandowski Elisabeth , Tribouilloy Chritstophe , Massy Ziad A , Choukroun Gabriel , Slama Michel 
Published: April 2013

Abstract

Background
Chronic kidney disease (CKD) is known to expose the patient to a high risk of death due to cardiovascular and infective causes. In parallel, septic shock is a major challenge for cardiovascular and immune system. Therefore we tried to determine whether non-dialysis CKD, defined as a baseline estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2, for three months prior to the onset of septic shock is an independent risk factor for death.

Methods
All patients treated in a teaching hospital medical ICU for septic shock between January 2007 and December 2009 were retrospectively analyzed. Patients in whom baseline eGFR could not be determined (n=14) or patients treated by chronic dialysis (n=21) or kidney transplantation (n=14) were excluded. A total of 163 patients were included. The population was divided according to baseline eGFR ≥ 60ml/min/1.73m2 (non-CKD group, n=107) and < 60ml/min/1.73m2 (CKD group, n=56). Twenty-eight-day and 1-year survival curves were plotted. Prognostic factors were determined using Cox proportional hazards models.

Results
Baseline eGFR was significantly higher in the non-CKD group than in the CKD group (81 (67–108) vs. 36 (28–44) ml/min/1.73m2, respectively; p=0.001). Age, SAPS II, serum creatinine on admission and the number of patients with a history of diabetes, hypertension, heart failure, peripheral artery disease, coronary artery disease and statin medication were significantly higher in the CKD group than in the non-CKD group. The mortality rate was lower in the non-CKD group than in the CKD group after 28 days (50% vs. 70%, respectively; p=0.03) and 1 year (64% vs. 82%, respectively; p=0.03). On multivariate analysis, the dichotomous variable CKD (eGFR < 60ml/min/1.73m2) remained significantly associated with the 28-day and 1-year mortality.

Conclusions
Non-dialysis CKD appears to be an independent risk factor for death after septic shock.