bluuebunny/crossref_metadata_2025_split huggingface dataset:
Choosing Phase II Endpoints and Designs: Evaluating the Possibilities
Authors: LeBlanc Michael , Tangen Catherine 
Published: March 2012

Abstract
Selecting the phase II design and endpoint to achieve the best possible chance of success for a confirmatory phase III study in a particular disease and treatment setting is challenging but critical. Simulating from existing clinical trial data sets and from mathematical models can be useful tools for evaluating statistical properties. Clin Cancer Res; 18(8); 2130–2. ©2012 AACR.
JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells
Authors: Yamada Osamu , Ozaki Kohji , Akiyama Masaharu , Kawauchi Kiyotaka 
Published: March 2012

AbstractAdult T-cell leukemia (ATL) is a heterogeneous tumor that is resistant to chemotherapy. Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients. Interleukin (IL)-2 commonly promotes tumor growth in chronic ATL cells. The signaling pathways involved in IL-2–regulated telomerase activation were studied in ATL cells derived from chronic ATL patients. IL-2 challenge enhanced tyrosine phosphorylation of Janus-activated kinase (JAK)1–3 and STAT5, and induced JAK1 and JAK2 to associate with STAT5 in IL-2–dependent ATL cells. Chromatin immunoprecipitation assays revealed that STAT5 directly bound to the human telomerase reverse transcriptase (hTERT) promoter. STAT5 short interfering RNA inhibited hTERT transcription in IL-2–stimulated ATL cells. Inhibitors of PI3K, HSP90, and mTOR reduced IL-2–induced hTERT mRNA, protein expression, and telomerase activity. AKT, HSP90, mTOR, S6 kinase, and hTERT immunoprecipitate from IL-2–stimulated cells contained telomerase activity, suggesting that hTERT directly interacts with, and is regulated by, these proteins. Binding of the p85 regulatory subunit of PI3K to JAK2 was enhanced in an IL-2–dependent manner, indicating that JAK2 propagates activation signals from the IL-2 receptor and links hTERT activation to both the STAT5 and PI3K pathways. Finally, IL-2–induced activation of telomerase and STAT5 was observed in primary leukemic cells. These results indicate that IL-2 stimulation induces hTERT activation through the JAK/STAT pathway and the JAK/PI3K/AKT/HSP90/mTORC1 pathway in IL-2–responsive ATL cells. These signaling proteins represent novel and promising molecular therapeutic targets for IL-2–dependent ATL. Mol Cancer Ther; 11(5); 1112–21. ©2012 AACR.
Aerosolized 3-Bromopyruvate Inhibits Lung Tumorigenesis without Causing Liver Toxicity
Authors: Zhang Qi , Pan Jing , North Paula E. , Yang Shoua , Lubet Ronald A. , Wang Yian , You Ming 
Published: March 2012

Abstract3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer. Cancer Prev Res; 5(5); 717–25. ©2012 AACR.
Allelic Transcripts Dosage Effect in Morphologically Normal Ovarian Cells from Heterozygous Carriers of a BRCA1/2 French Canadian Founder Mutation
Authors: Abd-Rabbo Diala , Abaji Christine , Cardin Guillaume B. , Filali-Mouhim Abdelali , Arous Caroline , Portelance Lise , Escobar Enrique , Cloutier Sophie , Tonin Patricia N. , Provencher Diane M. , Mes-Masson Anne-Marie , Maugard Christine M. 
Published: March 2012

Abstract
We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation. We aimed to discover early events associated with ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from BRCA2-8765delAG carriers. Further analysis of morphologically normal ovarian and tumor cells from BRCA1-4446C&gt;T carriers lead to the same observation. Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cells. The highest level of BRCA2-mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript. Cancer Prev Res; 5(5); 765–77. ©2012 AACR.
Metalloproteinase Processing of HBEGF Is a Proximal Event in the Response of Human Aortic Endothelial Cells to Oxidized Phospholipids
Authors: Lee Sangderk , Springstead James R. , Parks Brian W. , Romanoski Casey E. , Palvolgyi Roland , Ho Tiffany , Nguyen Phuc , Lusis Aldons J. , Berliner Judith A. 
Published: March 2012

Objective—

Atherosclerosis is a chronic inflammatory disease initiated by monocyte recruitment and retention in the vessel wall. An important mediator of monocyte endothelial interaction is the chemokine interleukin (IL)-8. The oxidation products of phospholipids, including oxidized 1-palmitoyl-2-arachidonyl-
sn
-glycerol-3-phosphocholine (Ox-PAPC), accumulate in atherosclerotic lesions and strongly induce IL-8 in human aortic endothelial cells (HAECs). The goal of this study was to identify the proximal events leading to induction of IL-8 by Ox-PAPC in vascular endothelial cells.

Methods and Results—
In a systems genetics analysis of HAECs isolated from 96 different human donors, we showed that heparin-binding EGF-like growth factor (HBEGF) transcript levels are strongly correlated to IL-8 induction by Ox-PAPC. The silencing and overexpression of HBEGF in HAECs confirmed the role of HBEGF in regulating IL-8 expression. HBEGF has been shown to be stored in an inactive form and activation is dependent on processing by a dysintegrin and metalloproteinases (ADAM) to a form that can activate the epidermal growth factor (EGF) receptor. Ox-PAPC was shown to rapidly induce HBEGF processing and EGF receptor activation in HAECs. Using siRNA we identified 3 ADAMs that regulate IL-8 induction and directly demonstrated that Ox-PAPC increases ADAM activity in the cells using a substrate cleavage assay. We provide evidence for one mechanism of Ox-PAPC activation of ADAM involving covalent binding of Ox-PAPC to cysteine on ADAM. Free thiol cysteine analogs showed inhibition of IL-8 induction by Ox-PAPC, and both a cysteine analog and a cell surface thiol blocker strongly inhibited ADAM activity induction by Ox-PAPC. Using microarray analyses, we determined that this ADAM pathway may regulate at least 30% of genes induced by Ox-PAPC in HAECs.

Conclusion—
This study is the first report demonstrating a role for the ADAM-HBEGF-EGF receptor axis in Ox-PAPC induction of IL-8 in HAECs. These studies highlight a role for specific ADAMs as initiators of Ox-PAPC action and provide evidence for a role of covalent interaction of Ox-PAPC in activation of ADAMs.
Accuracy of a Novel Risk Index Combining Degree of Stenosis of the Carotid Artery and Plaque Surface Echogenicity
Authors: Momjian-Mayor Isabelle , Kuzmanovic Igor , Momjian Shahan , Bonvin Christophe , Albanese Stefane , Bichsel Denis , Comelli Mario , Pereira Vitor Mendez , Lovblad Karl O. , Sztajzel Roman F. 
Published: March 2012

Background and Purpose—
The purpose of this study was to determine the accuracy of a risk index in symptomatic or asymptomatic carotid stenoses.

Methods—
Consecutive patients presenting 50% to 99% carotid stenoses were included. A semiautomated gray scale-based color mapping (red, yellow, and green) of the whole plaque and of its surface was achieved. Surface was defined as the region located between the lumen (Level 0) and, respectively, 0.5, 1, 1.5, and 2 mm. Risk index was based on a combination of degree of stenosis and the proportion of the red color (reflecting low echogenicity) on the surface or on the whole plaque.

Results—

There were 67 (36%) symptomatic and 117 (64%) asymptomatic carotid stenoses. Risk index values were higher among symptomatic stenoses (0.46 mean versus 0.29;
P
<0.0001); on receiver operating characteristic curves, risk index presented a stronger predictive power compared with degree of stenosis or surface echogenicity alone. Also, in a regression model including age, gender, degree of stenosis, surface echogenicity, gray median scale of the whole plaque, and risk index, risk index measured within the surface region located at 0.5 mm from the lumen was the only parameter significantly associated with the presence of symptoms (OR, 4.89; 95% CI, 2.7–8.7;
P
=0.0000002). The best criterion to differentiate between symptomatic and asymptomatic stenoses was a risk index value >0.36 (sensitivity and specificity of 78% and 65%, respectively).

Conclusions—
Risk index was significantly higher in the presence of symptoms and could therefore be a valuable tool to assess the clinical risk of a carotid plaque.
Alcohol Consumption and Risk of Stroke in Women
Authors: Jimenez Monik , Chiuve Stephanie E. , Glynn Robert J. , Stampfer Meir J. , Camargo Carlos A. , Willett Walter C. , Manson JoAnn E. , Rexrode Kathryn M. 
Published: March 2012

Background and Purpose—
Light-to-moderate alcohol consumption has been consistently associated with lower risk of heart disease, but data for stroke are less certain. A lower risk of stroke with light-to-moderate alcohol intake has been suggested, but the dose response among women remains uncertain and the data in this subgroup have been sparse.

Methods—
A total of 83 578 female participants of the Nurses' Health Study who were free of diagnosed cardiovascular disease and cancer at baseline were followed-up from 1980 to 2006. Data on self-reported alcohol consumption were assessed at baseline and updated approximately every 4 years, whereas stroke and potential confounder data were updated at baseline and biennially. Strokes were classified according to the National Survey of Stroke criteria.

Results—
We observed 2171 incident strokes over 1 695 324 person-years. In multivariable adjusted analyses, compared to abstainers, the relative risks of stroke were 0.83 (95% CI, 0.75–0.92) for <5 g/d, 0.79 (95% CI, 0.70–0.90) for 5 to 14.9 g/d, 0.87 (0.72–1.05) for 15 to 29.9 g/d, and 1.06 (95% CI, 0.86–1.30) for 30 to 45 g/d. Results were similar for ischemic and hemorrhagic stroke.

Conclusions—
Light-to-moderate alcohol consumption was associated with a lower risk of total stroke. In this population of women with modest alcohol consumption, an elevated risk of total stroke related to alcohol was not observed.
Toll-Like Receptor 7 Preconditioning Induces Robust Neuroprotection Against Stroke by a Novel Type I Interferon-Mediated Mechanism
Authors: Leung Philberta Y. , Stevens Susan L. , Packard Amy E.B. , Lessov Nikola S. , Yang Tao , Conrad Valerie K. , van den Dungen Noortje N.A.M. , Simon Roger P. , Stenzel-Poore Mary P. 
Published: March 2012

Background and Purpose—
Systemic administration of Toll-like receptor (TLR) 4 and TLR9 agonists before cerebral ischemia have been shown to reduce ischemic injury by reprogramming the response of the brain to stroke. Our goal was to explore the mechanism of TLR-induced neuroprotection by determining whether a TLR7 agonist also protects against stroke injury.

Methods—

C57Bl/6, TNF
−/−
, interferon (IFN) regulatory factor 7
−/−
, or type I IFN receptor (IFNAR)
−/−
mice were subcutaneously administered the TLR7 agonist Gardiquimod (GDQ) 72 hours before middle cerebral artery occlusion. Infarct volume and functional outcome were determined after reperfusion. Plasma cytokine responses and induction of mRNA for IFN-related genes in the brain were measured. IFNAR
−/−
mice also were treated with the TLR4 agonist (lipopolysaccharide) or the TLR9 agonist before middle cerebral artery occlusion and infarct volumes measured.

Results—

The results show that GDQ reduces infarct volume as well as functional deficits in mice. GDQ pretreatment provided robust neuroprotection in TNF
−/−
mice, indicating that TNF was not essential. GDQ induced a significant increase in plasma IFNα levels and both IRF7
−/−
and IFNAR
−/−
mice failed to be protected, implicating a role for IFN signaling in TLR7-mediated protection.

Conclusions—
Our studies provide the first evidence that TLR7 preconditioning can mediate neuroprotection against ischemic injury. Moreover, we show that the mechanism of protection is unique from other TLR preconditioning ligands in that it is independent of TNF and dependent on IFNAR.
Prospects for Trust in Russia: The Perspective as Seen from 2010 and 2011 Drafts Amendments to the Russian Civil Code
Authors: Benevolenskaya Z.E. 
Published: March 2012

AbstractThe reader of this work is offered two theses by the author: Firstly, the myopic focus on the privatization in the early 1990s reflected the general view that this was the 'only' way to divest the state of property. Because of the predominance of this policy, the state—as an owner—has been deprived of the possibility of managing state property efficiently and effectively in another way short of total divestiture of ownership; i.e., transferring state-owned assets by way of a trust (trust agreement, trust management) to professional mangers. Secondly, that the trust doctrine is not totally alien to Russian legal tradition as many renowned Russian law thinkers argued in the 1990s for example and continue to believe to this day.
Indeed, the issue of whether or not the trust doctrine—as a construct involving 'split' ownership—can be 'transplanted' into Russian legal soil has been a particularly contentious part of law reform in post-Soviet Russia continuing through the present.
After highlighting the 'rush to privatization' mentality in Russia, the author of the present article takes the reader into nineteenth-century Russian legal theory as she demonstrates that trust is not alien to Russia. She also traces this clear thread through the Soviet era by reference to the works of one of its leading intellectual lights in the civil-law field of that time.
In the post-Soviet era, trust has already been explicitly introduced (in the first decade of the twenty-first century) into the legal space immediately bordering the Russian Federation: the new Ukrainian Civil Code.
These historical digressions should help the reader appreciate more clearly the proposed 2010/2011 amendments to the Russian Civil Code. It is the view of the present author that these proposals pave the way for the recognition of the doctrine of trust in modern-day Russian law—augmenting the more limited nature of the institute of 'trust management' currently provided for under the Russian Civil Code.
The Romanian Constitutional Court's Relationship with the Ordinary Courts: What Are Some of the Causes of Its High Caseload?
Authors: Gâdiuţă Filip 
Published: March 2012

AbstractThis article examines the recent high caseload of the Romanian Constitutional Court from a comparative perspective. In investigating possible causes of this phenomenon, the author has created several aggregated data sets based on the primary data available on the website of the Romanian Constitutional Court (over 20,000 referrals since 1992) and has examined the following hypotheses, most of which concern relations between the Constitutional Court and the ordinary courts: automatic suspension of proceedings as a delaying tactic, the ordinary courts as a filter, and the possibility of mass litigation as a storm flood caused by the strict ex nunc effects of the decisions of the Constitutional Court. The author has concluded that, while mass litigation is a substantial factor (responsible for three-quarters of the caseload in 2009), there was an underlying upward trend that can be explained by other causes. The available data are not particularly conclusive, but a recent legislative amendment could—in the near future—provide a test of the 'automatic suspension as a delaying tactic' hypothesis.
The author also has evaluated the extent to which the Court may have been overwhelmed by the number of cases. Surprisingly, the Court has adjusted rather well to the exponential increase in its caseload since it was established in 1992. While its backlog has increased, the lower number of referrals submitted in 2010 and 2011 should relieve part of the pressure.
Furthermore, the author assesses whether key cases involving politicians have been delayed by the Court. The available data seem to indicate that such cases are not being excessively delayed.
Ethical Formation and Subjection
Authors: Schofer Jonathan 
Published: March 2012

AbstractEthical formation in and through subjection is an extremely widespread pattern that is not limited to particular traditions, time periods, or regions. Examining this pattern requires us to integrate the study of power with the study of virtue and self-cultivation: power is productive of selves, and selves appropriate the ideals presented to or pressed upon them. This paper refines our approaches to power and ethics by showing that we need to address at least three facets of ethical formation and subjection: (a) material power relations, including the ability to kill, torture, punish, imprison, confine, observe, and censor; (b) discourses, and particularly figurative discourses, that convey conceptions of the self as well as ethical ideals; and (c) emotions and motivations of embodied persons who encounter norms and ideals.
Morphological, molecular characterisation and phylogenetic position of Longidorus mindanaoensis n. sp. (Nematoda: Longidoridae) from a Philippine Avicennia mangrove habitat
Authors: Coomans August , Tandingan De Ley Irma , Angsinco Jimenez Lea , De Ley Paul 
Published: March 2012

Longidorus mindanaoensis n. sp. is described from samples associated with riverine mangroves in the Philippines and is the first Longidorus species collected from such a habitat. Its relationship within the genus is inferred from molecular and morphological data. Phylogenetic inferences were performed for D2-D3 and SSU rDNA using appropriate phylogenetic algorithms. The new species is characterised by a thickened basal layer of the body cuticle with prominent spiral fibres, a dome-shaped continuous lip region, an oval to elliptical fovea with pore-like opening, the guiding ring at 2.2-2.5 lip region diam. from the anterior end, very weakly developed odontophore, all three pharyngeal gland nuclei at about the mid-point of the basal bulb, vulva at 30-39%, tail convex-conoid to hemispherical, shorter than anal body diam., males with 19-24 ventromedian supplements, and four juvenile stages, all with the replacement odontostyle at a short distance from the functional one. On the basis of amphid shape and structure, shape of anterior body region and general body shape, L. mindanaoensis n. sp. comes close to L. caespiticola, L. eridanicus, L. helveticus, L. macrosoma, L. poessneckensis, L. orongorongensis, L. waikouaitii and L. belondiroides. D2-D3 analysis placed the new species as sister to L. pisi and the two combined are sister clade to a monophyletic group that includes (L. poessneckensis (L. caespiticola (L. helveticus, L. macrosoma))). However, on the basis of SSU phylogeny, L. mindanaoensis n. sp. is positioned within a clade that includes (Longidorus sp. (L. mindanaoensis n. sp. (L. poessneckensis (L. helveticus, L. macrosoma)))). The ‘close’ relationship of the new species with L. pisi in the D2-D3 tree is incongruent with the widely different morphology of the two species. The other species that are close to the new species in the cladogram are in agreement with the morphology.
A new entomopathogenic nematode, Steinernema tielingense n. sp. (Rhabditida: Steinernematidae), from north China
Authors: Ma Juan , Chen Shulong , Li Xiuhua , Han Richou , Khatri-Chhetri Hari Bahadur , De Clercq Patrick , Moens Maurice 
Published: March 2012

A new species of Steinernema was isolated from shrub soils in Liaoning province during a survey for entomopathogenic nematodes in north China. This nematode was obtained by the insect-baiting technique using last instar larvae of Galleria mellonella (Lepidoptera: Pyralidae). This new species is described herein as S. tielingense n. sp. It belongs to the ‘feltiae-kraussei-oregonense’ group and is characterised by infective third-stage juvenile (IJ) with a body length of 915 (824-979) μm, distance from head to excretory pore of 69 (64-73) μm, tail length of 81 (74-85) μm, ratio E=88 (85-94)%, lateral field with eight ridges at mid-body, first generation male spicule 88 (79-98) μm and gubernaculum 61 (49-70) μm long, and first generation female with a vulval protrusion and ratio D=41 (32-49)%. The new species distinctly differs from the related species S. kraussei, S. silvaticum, S. oregonense and S. cholashanense in the different number of ridges in the lateral fields and hyaline tail length as % of total tail length of IJ and male body length and distance from head to excretory pore. Cross hybridisation tests showed that these species were reproductively isolated. The sequences analyses of the internal transcribed spacers (ITS) and D2-D3 regions of the ribosomal DNA confirm this to be a new species.