bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autocrine Induction of Invasive and Metastatic Phenotypes by the MIF-CXCR4 Axis in Drug-Resistant Human Colon Cancer Cells
Authors: Dessein Anne-Frédérique , Stechly Laurence , Jonckheere Nicolas , Dumont Patrick , Monté Didier , Leteurtre Emmanuelle , Truant Stéphanie , Pruvot François-René , Figeac Martin , Hebbar Mohamed , Lecellier Charles-Henri , Lesuffleur Thécla , Dessein Rodrigue , Grard Georges , Dejonghe Marie-José , de Launoit Yvan , Furuichi Yasuhiro , Prévost Grégoire , Porchet Nicole , Gespach Christian , Huet Guillemette 
Published: May 2010

Abstract
Metastasis and drug resistance are major problems in cancer chemotherapy. The purpose of this work was to analyze the molecular mechanisms underlying the invasive potential of drug-resistant colon carcinoma cells. Cellular models included the parental HT-29 cell line and its drug-resistant derivatives selected after chronic treatment with either 5-fluorouracil, methotrexate, doxorubicin, or oxaliplatin. Drug-resistant invasive cells were compared with noninvasive cells using cDNA microarray, quantitative reverse transcription-PCR, flow cytometry, immunoblots, and ELISA. Functional and cellular signaling analyses were undertaken using pharmacologic inhibitors, function-blocking antibodies, and silencing by retrovirus-mediated RNA interference. 5-Fluorouracil– and methotrexate-resistant HT-29 cells expressing an invasive phenotype in collagen type I and a metastatic behavior in immunodeficient mice exhibited high expression of the chemokine receptor CXCR4. Macrophage migration-inhibitory factor (MIF) was identified as the critical autocrine CXCR4 ligand promoting invasion in drug-resistant colon carcinoma HT-29 cells. Silencing of CXCR4 and impairing the MIF-CXCR4 signaling pathways by ISO-1, pAb FL-115, AMD-3100, monoclonal antibody 12G5, and BIM-46187 abolished this aggressive phenotype. Induction of CXCR4 was associated with the upregulation of two genes encoding transcription factors previously shown to control CXCR4 expression (HIF-2α and ASCL2) and maintenance of intestinal stem cells (ASCL2). Enhanced CXCR4 expression was detected in liver metastases resected from patients with colon cancer treated by the standard FOLFOX regimen. Combination therapies targeting the CXCR4-MIF axis could potentially counteract the emergence of the invasive metastatic behavior in clonal derivatives of drug-resistant colon cancer cells. Cancer Res; 70(11); 4644–54. ©2010 AACR.
Aurora-A Is Essential for the Tumorigenic Capacity and Chemoresistance of Colorectal Cancer Stem Cells
Authors: Cammareri Patrizia , Scopelliti Alessandro , Todaro Matilde , Eterno Vincenzo , Francescangeli Federica , Moyer Mary Pat , Agrusa Antonino , Dieli Francesco , Zeuner Ann , Stassi Giorgio 
Published: May 2010

Abstract
Colorectal cancer stem cells (CR-CSC) are responsible for the generation and maintenance of intestinal tumors and are highly resistant to conventional chemotherapeutic agents. Aurora-A, a serine-threonine kinase involved in mitosis regulation, plays multiple key functions in tumor initiation and progression. We found that Aurora-A is overexpressed in primary colorectal tumor cells, in the CR-CSC fraction, and in stem cell–derived differentiated cells, compared with normal colon tissue. Aurora-A expression was functionally linked to centrosome amplification in CR-CSC, as indicated by the decrease in cells with multiple centrosomes that followed Aurora-A silencing. Knockdown of Aurora-A resulted in growth inhibition of CR-CSC, alteration of cell cycle kinetics, and downregulation of the expression levels of antiapoptotic Bcl-2 family members, strongly sensitizing to chemotherapy-induced cell death. Moreover, Aurora-A silencing compromised the ability to form tumor xenografts in immunocompromised mice and reduced the migratory capacity of CR-CSC. Altogether, these results indicate that Aurora-A is essential for CR-CSC regeneration and resistance to cytotoxic stimuli and suggest that therapies directed against Aurora-A may effectively target the stem cell population in colorectal cancer. Cancer Res; 70(11); 4655–65. ©2010 AACR.
Phase I Open-Label Study of Continuous Treatment with BIBF 1120, a Triple Angiokinase Inhibitor, and Pemetrexed in Pretreated Non–Small Cell Lung Cancer Patients
Authors: Ellis Peter M. , Kaiser Rolf , Zhao Yihua , Stopfer Peter , Gyorffy Steve , Hanna Nasser 
Published: May 2010

Abstract
Introduction: BIBF 1120 (planned brand name Vargatef) is a novel, oral, triple angiokinase inhibitor targeting three receptor classes involved in blood vessel formation. The objectives of this phase I, open-label dose-escalation study were to determine the safety, tolerability, and maximum tolerated dose (MTD) of BIBF 1120 with pemetrexed in patients with recurrent advanced-stage non–small cell lung carcinoma.
Patients and Methods: Patients harboring a tumor of any non–small cell lung carcinoma histology, previously treated with one first-line platinum-based chemotherapy regimen, received a BIBF 1120 starting dose of 100 mg bid (days 2-21) with pemetrexed 500 mg/m2 (day 1) over a 21-day cycle. Previous pemetrexed treatment was not permitted. BIBF 1120 dose was escalated until the MTD was determined.
Results: Twenty-six patients were treated. During treatment cycle (TC) 1, dose-limiting toxicities were experienced by one patient receiving 100 mg bid, one patient receiving 150 mg bid, one patient receiving 200 mg bid, and two patients receiving 250 mg bid BIBF 1120. Two additional dose-limiting toxicities were observed in TC 1 in an expanded patient cohort receiving 200 mg bid. Gastrointestinal disorders (84.6%), general disorders, and administration site conditions (76.9%) were the most frequent drug-related adverse events. One patient had a complete response 44 days after initiating trial medication; 50% had stable disease as the best overall response. No clinically relevant pharmacokinetic interactions between BIBF 1120 and pemetrexed were observed.
Conclusion: The MTD of BIBF 1120 in combination with standard-dose pemetrexed was 200 mg bid. Continuous daily treatment with BIBF 1120 in this combination was tolerable, with promising signs of efficacy. Clin Cancer Res; 16(10); 2881–9. ©2010 AACR.
Pemetrexed Safety and Pharmacokinetics in Patients with Third-Space Fluid
Authors: Dickgreber Nicolas J. , Sorensen Jens Benn , Paz-Ares Luis G. , Schytte Tine Kjestrup , Latz Jane E. , Schneck Karen B. , Yuan Zheng , Sanchez-Torres José Miguel 
Published: May 2010

Abstract
Purpose: Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non–small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated.
Experimental Design: Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF.
Results: Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF.
Conclusions: No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary. Clin Cancer Res; 16(10); 2872–80. ©2010 AACR.
Tumor Metabolism and Blood Flow as Assessed by Positron Emission Tomography Varies by Tumor Subtype in Locally Advanced Breast Cancer
Authors: Specht Jennifer M. , Kurland Brenda F. , Montgomery Susan K. , Dunnwald Lisa K. , Doot Robert K. , Gralow Julie R. , Ellis Georgina K. , Linden Hannah M. , Livingston Robert B. , Allison Kimberly H. , Schubert Erin K. , Mankoff David A. 
Published: May 2010

Abstract
Purpose: Dynamic positron emission tomography (PET) imaging can identify patterns of breast cancer metabolism and perfusion in patients receiving neoadjuvant chemotherapy (NC) that are predictive of response. This analysis examines tumor metabolism and perfusion by tumor subtype.
Experimental Design: Tumor subtype was defined by immunohistochemistry in 71 patients with locally advanced breast cancer undergoing NC. Subtype was defined as luminal [estrogen receptor (ER)/progesterone receptor (PR) positive], triple negative [TN; ER/PR negative, human epidermal growth factor receptor 2 (HER2) negative], and HER2 (ER/PR negative, HER2 overexpressing). Metabolic rate (MRFDG) and blood flow (BF) were calculated from PET imaging before NC. Pathologic complete response (pCR) to NC was classified as pCR versus other.
Results: Twenty-five (35%) of 71 patients had TN tumors; 6 (8%) were HER2 and 40 (56%) were luminal. MRFDG for TN tumors was on average 67% greater than for luminal tumors (95% confidence interval, 9-156%) and average MRFDG/BF ratio was 53% greater in TN compared with luminal tumors (95% confidence interval, 9-114%; P &lt; 0.05 for both). Average BF levels did not differ by subtype (P = 0.73). Most luminal tumors showed relatively low MRFDG and BF (and did not achieve pCR); high MRFDG was generally matched with high BF in luminal tumors and predicted pCR. This was not true in TN tumors.
Conclusion: The relationship between breast tumor metabolism and perfusion differed by subtype. The high MRFDG/BF ratio that predicts poor response to NC was more common in TN tumors. Metabolism and perfusion measures may identify subsets of tumors susceptible and resistant to NC and may help direct targeted therapy. Clin Cancer Res; 16(10); 2803–10. ©2010 AACR.
IFNγ Restores Breast Cancer Sensitivity to Fulvestrant by Regulating STAT1, IFN Regulatory Factor 1, NF-κB, BCL2 Family Members, and Signaling to Caspase-Dependent Apoptosis
Authors: Ning Yanxia , Riggins Rebecca B. , Mulla Jennifer E. , Chung Haniee , Zwart Alan , Clarke Robert 
Published: May 2010

AbstractAntiestrogens are effective therapies for the management of many estrogen receptor-α (ER)–positive breast cancers. Nonetheless, both de novo and acquired resistance occur and remain major problems in the clinical setting. IFNγ is an inflammatory cytokine that induces the expression and function of IFN regulatory factor 1 (IRF1), a tumor suppressor gene that can increase antiestrogen responsiveness. We show that IFNγ, but not IFNα, IFNβ, or fulvestrant (ICI; ICI 182,780; Faslodex), induces IRF1 expression in antiestrogen-resistant MCF7/LCC9 and LY2 cells. Moreover, IFNγ restores the responsiveness of these cells to fulvestrant. Increased IRF1 activation suppresses NF-κB p65 (RELA) activity, inhibits the expression of prosurvival (BCL2, BCL-W), and induces the expression of proapoptotic members (BAK, mitochondrial BAX) of the BCL2 family. This molecular signaling is associated with the activation of signal transducer and activator of transcription 1 and leads to increased mitochondrial membrane permeability; activation of caspase-7 (CASP7), CASP8, and CASP9; and induction of apoptosis but not autophagy. Whereas antiestrogen-resistant cells are capable of inducing autophagy through IFN-mediated signaling, their ability to do so through antiestrogen-regulated signaling is lost. The abilities of IFNγ to activate CASP8, induce apoptosis, and restore antiestrogen sensitivity are prevented by siRNA targeting IRF1, whereas transient overexpression of IRF1 mimics the effects of IFNγ treatment. These observations support the exploration of clinical trials combining antiestrogens and compounds that can induce IRF1, such as IFNγ, for the treatment of some ER-positive breast cancers. Mol Cancer Ther; 9(5); 1274–85. ©2010 AACR.
Low- but not high-dose FK506 treatment confers atheroprotection due to alternative macrophage activation and unaffected cholesterol levels
Authors: Wijnands Erwin , Rousch Mat , Daemen Mat J. A. P. , Cohen Tervaert J. W. , Biessen Erik A. L. , Bai Lili , Gabriels Karen , Heeneman Sylvia 
Published: May 2010

SummaryPrevious studies showed both proand anti-atherogenic effects of immunosuppressant drug FK506 on atherosclerosis. As these divergent/paradoxical results of FK506 may at least in part be attributable to differences in FK506 dosing, we have, in the current study, assessed dosedependent effects of FK506 on atherosclerotic lesion formation as well as on inflammatory parameters relevant to atherosclerosis. Unlike low-dose FK506, high-dose FK506 did not protect against atherosclerosis in ApoE-/mice. The high-dose induced hypercholesterolaemia, whereas the low-dose did not. Both lowand high-dose FK506 treatment significantly reduced systemic CD3+ and CD4+CD25+ T-cell populations, and showed similar suppression of FoxP3 regulatory T-cell populations. Increased IL-4+ CD4+ T-cells and decreased IgG-MDA-LDL antibody titres pointed to a selective, albeit modest Th2 skewing in the high-dose treatment group, despite the advanced stage of atherosclerosis. Low concentrations of FK506, however, skewed bone marrow-derived macrophage polarisation towards a M2 macrophage phenotype, whereas high concentration did not. A low-dose FK506 treatment regime protected against atherosclerosis by suppressing T-cell activation and favouring (M2) macrophage polarisation. Although a high-dose FK506 treatment effected a similar T-cell suppressive effect, with an even more pronounced shift towards Th2 type immune responses, this did not translate in atheroprotection due to the hypercholesterolaemia and absent M2 skewing.
Early-onset ischaemic stroke: Analysis of 58 polymorphisms in 17 genes involved in methionine metabolism
Authors: Saracini Claudia , Bolli Paola , Magi Alberto , Martinelli Ida , Peyvandi Flora , Rasura Maurizia , Volpe Massimo , Lotta Luca , Rubattu Speranza , Mannucci Pier , Abbate Rosanna , Giusti Betti 
Published: May 2010

SummaryThe hypothesis underlying this study is that variations in genes involved in methionine metabolism may contribute to genetic susceptibility for early-onset ischaemic stroke. We investigated 58 polymorphisms in AHCY, BHMT, BHMT2, CBS, ENOSF1, FOLH1, MTHFD1, MTHFR, MTR, MTRR, NNMT, PON1, PON2, SLC19A1, SHMT1, TCN2, TYMS genes on genomic DNA from 501 young patients who survived ischaemic stroke and 1,211 sex and age comparable controls. Genotype distribution was significantly different between patients and controls for the following SNPs: rs10037045 BHMT, rs682985 BHMT2, rs1051319 CBS, rs202680 FOLH1, rs2274976 MTHFR, rs1979277 SHMT1, rs20721958 TCN2. On multiple logistic regression analysis adjusted for traditional risk factors, rs10037045 BHMT, rs682985 BHMT2, rs1051319 CBS, and rs202680 FOLH1 remained independent risk factors for stroke. After haplotype reconstruction, generalised linear model analyses adjusted for traditional risk factors and using the FDR multiple testing correction showed significant associations between ischaemic stroke and BHMT, CBS, FOLH1, MTR, PON2, TCN2 and TYMS haplotypes. This study identifies significant genetic associations between premature ischaemic stroke and haplotypes in BHMT, CBS, FOLH1, MTR, PON2, TCN2 and TYMS genes involved in methionine metabolism.
Oral vitamin K effectively treats international normalised ratio (INR) values in excess of 10
Authors: Garcia David , Ageno Walter , Wang Luqi , Witt Dan , Clark Nathan , Blostein Mark , Kahn Susan , Schulman Sam , Kovacs Michael , Rodger Marc , Wells Philip , Anderson David , Ginsberg Jeffrey , Selby Rita , Siragusa Sergio , Silingardi Mauro , Dowd MaryBeth , Kearon Clive , Crowther Mark 
Published: May 2010

SummaryUnanticipated elevation of the INR is common in patients receiving warfarin. We performed a prospective cohort study of 107 warfarintreated patients with INR values of more than 10 who received a single 2.5 mg dose of oral vitamin K. During the first week, one patient experienced major bleeding, and one died. In the first 90 days after enrolment four patients had major bleeding (3.7%, 1.0% to 9.3%), eight patients (7.5%, 3.3% to 14.2%) died and two had objectively confirmed thromboembolism. Based on our low rate of observed major bleeding we conclude that 2.5 mg of oral vitamin K is a reasonable treatment for patients with INR values of more than 10 who are not actively bleeding.
Risky Business: Of Dogs and Ethics in a Story by Yayā aqqī
Authors: Lowry Joseph E. 
Published: May 2010

AbstractYahyā Haqqī’s short story “Antar and Juliet” depicts a tragic encounter between two characters from different social worlds. Although the story could be read as a depiction of the stark reality of class difference, this article explores the characters’ varying degrees of willingness to expose themselves to risk. Using ideas about tragedy and ethics developed by Martha Nussbaum, it is argued that the story portrays the good life as one constituted by ties to others, but also as one that, because of its openness to the world, brings with it the very real possibility of disaster.
Georg Lukács and the Improbable Realism of Sun Allah Ibrāhīm’s The Committee
Authors: Stone Christopher 
Published: May 2010

AbstractBy a traditional definition of “realism” Sun Allah Ibrāhīm’s The Committee is perhaps the least “realistic” of his novels. The novel ends, for example, with the protagonist eating himself. This paper examines The Committee through the lens of the Marxist critic Georg Lukács’s definition of realism, a definition that prioritizes hope over feasibility. The opposite of realism for Lukács is modernism, which he defines, among other ways, by its dependence on allegory. I argue that by Lukács’s definition The Committee is a work of realism. Despite the novel’s air of gloom, I find in it elements of hope. I also argue that the gruesome ending does not have to be read allegorically. And though the protagonist does eat himself, I argue that this can be read as a feat of activism, a crucial component in Lukács’s definition of realism. I conclude by arguing for the relevance of the ideas of Georg Lukács and Sun Allah Ibrāhīm’s 28 year-old novel.
When Ibn Rushd Met Borges
Authors: Berg Nancy E. 
Published: May 2010

AbstractThis article both analyzes the East-West dialogue through which Ibn Rushd (Averroës) has been reintroduced to Western and Eastern audiences alike, and contributes to that dialogue. Using Haun Saussy’s concept of the membrane text, through which different cultures are imported, Jabbar Yussin Hussin’s short story “The Day in Buenos Aires” is read in conversation with Jorge Luis Borges’s story “Averroës’s Search.” Each story is rich with layers of meaning; read together, they reverberate against each other exponentially. Borges reveals Ibn Rushd’s writing as the membrane through which Aristotle is brought into Arabic letters, and Hussin, in turn, identifies Borges’s story as the membrane through which Ibn Rushd is introduced to Spanish readers, and also returned to al-Andalus.
Comparisons of CCN with Supercooled Clouds
Authors: Hudson James G. , Noble Stephen , Jha Vandana 
Published: May 2010

Abstract
More than 140 supercooled clouds were compared with corresponding out-of-cloud cloud condensation nuclei (CCN) measurements. In spite of significant differences in altitude, temperature, distances from cloud base, updraft velocity (W), entrainment, and so on, the correlation coefficients (R) between droplet and CCN concentrations were substantial although not as high as those obtained in warm clouds with less variability of nonaerosol influences. CCN at slightly lower altitudes than the clouds had higher R values than CCN measured at the same altitude. Ice particle concentrations appeared to reduce droplet concentrations and reduce R between CCN and droplet concentrations, but only above 6-km altitude and for temperatures below −20°C.
Although higher CCN concentrations generally resulted in higher droplet concentrations, increases in droplet concentrations were generally less than the increases in CCN concentrations. This was apparently due to the expected lower cloud supersaturations (S) when CCN concentrations are higher as was usually the case at lower altitudes. Cloud supersaturations showed more variability at higher altitudes and often very high values at higher altitudes. The use of liquid water content rather than droplet concentrations for cloud threshold resulted in higher R between CCN and droplet concentrations. The same R pattern for cumulative droplet–CCN concentrations as a function of threshold droplet sizes as that recently uncovered in warm clouds was found. This showed R changing rapidly from positive values when all cloud droplets were considered to negative values for slightly larger droplet size thresholds. After reaching a maximum negative value at intermediate droplet sizes, R then reversed direction to smaller negative or even positive values for larger cloud droplet size thresholds. This R pattern of CCN concentrations versus cumulative droplet concentrations for increasing size thresholds is consistent with adiabatic model predictions and thus suggests even greater CCN influence on cloud microphysics.
Atmospheric Effects of the Kuroshio Large Meander during 2004–05*
Authors: Xu Haiming , Tokinaga Hiroki , Xie Shang-Ping 
Published: May 2010

Abstract
In the summer of 2004, the Kuroshio took a large meander path south of Japan for the first time since 1991, and this large meander event persisted until the next summer. Satellite observations and numerical model simulations are used to study the effect of this large meander event on the atmosphere. The large meander leaves a cool water pool between the Kuroshio and Japanese coast. Sea surface temperature (SST) in the cool water pool is about 2°–3°C colder than the surroundings during winter and spring, whereas the SST signature substantially weakens in summer. A local reduction of wind speed is found over the cool water pool, and the positive SST–wind speed correlation is indicative of ocean forcing of the atmosphere. Cloud liquid water (CLW) content and precipitation also decrease over the cool SST pool.
A regional atmospheric model successfully simulates atmospheric response to the Kuroshio large meander. The model experiments suggest that the reduced surface wind speed and precipitation are due to the large meander-induced SST cooling. Analysis of the surface perturbation momentum budgets shows the importance of the pressure adjustment mechanism in surface wind response to the cold SST anomalies.