bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell Surface Tetraspanin CD9 Mediates Chemoresistance in Small Cell Lung Cancer
Authors: Kohmo Satoshi , Kijima Takashi , Otani Yasushi , Mori Masahide , Minami Toshiyuki , Takahashi Ryo , Nagatomo Izumi , Takeda Yoshito , Kida Hiroshi , Goya Sho , Yoshida Mitsuhiro , Kumagai Toru , Tachibana Isao , Yokota Soichiro , Kawase Ichiro 
Published: October 2010

Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy with extremely high mortality due to the appearance of widespread metastases early in its clinical course and rapid acquisition of chemoresistance after initial therapy. A theory of cell adhesion–mediated drug resistance is thought to be a principal mechanism in which extracellular matrix proteins provide a survival advantage against cytotoxic drug-induced apoptosis. We found that the tetraspanin family member CD9 was expressed preferentially in SCLC tumors and metastases from three of seven relapsed patients, whereas chemonaïve primary tumors from 16 patients were CD9 negative with only one exception. Additionally, CD9 was highly expressed on SCLC cell lines rendered resistant to cisplatin or etoposide, and was upregulated in parental chemosensitive cells within 48 hours after exposure to either of these compounds. CD9-expressing chemoresistant SCLC cells adhered more tightly to fibronectin via β1 integrin, but they were less motile than the respective chemosensitive parental lines. Notably, treatment of the chemoresistant cells with chemokine CXCL12 downregulated CD9 and transiently restored motility. Moreover, selective targeting of CD9 by treatment with specific monoclonal antibody ALB6 or a small interfering RNA triggered apoptosis in the chemoresistant cells. Taken together, our findings implicate CD9 in the cell adhesion–mediated drug resistance mechanism, highlighting CD9 as an attractive therapeutic target to improve therapeutic outcomes in SCLC. Cancer Res; 70(20); 8025–35. ©2010 AACR.
Transforming Properties of 8p11-12 Amplified Genes in Human Breast Cancer
Authors: Yang Zeng-Quan , Liu Gang , Bollig-Fischer Aliccia , Giroux Craig N. , Ethier Stephen P. 
Published: October 2010

Abstract
Amplification of the 8p11-12 region has been found in about 15% of human breast cancers and is associated with poor prognosis. Earlier, we used genomic analysis of copy number and gene expression to perform a detailed analysis of the 8p11-12 amplicon to identify candidate oncogenes in breast cancer. We identified 21 candidate genes and provided evidence that three genes, namely, LSM-1, TC-1, and BAG4, have transforming properties when overexpressed. In the present study, we systematically investigated the transforming properties of 13 newly identified 8p11-12 candidate oncogenes in vitro. WHSC1L1, DDHD2, and ERLIN2 were most potently transforming oncogenes based on the number of altered phenotypes expressed by the cells. WHSC1L1 contains a PWWP-domain that is a methyl-lysine recognition motif involved in histone code modification and epigenetic regulation of gene expression. Knockdown of WHSC1L1 in 8p11-12–amplified breast cancer cells resulted in profound loss of growth and survival of these cells. Further, we identified several WHSC1L1 target genes, one of which is iroquois homeobox 3 gene (IRX3), a member of the Iroquois homeobox transcription factor family. Cancer Res; 70(21); 8487–97. ©2010 AACR.
The Myc–miR-17∼92 Axis Blunts TGFβ Signaling and Production of Multiple TGFβ-Dependent Antiangiogenic Factors
Authors: Dews Michael , Fox Jamie L. , Hultine Stacy , Sundaram Prema , Wang Wenge , Liu Yingqiu Y. , Furth Emma , Enders Gregory H. , El-Deiry Wafik , Schelter Janell M. , Cleary Michele A. , Thomas-Tikhonenko Andrei 
Published: October 2010

Abstract
c-Myc stimulates angiogenesis in tumors through mechanisms that remain incompletely understood. Recent work indicates that c-Myc upregulates the miR-17∼92 microRNA cluster and downregulates the angiogenesis inhibitor thrombospondin-1, along with other members of the thrombospondin type 1 repeat superfamily. Here, we show that downregulation of the thrombospondin type 1 repeat protein clusterin in cells overexpressing c-Myc and miR-17∼92 promotes angiogenesis and tumor growth. However, clusterin downregulation by miR-17∼92 is indirect. It occurs as a result of reduced transforming growth factor-β (TGFβ) signaling caused by targeting of several regulatory components in this signaling pathway. Specifically, miR-17-5p and miR-20 reduce the expression of the type II TGFβ receptor and miR-18 limits the expression of Smad4. Supporting these results, in human cancer cell lines, levels of the miR-17∼92 primary transcript MIR17HG negatively correlate with those of many TGFβ-induced genes that are not direct targets of miR-17∼92 (e.g., clusterin and angiopoietin-like 4). Furthermore, enforced expression of miR-17∼92 in MIR17HGlow cell lines (e.g., glioblastoma) results in impaired gene activation by TGFβ. Together, our results define a pathway in which c-Myc activation of miR-17∼92 attenuates the TGFβ signaling pathway to shut down clusterin expression, thereby stimulating angiogenesis and tumor cell growth. Cancer Res; 70(20); 8233–46. ©2010 AACR.
Antiangiogenic Activity of a Neutralizing Human Single-Chain Antibody Fragment against Fibroblast Growth Factor Receptor 1
Authors: Ronca Roberto , Benzoni Patrizia , Leali Daria , Urbinati Chiara , Belleri Mirella , Corsini Michela , Alessi Patrizia , Coltrini Daniela , Calza Stefano , Presta Marco , Dell'Era Patrizia 
Published: October 2010

Abstract
Fibroblast growth factor receptor-1 (FGFR-1) transduces proangiogenic and proliferative signals in human cancers. Thus, FGFR-1 may represent a target for the development of antiangiogenic/antineoplastic therapies. We screened a human single-chain fragment variable (scFv) antibody phage display library against the extracellular domain of the FGFR-1-IIIc isoform that harbors the FGF binding site. Several phages were isolated and tested for specificity and sensitivity, and the most promising antibody fragment RR-C2 was characterized for its biochemical and biological properties. ScFv RR-C2 specifically recognizes FGFR-1α and FGFR-1β isoforms in ELISA, Western blotting, and surface plasmon resonance analysis with a Kd value of 300 and 144 nmol/L for the 2 receptor isoforms, respectively. The antibody fragment also recognizes FGFR-1 when the receptor is exposed on the cell surface, thus preventing the formation of the ternary complex among FGFR-1, its ligand FGF2, and cell surface heparan sulfate proteoglycans. Accordingly, scFv RR-C2 specifically inhibits FGF2-mediated mitogenic activity in endothelial cells of human, bovine, and murine origin in a nanomolar range of concentrations. Also, the antibody fragment prevents FGF2-triggered sprouting of both human umbilical vein endothelial cell spheroids and of murine endothelium from aortic rings. Finally, the antibody fragment hampers the angiogenic activity exerted both by FGF2 in the chick embryo chorioallantoic membrane assay and by S115 mouse mammary tumor cells in the Matrigel plug assay. Taken together, the data show that scFv RR-C2 recognizes and neutralizes FGFR-1 activity in different animal species, including humans, thus representing a novel tool for the development of antiangiogenic/antineoplastic therapies. Mol Cancer Ther; 9(12); 3244–53. ©2010 AACR.
Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis
Authors: DeCensi Andrea , Puntoni Matteo , Goodwin Pamela , Cazzaniga Massimiliano , Gennari Alessandra , Bonanni Bernardo , Gandini Sara 
Published: October 2010

Abstract
Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. We performed a comprehensive literature search and meta-analysis of epidemiologic studies to assess the effect of metformin on cancer incidence and mortality in diabetic patients, using Pubmed, ISI Web of Science, Embase, and the Cochrane library until May 2009, with no language or time restrictions. Independent reports with sufficient information to allow risk estimation of cancer risk/mortality and a measure of uncertainty were reviewed and cross-checked independently by three investigators. Eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and nonsignificant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin is associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients. Given the retrospective nature of most studies and the possibility that the control treatments increase risk, phase II trials are needed before large cancer prevention trials are launched. Cancer Prev Res; 3(11); 1451–61. ©2010 AACR.
Alcohol Inhibits Smooth Muscle Cell Proliferation via Regulation of the Notch Signaling Pathway
Authors: Morrow David , Cullen John P. , Liu Weimin , Cahill Paul A. , Redmond Eileen M. 
Published: October 2010

Objective—To determine the role of Notch signaling in mediating alcohol’s inhibition of smooth muscle cell (SMC) proliferation.Methods and Results—Treatment of human coronary artery SMCs with ethanol (EtOH) decreased Notch 1 mRNA and Notch 1 intracellular domain protein levels, in the absence of any effect on Notch 3. EtOH treatment also decreased C-promoter binding factor-1 (CBF-1)/recombination signal-binding protein (RBP)-jk promoter activity and Notch target gene (hairy related transcription factor [HRT-1] orHRT-2) expression. These effects were concomitant with an inhibitory effect of EtOH on SMC proliferation. Overexpression of constitutively active Notch 1 intracellular domain or human hairy related transcription factor-1 (hHRT-1) prevented the EtOH-induced inhibition of SMC proliferation. In vivo, Notch 1 and HRT-1 mRNA expression was increased after ligation-induced carotid artery remodeling. The vessel remodeling response was inhibited in mice that received “moderate” amounts of alcohol by gavage daily; intimal-medial thickening was markedly reduced, and medial and neointimal SMC proliferating cell nuclear antigen expression was decreased. Moreover, Notch 1 and HRT-1 expression, induced after ligation injury, was inhibited by moderate alcohol consumption.Conclusion—EtOH inhibits Notch signaling and, subsequently, SMC proliferation, in vitro and in vivo. The modulation of Notch signaling in SMCs by EtOH may be relevant to the cardiovascular protective effects of moderate alcohol consumption purported by epidemiological studies.
Vascular Hospitalization Rates and Costs in Patients With Peripheral Artery Disease in the United States
Authors: Mahoney Elizabeth M. , Wang Kaijun , Keo Hong H. , Duval Sue , Smolderen Kim G. , Cohen David J. , Steg Gabriel , Bhatt Deepak L. , Hirsch Alan T. ,   on behalf of the Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators*
Published: October 2010

Background—

Peripheral artery disease (PAD) is common and imposes a high risk of major systemic and limb ischemic events. The
RE
duction of
A
therothrombosis for
C
ontinued
H
ealth (REACH) Registry is an international prospective registry of patients at risk of atherothrombosis caused by established arterial disease or the presence of ≥3 atherothrombotic risk factors.

Methods and Results—

We compared the 2-year rates of vascular-related hospitalizations and associated costs in US patients with established PAD across patient subgroups. Symptomatic PAD at enrollment was identified on the basis of current intermittent claudication with an ankle-brachial index (ABI) <0.90 or a history of lower-limb revascularization or amputation. Asymptomatic PAD was diagnosed on the basis of an enrollment ABI <0.90 in the absence of symptoms. Overall, 25 763 of the total 68 236–patient REACH cohort were enrolled from US sites; 2396 (9.3%) had symptomatic and 213 (0.8%) had asymptomatic PAD at baseline. One- and cumulative 2-year follow-up data were available for 2137 (82%) and 1677 (64%) of US REACH patients with either symptomatic or asymptomatic PAD, respectively. At 2 years, mean cumulative hospitalization costs, per patient, were $7445, $7000, $10 430, and $11 693 for patients with asymptomatic PAD, a history of claudication, lower-limb amputation, and revascularization, respectively (
P
=0.007). A history of peripheral intervention (lower-limb revascularization or amputation) was associated with higher rates of subsequent procedures at both 1 and 2 years.

Conclusions—
The economic burden of PAD is high. Recurring hospitalizations and repeat revascularization procedures suggest that neither patients, physicians, nor healthcare systems should assume that a first admission for a lower-extremity PAD procedure serves as a permanent resolution of this costly and debilitating condition.
Improvements in Symptoms and Quality of Life in Patients With Paroxysmal Atrial Fibrillation Treated With Radiofrequency Catheter Ablation Versus Antiarrhythmic Drugs
Authors: Reynolds Matthew R. , Walczak Joshua , White Sarah A. , Cohen David J. , Wilber David J. 
Published: October 2010

Background—
In patients with paroxysmal atrial fibrillation (AF), catheter ablation maintains sinus rhythm more effectively than antiarrhythmic drugs (AADs), but its effect on symptoms and quality of life (QOL) has not been fully characterized.

Methods and Results—
We evaluated symptoms and QOL in a multicenter, randomized trial comparing catheter ablation with AADs as second-line treatment for patients with paroxysmal AF. The Short Form (SF)-36 health survey and the AF Symptom Checklist were administered at baseline and 3, 6, and 9 months after a blanking or dose-titration period. The primary between-group comparisons were conducted at 3 months because of permitted crossover from AAD to ablation beyond this time. Additional analyses based on subsequent follow-up were performed, including the construction of mixed linear regression models to assess the impact of multiple factors on follow-up QOL scores.

At baseline in both the ablation (n=103) and the AAD (n=56) groups, 7 of 8 SF-36 scales were well below population norms, as were the physical (PCS) and mental (MCS) summary scores. At 3 months, the same 7 SF-36 scales were significantly (
P
<0.01) higher in the ablation than in the AAD group, as were the PCS (52.0±7.8 versus 47.1±10.6;
P
<0.01) and MCS (52.4±8.1 versus 46.6±9.8;
P
<0.01) scores, whereas symptom frequency (9.3±9.2 versus 19.0±12.6;
P
<0.001) and symptom severity (7.7±7.2 versus 16.2±10.0;
P
<0.001) were significantly reduced. In multivariable analysis, ablation and recurrent arrhythmias most strongly correlated with QOL changes over time.

Conclusions—
For second-line therapy of paroxysmal AF, ablation is superior to AAD treatment at improving symptoms and QOL.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00116428.
Lamb, Mutton, and Goat in the Babylonian Temple Economy
Authors: Kozuh Michael 
Published: October 2010

AbstractIn the mid-first millennium B.C.E., the Eanna temple of Uruk distributed the meat of sheep and goats to its associates and dependents. The meat of post-sacrificial lambs went to the Eanna’s prebend holding elite, while others received the meat of goats and older sheep without ceremony and on the hoof. Many assume this latter distribution worked to supply the Eanna’s lowest classes with substandard meat. I argue, instead, that there was nothing inherently substandard about this meat; moreover, there is little evidence that it was intended for the Eanna’s lowest classes. This paper then explores the distribution of meat to the Eanna’s sub-elite, especially in place of temple rations and payments of silver.
The Christians Whose Force is Hard: Non-Ecclesiastical Judicial Authorities in the Early Islamic Period
Authors: Simonsohn Uriel 
Published: October 2010

AbstractThis paper examines the context in which church leaders in the regions of Mesopotamia and the Fertile Crescent, during the first few centuries after the Arab conquest, were objecting to the appeal of the their coreligionists to judicial authorities outside ecclesiastical control. Rather than assuming that from the outset of the Islamic conquest Muslim judges served as immediate judicial alternatives, the paper shows that, at least in the early Islamic period, church leaders were often aiming their exhortations towards Christians who sought the authority of other Christian figures from outside ecclesiastical jurisdiction.
Animals as Property in Early Modern Ottoman Egypt
Authors: Mikhail Alan 
Published: October 2010

AbstractThrough an examination of the role of domesticated animals as forms of property in rural Ottoman Egypt, this article argues that historians of the early modern Muslim world must pay greater attention to the economic and social importance of animals. Based on the sharīa court records of multiple cities in both the Nile Delta and Upper Egypt, this study documents the role of animals as agricultural laborers, as means of transport, and as sources of food. It then analyzes several court cases in which the abilities of animals to move, die, and procreate serve to challenge notions of property and legal ownership in Ottoman Egypt.À travers l’examen du rôle que jouaient les animaux domestiques, en tant qu’objets de propriété, dans les campagnes de l’Égypte ottomane, cet article propose qu’une attention accrue devrait être prêtée à l’importance économique et sociale des animaux à l’époque moderne. Basée sur les registres de tribunaux religieux de nombreuses villes du Delta et de Haute Égypte, cette étude révèle le rôle des animaux en tant qu’ouvriers agricoles, moyens de transport et sources d’alimentation. Une série de procès menés devant ces tribunaux montre que la capacité des animaux à se déplacer, à mourir et à procréer servait à remettre en cause les notions de propriété et de possession légale dans l’Égypte ottomane.
Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease
Authors: van Schie Marianne C. , de Maat Moniek P. M. , Isaacs Aaron , van Duijn Cornelia M. , Deckers Jaap W. , Dippel Diederik W. J. , Leebeek Frank W. G. 
Published: October 2010

Abstract
High levels of von Willebrand factor (VWF) are associated with an increased risk for cardiovascular disease (CVD). Although VWF levels are strongly heritable and genetic susceptibility is an important risk factor for CVD, information on the contribution of common VWF gene variants to VWF levels and CVD risk is limited. In a case-control study of 421 young patients with a first event of acute coronary heart disease (CHD) or ischemic stroke (IS), and 409 healthy control participants (men aged ≤ 45 years, women aged ≤ 55 years), 27 haplotype-tagging single-nucleotide polymorphisms (ht-SNPs), covering the total common VWF gene variation, were selected and genotyped. The associations between these SNPs, VWF antigen (VWF:Ag) levels, VWF collagen-binding (VWF:CB) activity, and CVD risk was investigated. Two new associations were identified. For ht-SNP rs4764478 (intron 45), the increase in VWF:Ag levels and VWF:CB activity per minor allele was 0.082 (± 0.026) IU/mL (P = .001) and 0.096 (± 0.030) IU/mL (P = .002), respectively. ht-SNP rs216293 (intron 17) was associated with CVD risk (odds ratio, 1.44; 95% confidence interval [CI], 1.12-1.86 per minor allele). We confirmed the association between rs1063857 and CVD risk. Our data show that common variants in the VWF gene are associated with VWF levels and with the risk for CVD.
The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia
Authors: Herishanu Yair , Pérez-Galán Patricia , Liu Delong , Biancotto Angélique , Pittaluga Stefania , Vire Berengere , Gibellini Federica , Njuguna Ndegwa , Lee Elinor , Stennett Lawrence , Raghavachari Nalini , Liu Poching , McCoy J. Philip , Raffeld Mark , Stetler-Stevenson Maryalice , Yuan Constance , Sherry Richard , Arthur Diane C. , Maric Irina , White Therese , Marti Gerald E. , Munson Peter , Wilson Wyndham H. , Wiestner Adrian 
Published: October 2010

AbstractChronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes, involves blood, bone marrow, and secondary lymphoid organs such as the lymph nodes (LN). A role of the tissue microenvironment in the pathogenesis of CLL is hypothesized based on in vitro observations, but its contribution in vivo remains ill-defined. To elucidate the effects of tumor-host interactions in vivo, we purified tumor cells from 24 treatment-naive patients. Samples were obtained concurrently from blood, bone marrow, and/or LN and analyzed by gene expression profiling. We identified the LN as a key site in CLL pathogenesis. CLL cells in the LN showed up-regulation of gene signatures, indicating B-cell receptor (BCR) and nuclear factor-κB activation. Consistent with antigen-dependent BCR signaling and canonical nuclear factor-κB activation, we detected phosphorylation of SYK and IκBα, respectively. Expression of BCR target genes was stronger in clinically more aggressive CLL, indicating more effective BCR signaling in this subtype in vivo. Tumor proliferation, quantified by the expression of the E2F and c-MYC target genes and verified with Ki67 staining by flow cytometry, was highest in the LN and was correlated with clinical disease progression. These data identify the disruption of tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic strategies in CLL. This study is registered at http://clinicaltrials.gov as NCT00019370.
Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine
Authors: Itzykson Raphael , Thépot Sylvain , Quesnel Bruno , Dreyfus Francois , Beyne-Rauzy Odile , Turlure Pascal , Vey Norbert , Recher Christian , Dartigeas Caroline , Legros Laurence , Delaunay Jacques , Salanoubat Célia , Visanica Sorin , Stamatoullas Aspasia , Isnard Francoise , Marfaing-Koka Anne , de Botton Stephane , Chelghoum Youcef , Taksin Anne-Laure , Plantier Isabelle , Ame Shanti , Boehrer Simone , Gardin Claude , Beach C. L. , Adès Lionel , Fenaux Pierre ,   on behalf of the Groupe Francophone des Myelodysplasies (GFM)
Published: October 2010

Abstract
Prognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P = .009), bone marrow blasts > 15% (P = .004), and abnormal karyotype (P = .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P = .0003). Performance status ≥ 2, intermediate- and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency ≥ 4 units/8 weeks (all P < 10−4) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10−4). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P = .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10−4). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment.