bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 343: Molecular markers for detection of micrometastases in regional lymph nodes from patients undergoing surgery for non-small cell lung cancer
Authors: Nordgård Oddmund , Ulas Mona , Singh Gurpartap , Fleischer Thomas , Sagerup Camilla M. , Småland Rune , Brustugun Odd Terje , Helland Åslaug 
Published: June 2012

Abstract
PURPOSE: Lung cancer retains its status as the most common cancer in the world, with an estimated 1.5 million cases diagnosed in 2007, accounting for about 12% of all cancers. Identifying microscopic lynph-node metastases, could have clinical importance in selecting patients for adjuvant treatment. The purpose of this study wasis to Iidentify and evaluate molecular markers for detection of micrometastases in regional lymph nodes from patients undergoing surgery for non-small cell lung cancer.
PATIENTS AND METHODS: Candidate micrometasis markers were selected based on digital transcript profiling in EST and SAGE databases, searching for transcripts with high levels in lung cancers and very low levels in normal lymph nodes. Surfactant protein C (SFTPC) and cytokeratin 19 (CK19) mRNA levels in tumor biopsies and resected regional lymp nodes (N=38) from 24 patients undergoing surgery for non-small cell lung cancer were measured by quantitative RT-PCR. A control material consisting of 22 normal mesenterial lymph nodes from patients undergoing surgery for benign colon disorders was analyzed in parallell.
RESULTS: The median relative CK19SFTPC mRNA level in the non-small cell lung tumor biopsies were 446 times higher than the highest level in normal control lymph nodes. SFTPC mRNA was not detectable in the normal lymph nodes, whereas the tumor levels were high (Cq-values ranging from 17-25). Using the highest CK19 mRNA level in the normal lymph nodes as a cut-off, four out of five (80%) lymph nodes from patients with known lymph node metastases (by routine histology) had elevated CK19 levels. Accordingly, 5 (15%) of 33 lymph nodes from patients without known metastases (node-negative) had elevated levels of CK19 mRNA. SFTPC mRNA were detectable in 31 of the 33 lymph nodes from node-negative patients, although the median relative level was 7.1 times higher in the 5 lymph nodes from node-positive patients (P=0.002, Mann-Witney test). Elevated CK19 and SFTPC mRNA levels in regional lymph nodes without known metastases may reflect the presence of micrometastases.
CONCLUSION: SFTPC and CK19 mRNA are promising surrogate markers for detection of micrometastases in regional lymph nodes from non-small cell lung cancer patients. However, clinical follow-up in a larger cohort is needed to eludicate the prognostic value of such findings.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 343. doi:10.1158/1538-7445.AM2011-343
Abstract 344: Oxygen sensors are poor prognosticators for survival in NSCLC
Authors: Andersen Sigve , Donnem Tom , Al-Shibli Khalid , Al-Saad Samer , Stenvold Helge , Busund Lill-Tove , Bremnes Roy 
Published: June 2012

Abstract
Background: Most solid tumors are at least partly hypoxic. To survive hypoxia, cancer cells must adapt by hypoxic gene activation. Hypoxia-inducible factors (HIFs) have been recognized as key regulators of this transcriptional control. However, oxygen tension is sensed by three HIF prolyl hydroxylases (PHD1, PHD2 and PHD3) and one asparaginyl hydroxylase, FIH (Foctor inhibiting HIF). This study evaluates the prognostic impact of these four oxygen sensors in the biggest killer in cancer, Non-Small Cell Lung Cancer (NSCLC).
Methods: 335 unselected stage I-IIIA NSCLC-patients were included. Duplicate 0.6 mm diameter cores from both the viable neoplastic cell compartment (tumor) and stroma were collected in tissue microarrays (TMAs). Immunohistochemistry (IHC) was used to semiquantitatively evaluate the expression.
Results: There was only scorable expression in the tumor compartment. In univariate analyses high expression of all the oxygen sensors in tumor were significantly associated with a poor prognosis (PHD1, P = 0.023; PHD2, P = 0.013; PHD3, P = 0.018; FIH, P = 0.033). There were only weak correlations between these markers (strongest between PHD2 and FIH; r = 0.18, P = 0.001). In the multivariate analysis, entering all the significant clinicopathological variables and the oxygen sensors, we found only high expression of PHD2 (HR 2.03; CI 95% 1.20-3.42; P = 0.008) and PHD1 (HR 1.45; CI 95% 1.01-2.10; P = 0.047) of the molecular variables to be independent poor prognosticators.
Conclusions: Oxygen sensors were only scorable in tumor. High expression of all the oxygen sensors was associated with a poor prognosis. High expression of PHD1 and PHD2 were also significantly and independently associated with a dismal prognosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 344. doi:10.1158/1538-7445.AM2011-344
Abstract 3440: YWHAZ promotes slug transcription activity and lung cancer metastasis
Authors: Chen Ching-Hsien , Chen Hsuan-Yu , Lin Sheng-Yi , Tsai Meng-Feng , Yu Sung-Liang , Chen Jeremy 
Published: June 2012

Abstract
Metastasis is a major cause leading to mortality for lung cancer patients and gene copy variation is one common mechanism contributing to human malignancies. To identify the novel metastasis-related genes, an approach combined array comparative genomic hybridization and expression microarray was applied in a lung cancer invasion cell model. YWHAZ was identified as a potential candidate, which plays an important role in a wide variety of cellular processes. Nevertheless, its role and underlying mechanism in lung cancer metastasis remain unclear. In this study, we found that YWHAZ promotes cell proliferation, anchorage-independent growth, invasion and migration in vitro, as well as tumorigenesis and metastasis in vivo. It not only increases cell protrusions and branchings but also induces epithelial-mesenchymal transition. Furthermore, YWHAZ associates with β-catenin and enhances slug expression which is regulated by the β-catenin/TCF signaling pathway in lung cancer cells. Our findings demonstrate that YWHAZ plays a critical role in promoting invasion and metastasis of human lung adenocarcinoma cells, which might provide new insight into the future treatment of lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3440. doi:10.1158/1538-7445.AM2011-3440
Abstract 3445: The role of p38/MAPK14 in cerebellar granule neuron precursor proliferation and medulloblastoma
Authors: Guldal Cemile G. , Mainwaring Lori A. , Kenney Anna M. 
Published: June 2012

Abstract
Development of the cerbellum occurs primarily postnatally and is marked by a rapid proliferation of cerebellar granule neuron precursors (CGNPs). This proliferation requires the activity of the mitogen Sonic Hedgehog (Shh). CGNPs are proposed to be the cells of origin for some classes of medulloblastoma (MB), the most common solid pediatric tumor, making their proliferation an attractive target for cancer therapy. Since MAP kinases play important roles in many aspects of development, proliferation, and cancer, we investigated if any of the three major classes of MAP kinases were involved in Shh-driven CGNP proliferation. We have previously shown that p42/p44 ERK MAP kinases are not involved in Shh signaling in CGNP proliferation. We have also shown that JNK/SAP kinases are not involved in Shh-driven proliferation. However, p38/MAPK14 is induced and activated in proliferating CGNPs compared to CGNPs that exit the cell cycle and differentiate in the absence of Shh. Other known pathway components upstream and downstream of MAPK14, such as ASK1, MKK3 and ATF-2, are also activated in the presence of Shh. Antioxidants such as lipoic acid and n-acetyl-cysteine that relieve oxidative stress reduced Shh-induced activation of MAPK14 and caused a marked decrease in CGNP proliferation measured by Ki67 and BrdU staining. Knocking down p38 in CGNPs also causes a marked decrease in Shh-dependent proliferation and an increase in apoptosis, which indicates a role for MAPK14 in CGNP survival. We are currently investigating the mechanism of Shh regulation of p38 MAPK pathway, which will lead to a better understanding of CGNP proliferation, cerebellar development, and MB progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3445. doi:10.1158/1538-7445.AM2011-3445
Abstract 3452: Molecular genetic analysis of the WTX gene in medulloblastoma
Authors: Wenzl Eve-Kristin , Regehly Maren , Guse Katrin , Röhn Gabriele , Goldbrunner Roland , Hernáiz-Driever Pablo , Thomale Ulrich Wilhelm , Schüller Ulrich , Heppner Frank , Koch Arend 
Published: June 2012

Abstract
Medulloblastomas (MBs) represent the most frequent malignant brain tumors of childhood. Previous genetic studies in MBs have identified mutations in genes coding for beta-catenin, AXIN1 and Conductin (AXIN2), which cause activation of the Wnt signaling pathway in about 20% of this malignant tumors. The Wnt signaling pathway is negatively controlled by the Wilms tumor suppressor gene WTX, a component of this signaling complex.
To investigate whether alterations in WTX may also be involved in the pathogenesis of sporadic MBs, we performed a mutational screening of the WTX gene in 76 MB biopsy samples and 5 MB cell lines using single-strand conformation polymorphism and sequencing analysis. Two rare WTX single nucleotide polymorphisms (SNPs) c.135C&gt;T in exon 2 of two different MBs (Ser &gt; Ser; TCC &gt;TCT), both of them are not yet known, where identified.
To investigate if the tumor suppressor WTX is regulated in MBs an mRNA expression analysis in 46 MBs and 5 MB cell lines revealed reduced expression of WTX mRNA compared to fetal cerebella tissues. Interestingly, when compared to adult cerebella tissue, WTX is up-regulated in fetal cerebella of different embryonic ages, which indicates a possible involvement of WTX during cerebella development. Moreover, wild-type WTX was found to be over-expressed in tumor cell lines in which the Wnt signaling pathway is activated by mutations in beta-catenin. Our findings indicate that the activation of the Wnt signaling pathway in MBs is not caused by alterations in WTX. However, the down-regulation of WTX could be a possible explanation for the Wnt activation in a subset of MBs. The up-regulation of WTX (related to adult controls) and in particular in Wnt-activated tumor cells suggests that WTX could be a potential target gene of the Wnt signaling pathway, which interacts in a negative feedback loop mechanism.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3452. doi:10.1158/1538-7445.AM2011-3452
Abstract 3463: Treatment of young children with localized medulloblastoma by chemotherapy alone: Final results of the prospective multicenter trial HIT 2000 confirming the prognostic impact of histology
Authors: von Bueren Andre O. , von Hoff Katja , Pietsch Torsten , Gerber Nicolas , Warmuth-Metz Monika , Deinlein Frank , Zwiener Isabella , Faldum Andreas , Fleischhack Gudrun , Benesch Martin , Krauss Juergen , Kuehl Joachim , Kortmann Rolf D. , Rutkowski Stefan 
Published: June 2012

Abstract
Background: This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with non-metastatic medulloblastoma (MB) treated by postoperative chemotherapy alone.
Methods: Patients diagnosed between January 2001 and December 2005 and younger than 4 years received three cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In case of complete remission, treatment was terminated after two additional cycles of chemotherapy. Otherwise secondary surgery, radiotherapy and consolidation chemotherapy were recommended.
Results: The 5-year event-free survival (EFS) and overall survival (OS) (±SE) rates of 45 patients were 57 ± 8% and 80 ± 6% (median follow-up: 4.5 years, median age: 2.5 years). Nineteen patients with desmoplastic / nodular MB variants had better EFS and OS (5-year rates: 90 ± 7% and 100 ± 0%) compared to 23 patients with classic MB (30 ± 11% and 68 ± 10%; p&lt; 0.001 for EFS, p=0.008 for OS). Five-year EFS and OS rates of 3 children with anaplastic MB were 33 ± 27%. Desmoplastic / nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 (97%) patients without postoperative residual tumor remained in continuous complete remission.
Conclusions: Our results confirm histology of MB variants as a strong prognostic factor in this age-group. Sustained tumor control and favorable survival rates can be achieved by this chemotherapy regimen in young children with desmoplastic / nodular MB variants. For children with non-desmoplastic / non-nodular MB variants, where predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3463. doi:10.1158/1538-7445.AM2011-3463
Abstract 3472: Endothelial FAK is required for tumor angiogenesis
Authors: Tavora Bernardo , Hodivala-dilke Kairbaan 
Published: June 2012

Abstract
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays a fundamental role in integrin and growth factor mediated signalling and is an important player in cell migration and proliferation, processes vital for angiogenesis. However, the role of FAK in adult pathological angiogenesis is unknown. We have generated endothelial-specific tamoxifen-inducible FAK knockout mice by crossing FAK-floxed (FAKfl/fl) mice with the Pdgfb-iCreER mice. Tamoxifen-treatment of Pdgfb-iCreER;FAKfl/fl mice results in FAK deletion in adult endothelial cells (EC) without any adverse effects. Importantly however, endothelial FAK-deletion in adult mice inhibited tumour growth and reduced tumour angiogenesis. Furthermore, in in vivo angiogenic assays FAK-deletion impairs vascular endothelial growth factor (VEGF) induced neovascularisation. In addition, in vitro deletion of FAK in ECs resulted in reduced VEGF-stimulated AKT phosphorylation, and correlating reduced cellular proliferation and increased cell death.
Furthermore, using a combination of genetic ablation and inhibition of FAK we are studying a new role of endothelial FAK in the regulation of the vascular barrier function with implications on the metastatic process.
Our data suggest that FAK is required for adult pathological angiogenesis and suggests a possible role of endothelial FAK in the regulation of the vascular barrier function.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3472. doi:10.1158/1538-7445.AM2011-3472
Abstract 3473: Endothelin axis autocrine loop is positively regulated by the interplay between ET-1 and hypoxia-inducible factor-1α in melanoma cells
Authors: Spinella Francesca , Caprara Valentina , Cianfrocca Roberta , Rosanò Laura , DiCastro Valeriana , Natali Pier Giorgio , Bagnato Anna 
Published: June 2012

Abstract
Phenotypic and genotypic analyses of cutaneous melanoma have identified the endothelin B receptor (ETBR) as tumor progression marker, thus representing a potential therapeutic target. We previously demonstrated that ETBR activation by endothelin (ET)-1, promotes melanoma progression and lymphatic vessel growth through a hypoxia-inducible factor (HIF)-1α-mediated mechanism and cooperates with hypoxia to increase this effect. In this study we show that in melanoma cells ETs increase ET-1 and ETBR mRNA and protein expression and their promoter activity that were completely blocked by the selective ETBR antagonist, BQ788, supporting the presence of a positive ET-1-autocrine loop. Moreover when melanoma cells were exposed to hypoxia the induction of both ETBR and ET-1 was markedly enhanced demonstrating that hypoxia potentiates the ET-1-autocrine loop by reinforcing the expression of ETBR and the secretion of ET-1 that, in turn, increases simultaneously ET-1/ETBR expression. Silencing HIF-1α or HIF-2α significantly reduced the promoter activity and the expression of ET-1 and ETBR in response to hypoxia or ETs. Chromatin immunoprecipitation assay showed increased HIF-1α and HIF-2α binding to ET-1 and ETBR promoter in response to hypoxia or ET-1 stimulation. Interestingly, ETs through ETBR enhance both vascular endothelial growth factor (VEGF)-A and VEGF-C mRNA and protein expression and promoter activity. At functional level silencing of HIF-1α and HIF-2α inhibited the ET-1 and hypoxia-induced VEGF-A and VEGF-C expression, providing that hypoxia and ET-1 axis share the same transcriptional machinery through which may control angiogenic and lymphangiogenic response. Moreover, in melanoma xenografts, ETBR antagonist suppressed tumor growth, neovascularization-related effectors, indicating that targeting ETBR related signalling cascade may represent a novel treatment of melanoma by impairing the positive feedback loop between ET axis and hypoxic melanoma microenvironment. Supported by AIRC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3473. doi:10.1158/1538-7445.AM2011-3473
Abstract 3479: Claudin-14: A novel regulator of angiogenesis
Authors: Baker Marianne , Robinson Stephen D. , Hodivala-Dilke Kairbaan , Ben-Yosef Tamar 
Published: June 2012

Abstract
Angiogenesis, the formation of new blood vessels from pre-existing ones, is vital for tumor growth and spread. A better understanding of angiogenic processes, particularly cell-cell adhesion, is required for the development of effective anti-angiogenic drugs.
Claudin-14 (Cldn14) is a component of Tight Junctions (TJ) and its function in angiogenesis is not yet known. Other TJ molecules such as JAMs are known to be involved in angiogenesis; for example, we have identified a novel dosage-dependent role for JAM-B in the regulation of angiogenesis in the context of trisomy of human chromosome 21 (Hsa21) genes (Reynolds et al. Nature 2010); Cldn14 is also present on Hsa21. Therefore we hypothesise that Cldn14 may also play a role in the regulation of angiogenesis.
Here we show that depletion of Cldn14 enhances VEGF-stimulated angiogenesis in the ex vivo aortic ring assay and increases primary mouse lung endothelial cell proliferation via changes in downstream signalling. Viable Cldn14 knockout mice exhibit normal vasculature in unchallenged organs, suggesting that the effect may be specific to pathological states. These data reveal novel regulatory roles for Cldn14 and future work will characterise further the functions of Cldn14 in angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3479. doi:10.1158/1538-7445.AM2011-3479
Abstract 3487: Molecular basis for induction of IL-8 expression by thymidine phosphorylase
Authors: Akiyama Shin-ichi 
Published: June 2012

Abstract
Thymidine phosphorylase (TP) is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and has an angiogenic activity. 2-Deoxy-D-ribose, one of the degradation products of thymidine, is a down stream mediator of the TP function.
We investigated the molecular basis for the induction of an angiogenic factor, interleukin-8 (IL-8) by TP. First we confirmed that the enzymatic activity of TP is needed for the induction of IL-8 by TP in KB cells, and 2-deoxy-D-ribose increased the expression level of IL-8. ROS generated by TP augmented the expression of heme oxygenase-1 (HO-1) and increased the expression of IL-8. Two inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, suppressed the expression of HO-1 and IL-8 in TP-overexpressing KB/TP cells. Knock down of the component of NADPH oxidase, Nox2 or p22phox, also suppressed the enhanced expression of IL-8 in KB/TP cells. ROS generated by TP activated NFκB, which subsequently enhanced the promoter activity of IL-8. Our findings suggest that NADPH oxidase is involved in the ROS generation by TP, and the ROS caused the activation of NF-κB, which subsequently enhanced the expression of IL-8.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3487. doi:10.1158/1538-7445.AM2011-3487
Abstract 3488: PGE2 promotes angiogenesis by activating PKA catalytic subunit gamma
Authors: Zhang Yushan , Daaka Yehia 
Published: June 2012

Abstract
The Cyclooxygenase-2 product PGE2 is suggested to be involved in angiogenesis, but its exact role and the underlying mechanisms remain unclear. In the present study, we show that PGE2 dose-dependently promotes the in vitro tube formation of human microvascular endothelial cells (HMVEC). PGE2 also increases vessel density in chicken chorioallantoic membrane, and vessel outgrowth of mouse aortic rings. All cognate PGE2 receptors, namely EP1, EP2, EP3 and EP4 can be detected in the HMVECs at both the gene and protein levels. Using EP-specific ligand agonists and antagonists our data demonstrate the EP4-dependent tube formation. Concordantly, knockdown of EP4, but not EP1, EP2 or EP3 with siRNA attenuates the PGE2-induced tube formation. Treatment with PGE2 increases cAMP accumulation and PKA activation, and knockdown of EP4 attenuates the PKA activation, suggesting a principally EP4-to-PKA signal. Remarkably, the treatment with selective PKA inhibitors H89 or PKI attenuates the PGE2-mediated tube formation. There are three PKA catalytic subunits and the knockdown of catalytic subunit gamma (PKACg) prevents the PGE2-regulated tube formation. To begin to identify the PKA substrate(s) involved in tube formation, a panel of SMARTpool siRNAs targeting 16 PKA substrates was tested. Results show that heat shock protein B6, endothelial nitric oxide synthase and small GTPase Rap1A exert pro-tube formation effects, whereas small GTPase RhoA and GSK3b may be involved in anti-tube formation. Our data suggest that PGE2 promotes angiogenesis through a EP4-cAMP-PKACgamma pathway. Targeting EP4 and PKACgamma may serve as an efficient strategy to control initiation and progression of diseases affected by angiogenesis, such as cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3488. doi:10.1158/1538-7445.AM2011-3488