bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-372: Expression and functional role of erbB2 in human hepatoblastoma
Authors: Steiger Barbara , Leuschner Ivo , Denkhaus Dorota , von Schweinitz Dietrich , Pietsch Torsten 
Published: August 2014

Abstract
The receptor tyrosine kinase erbB2 is known to play a role in the development of hepatic progenitor cells and is often found to be expressed and mutated in different solid tumors. Activated erbB2 is a marker of poor prognosis in several malignancies and to date, successful strategies have been developed to target erbb2 receptor. The aim of this study was to determine the expression of erbb2 in human hepatoblastoma, the most common primary hepatic malignancy in early childhood, and its functional role in hepatoblastoma cell biology. Expression of erbB2 on the protein level was analyzed by Western Blot, immunofluorescence and RT-PCR of lysates of primary tumors and cell lines HuH6, HepT1, HepT3 and HepG2. Immunohistochemical staining was performed to determine phosphorylated erbB2 and subsequent kinases. Single strand conformation polymorphism (SSCP) analysis was used to scan known hotspots for mutations (exons 6, 8, 18–23 of erbB2) in a panel of 56 tumor samples. Cells were stimulated with rhHRG1-β. Activation of subsequent kinases was determined via Western Blot and MTT assay was used to determine proliferation after stimulation and overexpression of erbb2 via transient transfection. The influence of rhHRG1-β on the activity of the Wnt/ß-catenin pathway was measured by transfection with the TOP-/FOP-Flash reporter assay. The effects of erbB2 kinase knockdown by transient transfection with siRNA against erbB2 on apoptosis and proliferation were also evaluated. Expression of erbB2 was detected in all four cell lines and most of the primary tumors. Immunohistochemistry indicated expression of phosphorylated (activated) Erbb2 proteins in 90% and activation of subsequent kinases, which are downstream targets of erbb2. Mutations were not present in the erbB2 gene. Stimulation with HRG1-β induced phosphorylation of Akt, Erk1/2 and p70S6K and resulted in increased cell proliferation. This effect was not mediated by an increase of activity of the Wnt/ß-catenin signaling pathway because TOP-Flash reporter activity was not further increased in the presence of rhHRG1-β. Overexpression of erbB2 resulted in enhanced proliferation after stimulation with HRG1-β in all four cell lines, whereas knockdown of erbB2 decreased the proliferative effect of HRG1-β on hepatoblastoma cell lines. Knockdown of erbB2 did not induce apoptosis in hepatoblastoma cell lines. These results indicate that erbB2 might play an important functional role in hepatoblastoma cell biology. Further experiments are needed to evaluate the clinical significance.
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 LB-372. doi:10.1158/1538-7445.AM2011-LB-372
Abstract LB-373: Lymphatic vessels and neoformed microvessels density in primary oral squamous cell carcinoma and associated lymph nodes
Authors: Sousa Sílvia F. , Gleber-Netto Frederico O. , Oliveira-Neto Helenisa H. , Batista Aline C. , Gomes Carolina C. , Gomez Ricardo S. , Aguiar Maria Cássia F. 
Published: August 2014

Abstract
The aim of this study was to evaluate the density of lymphatic vessels (LVD) and neoformed microvessels (MVD) in primary oral squamous cell carcinoma (OSCC) and associated lymph nodes, metastatic or not, and the association of such densities with clinicopathological behavior and metastasis presence. Since vascular endothelial growth factor C (VEGF-C) induces tumor lymphangiogenesis and lymphatic metastasis, this protein was also analyzed in tumor parenchyma. For evaluation of primary tumor, thirty-six paraffin-embedded samples of OSCC were investigated. The tumors were histologically graded and all clinical data of the patients, as tumor size and nodal metastasis were obtained from the medical records. Intratumoral and peritumoral lymphatic (LVD) and neoformed (MVD) vessels were identified by immunohistochemistry using D2–40 and CD105 antibodies respectively. The sum of intra and peritumoral lymphatic and neoformed microvessels was determined as total LVD and total MVD in a magnification of 400x. The same method of count was applied in the analysis of vascular density in lymph nodes. The immunoexpression of VEGF-C was determined by percentage of strongly positive tumour cells. Intratumoral lymphatic vessel density mean was 2.95±3.30, peritumoral mean was 2.96±2.23 and total LVD mean was 5.86±4.81. MVD intratumoral mean was 7.40±4.55, peritumoral mean was 6.25±3.92 and total MVD mean was 13.66±7.30. Intratumoral LVD was significantly lower in poor differentiated tumors (p&lt;0,05). Total MVD was higher in cases with lymph node involvement (p&lt;0.05). An association between VEGF-C positivity and metastasis was also observed (p&lt;0,05). The LVD and MVD in metastatic lymph nodes were significantly higher than in non metastatic lymph nodes (p&lt;0,001). In conclusion lower LVD and higher MVD were associated with high grade malignancy and presence of metastasis. In addition, the metastatic lymph nodes demonstrated a significantly higher vascular density comparatively to non metastatic lymph nodes and the influence of this finding in occurrence of distance metastasis should be investigated in further studies.
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 LB-373. doi:10.1158/1538-7445.AM2011-LB-373
Abstract LB-386: Targeting of induced cancer stem cells with iniparib in combination with carboplatin and gemcitabine
Authors: Ossovskaya Valeria , Canino Erica , Giritharan Gnanaratnam , Kim Kyung-Ah , Ilic Dusko , Krtolica Ana 
Published: August 2014

Abstract
BACKGROUND: Mounting evidence exists that human breast cancers include a stem-like cell population with self-renewing, tumorigenic properties. This population of cells, known as cancer stem cells (CSCs) or tumor-initiating cells, shares phenotypic characteristics with embryonic stem cells (ESCs), including activation of certain developmental pathways, and is resistant to many anticancer therapies. Distinguishing features of stem cells include active DNA repair and resistance to apoptosis, which enable their survival in the presence of conventional cytotoxic and cytostatic therapies that target actively proliferating cells. Identification of pharmaceuticals that preferentially target CSCs represents a novel strategy in modern drug discovery and development. We investigated whether treatment with iniparib (BSI-201) can potentiate the anti-proliferative effects of gemcitabine and carboplatin in CSCs.
METHODS: A multi-stage stem cell carcinogenesis model that mirrors the natural progression of carcinogenesis was previously developed using in vitro and in vivo selection of mutated ESCs, which exhibit specific tumor-initiating and cancer stem cell-associated behaviors (SLL Sciences). These induced CSCs (iCSCs) were treated with iniparib (3.7, 11, 33, or 100 μM), gemcitabine (1.5 nM), carboplatin (10 μM), or gemcitabine + carboplatin for 72 hours, and effects on iCSC proliferation were evaluated using an ELISA-based bromodeoxyuridine (BrdU) assay and an ATP-based detection assay for measuring cellular metabolism. Effects of iniparib and/or gemcitabine on DNA damage were evaluated by immunofluorescence staining of iCSC using antibodies against γH2AX (a marker of double strand DNA breaks) at 24 hours after treatment.
RESULTS: Treatment with iniparib alone resulted in a dose-dependent decrease in cellular proliferation and metabolism, with the IC50 established at 60 μM. Iniparib (60 μM), gemcitabine (1.5 nM), and carboplatin (10 μM) each induced &gt;50% reduction in iCSC proliferation; addition of iniparib to gemcitabine resulted in an 80% reduction in BrdU incorporation compared with gemcitabine alone (P = 0.027). To assess iniparib-associated DNA damage, γH2AX foci were quantified in &gt; 300 cells for each treatment combination. Cells treated with iniparib, gemcitabine, or iniparib + gemcitabine demonstrated 3.7-, 6.8-, and 8.8-fold increases in γH2AX foci, respectively, compared with untreated control (P &lt; 0.005).
CONCLUSIONS: These findings demonstrate that iniparib increases the effects of gemcitabine in terms of antiproliferative activity and DNA damage in this CSC model.
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 LB-386. doi:10.1158/1538-7445.AM2011-LB-386
Abstract LB-387: Blockade of the CXCL12/CXCR4 axis with AMD3100 induces multimodal antitumor effects in murine ovarian cancer and prolongs survival
Authors: Kashiwagi Satoshi , Righi Elda , Yuan Jianping , Santosuosso Michael , Ingraham Rachel , Orsulic Sandra , Birrer Michael , Penson Richard , Dranoff Glenn , Poznansky Mark C. 
Published: August 2014

Abstract
The chemokine, CXCL12, and its receptor, CXCR4, have been shown to be expressed by various tumors including ovarian cancer. CXCL12/CXCR4 expression by tumors has been associated with enhanced progression including tumor cell proliferation, invasion, and angiogenesis. We proposed that modulation of the CXCL12/CXCR4 axis in ovarian cancer would have multimodal effects on tumor pathogenesis. This was addressed using RNAi technology and a selective CXCR4 antagonist, AMD3100, in an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer derived from a syngeneic cell line (BR5–1) that constitutively expresses both CXCL12 and CXCR4. CXCL12 knockdown of BR5–1 cells using RNAi reduced cell proliferation in vitro (p&lt;0.01) and tumor growth in vivo (p&lt;0.05) compared to controls. AMD3100 treatment of BR5–1-derived tumors resulted in the increase of tumor apoptosis (p&lt;0.05)and necrosis and in a significant reduction of intraperitoneal dissemination, angiogenesis, and intratumoral infiltration of FoxP3+ regulatory T cells compared to controls (T-regs)(p &lt; 0.05). In addition, selective CXCR4 blockade with AMD3100 resulted in significantly increased anti-tumor T cell mediated immune responses compared to controls (p&lt;0.05). These multimodal anti-tumor effects translated into a significant survival advantage in AMD3100-treated mice as compared to controls (p&lt;0.05). Selective CXCR4 antagonism also significantly decreased intratumoral T-regs infiltration in a second model of aggressive melanoma (p&lt;0.05). In summary, these data generated in an immunocompetent syngeneic and orthotopic murine model of ovarian cancer lend important support to the view that the CXCL12/CXCR4 axis plays multiple roles in the pathogenesis of this disease. Furthermore, the availability of a safe, effective and clinically applicable CXCR4 antagonist in AMD3100 adds both to the direct clinical translatability of this study and to the potential for the use of this agent as an adjunct to conventional chemotherapy or in combination with other immunotherapies aimed at enhancing CD8+ T cell responses in human ovarian 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 LB-387. doi:10.1158/1538-7445.AM2011-LB-387
Abstract LB-392: JunB and cJun dependent PDGFRβ expression reveals imatinib/nilotinib treatment as effective therapeutic strategy for ALK driven lymphomas.
Authors: Schiefer Ana Iris , Kenner Lukas 
Published: August 2014

Abstract
Anaplastic large cell lymphomas (ALCLs) are frequent non Hodgkin Lymphomas of T-cell origin, comprising 40% of all non-Hodgkin Lymphomas of childhood and 2–8% of adulthood. Half of the cases are associated with a t(2;5) translocation, leading to the fusion of NPM gene and ALK tyrosine kinase, resulting in its constitutive activation. The AP-1 transcription factors JunB and cJun are downstream effectors of NPM-ALK. To investigate the role of JunB and cJun in NPM-ALK mediated tumorgenesis, we used a murine NPM-ALK T- cell lymphoma model in which the conditional deletion of JunB and cJun was selectively restricted to CD4+ T lymphocytes. Loss of JunB and cJun in transgenic T cells resulted in significantly increased disease latency and doubled the mean survival rate. We identified PDGFRβ as direct target of cJun and JunB. These transcription factors directly bind to a highly conserved AP-1 site within the promoter region of PDGFRβ and activate its transcription in vitro. We further investigated the effects of PDGFRβ inhibition in NPM-ALK xenografts and in a murine NPM-ALK T-cell lymphoma model using the kinase inhibitors imatinib and nilotinib. Treated xenografts showed significant smaller tumor masses, CD4-NPM-ALK mice displayed a drastic increase in mean survival rate. Based on these very promising data we even had the chance to check effects of imatinib therapy in a patient with relapsed ALK+ ALCL. After treatment with six cycles CHOP, one cycle ICE, allogenic stem cell transplantation with previous conditioning with BEAM, he received imatinib. Within one week of therapy lymph nodes regressed and B-symptoms declined. A PET-CT revealed complete remission two weeks after imatinib initiation. In summary, these data demonstrate a pathogenic role of JunB/cJun as well as PDGFRβ in NPM-ALK mediated lymphomagenesis. Our study encourages the development of specific clinical trials for human ALCLs using tyrosine kinase inhibitors.
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 LB-392. doi:10.1158/1538-7445.AM2011-LB-392
Abstract LB-395: Hepatocyte growth factor: a potential therapeutic target in pancreatic cancer
Authors: SJ Arun , Z Xu , Fiala-Beer E , Phillips P , Goldstein D , Biankin A , Pirola R , Wilson JS , Apte MV 
Published: August 2014

Abstract
Pancreatic stellate cells (PSCs, which produce the desmoplastic reaction of pancreatic cancer) interact with pancreatic cancer (PC) cells to potentiate PC progression. A candidate factor that may mediate this interaction is the hepatocyte growth factor (HGF). High serum HGF levels in PC patients correlate with poor outcome. However, there is limited knowledge about the role of HGF in PC. Aims: To i) determine whether human PSCs and PC cell lines express HGF; and
ii) assess the effects of HGF inhibition on PC progression in an orthotopic mouse model.
Methods:
i) HGF expression in PSCs and PC cells assessed by RT-PCR, immunoblotting/immunocytochemistry.
ii) Orthotopic model: AsPC-1 (a human PC cell line) ± human PSCs implanted into the pancreas mice. One week later, mice divided into groups (n=8 mice/group) and treated with: HGF antibody AMG102 [(Amgen Inc.), 300 or 600μg IP biweekly] or isotype IgG (600 μg IP biweekly). Seven weeks later, tumour size and metastasis assessed.
Results:
i) PSCs express HGF at both mRNA and protein levels. In contrast, PC cells (MiaPaCa2, Panc-1, AsPC-1) express negligible HGF mRNA.
ii) Orthotopic model: a) IgG treated AsPC-1+PSC mice showed larger tumours than mice injected with AsPC-1 alone (Table); b) 300 and 600μg AMG102 inhibited tumour growth in AsPC-1+PSC mice compared to the IgG treated group. However, AMG102 did not reduce tumour size in mice injected with AsPC-1 alone (Table). c) 600μg AMG102 inhibited metastasis (liver, diaphragm, mediastinum) in AsPC-1+PSC mice (p&lt;0.05) compared to IgG treated mice.
Conclusions: We have shown for the first time that i)human PSCs synthesise HGF; ii)HGF inhibition reduces tumour growth and metastasis of tumours representative of human PC i.e., exhibiting both tumour elements and a stromal reaction, but not in the clinically non-representative cancers formed by PC cells alone.
Implication: Targeting the stromal reaction with relevant specific inhibitors may represent a novel therapeutic approach in PC.

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 LB-395. doi:10.1158/1538-7445.AM2011-LB-395
Abstract LB-397: Functional characterization of IGF-1R antibodies and possible implications for clinical safety and efficacy
Authors: Kuenkele Klaus-Peter , Hofmann Marco H. , Scheiblich Stefan , Wartha Katharina , Klein Christian 
Published: August 2014

Abstract
Background
This is the first study performing a head to head comparison of monoclonal IGF-1R antibodies (mAb) based on published sequences for therapeutic mAbs from Pfizer (CP751,871, IgG2 kappa), Amgen (AMG479, IgG1 lambda), Merck (h7C10, cloned to R1507 backbone), Imclone (IMC-A12, IgG1 lambda) and Roche (R1507, IgG1).
Methods
In this study, sequence information for IGF-1R mAbs was extracted from patents and used to clone and transiently express IgGs (*=re-synthesized) in HEK293F cells. In vitro assays for ligand binding, IGF-1R auto-phosphorylation, IGF-1R downregulation, IR co-downregulation, and affinity analyses (Biacore) were used. In vivo comparison was done in BxPC3 xenograft mouse model.
Results
All antibodies inhibit IGF-1 binding and signaling at low nanomolar levels. While IMC-A12* and R1507 also prevent IGF-2 binding to IGF-1R and subsequent receptor activation, CP751,871* and h7C10* do not inhibit IGF-2 binding and have only limited impact (55%/30% inhibition) on IGF-2 signaling.
Analysis of IGF-1R phosphorylation in 0.5 % FCS medium revealed that all antibodies except R1507 exert agonistic activity. Interestingly, Fab fragments of agonistic mAbs became antagonistic, indicating that bivalent binding is necessary for agonistic effects.
All mAb (200nM, 24h treatment of MCF-7 cells) with the exception of AMG479* efficiently downregulated 78–82% the IGF-1R. Analysis of the same cell lysates revealed however striking differences in IR co-downregulation, a mechanism discussed as possible cause of clinical hyperglycemia. R1507 had the least side effects on Insulin co-downregulation (9%) compared to h7C10* (15%), CP751,871* (23%) and IMC-A12* (46%).
Differences were also seen in the binding kinetics. Both AMG479* and R1507 showed faster koff rates resulting in shorter retention times at the receptor. Since kon/koff rates are discussed to influence tumor penetration (1), we compared downregulation of IGF-1R by R1507 and CP751,871* in xenograft tumors. Although both mAbs downregulate IGF-1R in vitro to the same extent, R1507 was significantly more effective in the in-vivo setting.
Conclusion
The head to head comparison of IGF-1R mAbs revealed differences in regard to binding properties, tumor penetration, IR codownregulation, and inhibition of signaling via the ligand IGF-2.
Reference List
1. Adams, G. P., Schier, R., McCall, A. M., Simmons, H. H., Horak, E. M., Alpaugh, R. K., Marks, J. D., and Weiner, L. M. (2001) Cancer Res. 61, 4750–4755
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 LB-397. doi:10.1158/1538-7445.AM2011-LB-397
Abstract LB-40: Autophagy prevents leukemogenesis by protecting normal hematopoietic stem cells from transforming to leukemia stem cells
Authors: Yuan Na , Wang Qi , Zhang Aihong , Lin Weiwei , Liu Lei , Zhang Suping , Cao Yan , Xu Fei , Kong Yue , Li Lanzi , Xu Tiehan , Chen Si , Lu Tongyuan , Zhao Wenli , Zhang Xueguang , Wang Jianrong 
Published: August 2014

Abstract
Leukemia has long been considered unpreventable, and how leukemogenesis is initially triggered remains largely unknown. We observed that autophagy is frequently downregulated in the hematopoietic stem cells of various types of leukemia patients. Using a conditional Becn1 knockout mouse model, we found that impaired autophagy results in rapid accumulation of reactive oxygen species (ROS) that causes DNA damages, genome instabilities and chromosomal translocations of hematopoietic stem cells, leading to their transformation to leukemia stem cells, ultimately attributed to various leukemogenenesis. Restoration of autophagy in the hematopoietic stem cells of the autophagy defective mice by constitutive expression of Becn1 could clean up ROS, inhibit DNA damages and chromosomal translocations, and block the transformation of hematopoietic stem cells to leukemia stem cells, ultimately inhibiting leukemogenesis. Furthermore, enhancement of autophagy by rapamycin could effectively remove the ROS experimentally induced in hematopoietic stem cells and eliminate the leukemia stem cells either transplanted to wild-type recipient mice or transformed from normal hematopoietic stem cells due to pharmacological inhibition of autophagy. Our data thus suggest that autophagy prevent leukemogenesis by protecting normal hematopoietic stem cells from transforming to leukemia stem cells and that leukemia prevention is possible by securing autophagy machinery in hematopoietic stem cells.
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 LB-40. doi:10.1158/1538-7445.AM2011-LB-40