bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4332: Proprotein convertases as target for therapy of pediatric sarcomas
Authors: Bernasconi Michele , D'Alessandro Valentina , Bornhauser Beat C. , Niggli Felix , Schaefer Beat W. 
Published: August 2012

Abstract
One of the biggest challenges of treating children with cancer is achieving complete remission, while ensuring that they will be able to lead normal, productive life in adulthood. To improve therapies for embryonal pediatric tumors such as rhabdomyosarcoma (RMS) the most common soft tissue sarcoma in children, we have selected by in vivo phage display for peptides that bind to RMS with high specificity. We have shown that coupling of Doxorubicin to RMS-P3, a RMS targeting peptide, considerably increases its therapeutic impact in a mouse model for RMS. We have identified proprotein convertases (PC), a family of ten serine proteases which convert inactive proprotein into their active form, as targets RMS binding peptides. Now we aimed at elucidating the contribution to RMS growth in vivo of the two proprotein convertases, furin and PC7, which are highly expressed in RMS tumors. To this end, we have generated a panel of RMS cell lines overexpressing furin, overexpressing a specific intrinsic PC inhibitor called α1-PDX, as well as cell lines were expression of furin or PC7 has been stably blocked by shRNA. These cells have been tested for their growth, migration and invasion potential in vitro as well as for their growth in vivo as subcutaneous xenografts. Histological analysis of tumor sections, in particular of microvessel density and angiogenesis has been performed to reveal if PC activity correlates with RMS progression. Our results confirm a strong correlation between PCs activity and RMS growth in vivo and suggest furin and PC7 as viable targets for therapeutic intervention and warrant further studies in the development of novel therapeutic approaches based both on specific inhibition of PCs protease activity and on targeted drug delivery by PCs targeting peptides.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4332. doi:1538-7445.AM2012-4332
Abstract 4334: Expression of PID1 correlates with PFS in pediatric medulloblastomas and negatively impacts growth of medulloblastoma, glioblastoma and AT/RT brain tumor cell lines
Authors: Erdreich-Epstein Anat , Ren Xiuhai , Zhou Hong , Schur Matthew , Ji Lingyun , Sposto Richard , Asgharzadeh Shahab 
Published: August 2012

Abstract
PID1, discovered in 2006, encodes an adapter protein that contains a phosphotyrosine binding (PTB) domain. Overexpression of PID1 can have inhibitory or proliferative effect, depending on the cell line. In adipocytes and myocytes PID1 inhibits insulin-induced signaling via a yet-unknown mechanism. To date, there are no reports on PID1 effects in cancer. Using quantitative real time RT-PCR of PID1 expression in 78 pediatric medulloblastoma tumors at diagnosis we found that higher PID1 expression correlated with longer progression-free survival (PFS) in multivariate analysis. Similar correlation was found for PID1 variant 1 and variant 2. Interestingly, PID1 was higher in desmoplastic medulloblastomas, which carry better prognosis vs. anaplastic medulloblastomas, which have poorer prognosis. Query of the REMBRANDT database showed that higher PID1 expression was highly correlated with longer overall survival (OS) in gliomas. REMBRANDT also showed that PID1 expression in GBMs (n=228) was 0.47 of the PID1 expression in non-tumor brain (n=28) (p&lt;0.001) and similarly, was lower in GBMs compared to astrocytoma II/III or oligodendroglioma. TCGA similarly showed that PID1 expression in GBM was 0.40 of its expression in non-tumor brain. In tissue culture we found that transient transfection of PID1-tGFP, but not tGFP, inhibited colony formation in GBM (U251, LN229), medulloblastoma (D283MED) and ATRT (CHLA-06-ATRT) cell lines. PID1 expression decreased proliferation (BrdU, 7AAD), increased sub-G0/G1, increased apoptosis (AnnexinV), and increased mitochondrial depolarization (JC1 probe) of GBM, medulloblastoma and/or ATRT cell lines, supporting an inhibitory function for PID1 in these tumors. Studies are currently ongoing into the molecular mechanism that mediates these effects. In summary, our data demonstrate correlation between high PID1 expression and better patient outcome in two different brain tumors: medulloblastomas and gliomas, and inhibitory effect of PID1 in three types of brain tumor cell lines: medulloblastomas, gliomas, and ATRT. This suggests that PID1 may have a functional role in the biology, and possibly in response to therapy, of these three brain tumor types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4334. doi:1538-7445.AM2012-4334
Abstract 4335: The genomic landscape of childhood pre-B acute lymphoblastic leukemia
Authors: Spinella Jean-François , Saillour Virginie , Richer Chantal , Ouimet Manon , Cassart Pauline , Healy Jasmine , Bareke Eric , Larivière Mathieu , St-Onge Pascal , Busche Stephan , Ge Bing , Montpetit Alexandre , Pastinen Tomi , Sinnett Daniel 
Published: August 2012

Abstract
Precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the most frequent pediatric cancer. Increased understanding of the pathobiology of B-cell ALL has led to risk-targeted treatment regimens and increased survival rates. However, the underlying causes of this pediatric cancer are still unclear. We are using next-generation sequencing technology to better understand the genomic landscape of pre-B ALL and to build a catalogue of variations involved in pediatric ALL onset and/or progression. Using a unique “quartet” design that involves matched tumor (at diagnosis) and normal (remission) samples, as well as DNA from both parents, we will be able to identify somatic mutations driving the leukemic process. Here, we report the deep-sequencing of the whole exomes, and the partial miRNomes, of over 60 childhood B-cell ALL quartets. Using ABI SOLiD technology, we captured over 4.0 Gb of sequence on average per sample with a mean coverage of 40X. Genome-wide genotyping (Illumina's Omni 2.5 array) was also for quality control and structural variant identification. For each individual, approximately 97% of the targeted region was covered α1X and 80% of the targeted bases passed our thresholds for variant calling (≥ 5X coverage, MQV ≤ 20). According to these criteria, about 25,000 SNPs were found per individual. Using this quartet design we were able to incorporate parental sequence information to reduce sequencing errors and facilitate the identification of true variants within a given family, and of leukemia-specific variants within the ALL cohort. We investigated the somatic mutation profiles of the ALL genomes and identified both recurrent and private leukemia-specific mutations, and highlighted genes/pathways with an increased burden of somatic loss of function variants. Our goal now is to validate potential driver mutations that could play a direct role in leukemogenesis through functional assessment. Ultimately, this work will provide invaluable insights to understand the genetic mechanisms underlying pediatric ALL which could lead to the development of powerful clinical tools to improve detection, diagnosis and treatment of this childhood cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4335. doi:1538-7445.AM2012-4335
Abstract 4345: Inadequate repair of ionizing radiation damage: A consequence of the invasive tumor phenotype
Authors: Pond Erika D. , Sroka Thomas C. , Gard Jaime MC , Pawar Sangita C. , Nagle Raymond B. , Cress Anne E. 
Published: August 2012

Abstract
A major characteristic of the transition of prostatic intraepithelial neoplasia (PIN) to invasive prostate cancer is the progressive loss of laminin 322 in the basal lamina and loss of A6B4 integrin, a laminin 322 adhesion receptor in the basal cells. Previous work from our group reported that the loss of interaction with laminin 322 decreased the ability of normal prostate cells to respond to DNA damage. The defect was manifested as an alteration of an ionizing radiation (IR) induced G2 progression block. In this study, the goal was to determine if an invasive phenotype of human tumor cells, expressing A6B1 integrin, a laminin 511 adhesion receptor, influenced a DNA damage response (DDR) to IR. DU145 tumor cells were grown on laminin 511 and DDR was determined under conditions of stimulated invasion via HGF. The DDR endpoint chosen was the production, resolution and persistence of nuclear H2AX phosphorylation foci as an indicator of damage, repair and inadequate repair, respectively. Similar to a recent report, we observed a fast and transient phosphorylation of H2AX in response to IR within the basal cells of the normal human prostate epithelium that was both dose and time dependent. Utilizing tissue culture conditions, we determined that under optimal growth conditions on laminin 511 there was a dose and time response of H2AX phosphorylation in response to IR treatment. Under conditions of HGF stimulation, the persistence of H2AX foci 24 hours after IR was two to four fold higher as compared to unstimulated cells. The amplified persistence of H2AX foci was observed at 1, 2, 4, 6 and 8 Gy at both 24 and 36 hours after IR treatment. Current studies are determining if the inadequate repair response to IR under conditions of stimulated invasion results in an increased tumor cell killing or an increased genomic instability of surviving tumor cells. (Supported in part by NIH Cancer Center Core Grant CA 23074 and DOD grant W81XWH-10-1-0496)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4345. doi:1538-7445.AM2012-4345
Abstract 4347: γH2AX foci formation in lymphocytes in vivo is increased one hour after very low dose X-radiation in three young children
Authors: Halm Brunhild M. , Franke Adrian A. , Turner Helen C. , Lai Jennifer F. , Zohrabian Vatche , DiMauro Robert 
Published: August 2012

Abstract
Objective: Computer tomography (CT) involves ionizing X-irradiation which can cause DNA damage from free radicals. CT use has risen dramatically due to its high speed and diagnostic value but it leads to an estimated lifetime cancer risk of up to 4% with highest risk for children. Double strand breaks, the most serious DNA damage caused by X-rays and other types of ionizing radiation, leads to histone H2AX phosphorylation which causes recruitment of repair proteins to DNA damage sites. γH2AX foci therefore represent quantitatively double strand breaks and can be assayed by a fluorescent immunostaining procedure. This γH2AX assay has been shown to be useful as a reliable biodosimeter for X-irradiation in vitro, in animals, and in adults. Recently also children who received cardiac catheterization procedures involving fluoroscopy with intermediate X-irradiation doses showed a dose response in this assay. We tested whether the γH2AX assay can detect changes when children receive X-irradiation at very low doses (&lt;3 mSv) from CT scans. Methods: For this pilot study, three children aged 3 to 21 months and scheduled for a medically indicated CT were recruited through the emergency department at Kapi'olani Medical Center (Honolulu, Hawaii). These children donated blood immediately before and 1 hour after their CT exam (1.57- 2.86 mSv). Blood was immediately processed after the second blood draw and lymphocytes were isolated and fixed. For a blind analysis, the samples were coded in duplicate and shipped to Columbia University, New York, where the lymphocytes were immunolabeled with an anti-human γH2AX monoclonal antibody. The average number of γH2AX foci per cell nucleus was determined for each of the duplicate samples. Results: The γH2AX assay showed that the fluorescent frequencies were dose dependently higher in all patients 1 hour after CT exposure as compared to before CT (p=0.046 by paired t-test). Conclusion: In this pilot study we observed a significant induction of γH2AX foci in lymphocytes after very low dose ionizing X-irradiation (1-3 mSv) in vivo in children one hour after CT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4347. doi:1538-7445.AM2012-4347
Abstract 4349: Therapeutic radiation induces an epigenetic DNA methylation response
Authors: Antwih Deborah A. , Gabbara Kristina M. , Fasih Aisha , Ruden Douglas M. , Zielske Steven P. 
Published: August 2012

Abstract
Therapeutic radiation results in a cascade of cellular events culminating either in repair of DNA damage and cell survival, or failure to repair damage and cell death. Gene expression is partially under epigenetic control in the form of DNA methylation. We investigated whole genome DNA methylation profiles of MDA-MB-231 breast cancer cells following therapeutic radiation to determine genes and pathways that are differentially methylated. MDA-MB-231 cells were treated with a single dose of 0, 2, or 6 Gy and incubated at 1, 2 4, 8, 24, 48, and 72 hrs before obtaining DNA extracts. DNA was subjected to whole genome DNA methylation profile analysis using an Infinium BeadArray which has the ability to determine CpG methylation at 450,000 genomic sites and covering all genes. Compared to unirradiated cells, 2 and 6 Gy irradiated cells showed 419-1661 CpG sites with decreased methylation and 514-2657 CpG sites with increased methylation, depending on time and dose. The number of hypomethylated genes in 2 Gy irradiated cells increased over time while the number of hypermethylated genes decreased in the first 8 hrs and then increased to a maximum at 72 hrs. In 6 Gy irradiated cells, no pattern was detected, although there was overall more DNA methylation changes than in 2 Gy irradiated cells, indicated a dose effect. Gene ontology analysis using Genomatix Genome Analyzer showed significant changes in DNA repair, cell cycle, apoptosis, and cell survival pathway gene methylation. DNA repair genes were differentially methylated as early as 1 hr after irradiation and sustained through 72 hrs. Epigenetic changes persisted after DNA repair, as shown by gamma-H2AX immunofluorescence, had taken place. Cell cycle, cyclin-dependent kinase, and cyclin-dependent kinase inhibitor genes were differentially methylated 4-24 hrs post-irradiation, correlating with a G2 cell cycle arrest as determined by flow cytometry. These data suggest that epigenetic regulation in the form of DNA methylation is integrated with the cellular response to radiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4349. doi:1538-7445.AM2012-4349
Abstract 4366: miR-126 reduces the tumorigenicity of melanoma cells in vitro and alters the melanoma microenvironment
Authors: Gremel Gabriela , Mulrane Laoighse , Paul Toby , Williams Vivienne , Gallagher William M. , Pontén Fredrik 
Published: August 2012

Abstract
The microRNA (miRNA) miR-126 is highly expressed in endothelial cells and often reported as down-regulated in cancer. The present study thoroughly examines the functional relevance of miR-126 in melanoma progression and suggests a central role of this miRNA as prognostic marker and modulator of the melanoma microenvironment. Initially, the expression of miR-126 was quantified in two independent, isogenic cell line model series of melanoma progression. To further explore its functional role, two stable over-expression cell lines were generated and subjected to an extensive series of in vitro assays. Subsequently, the prognostic relevance of miR-126 was assessed via in situ hybridization on a large melanoma tissue microarray cohort. In both melanoma cell line systems, miR-126 expression was inversely correlated with the level of tumorigenicity. Over-expression of miR-126 in vitro resulted in a significant decrease in colony formation, both in the presence and absence of anchorage, while cell viability remained unaffected. Using a three-dimensional spheroid invasion assay, over-expression of miR-126 significantly reduced cell invasiveness. In addition, a substantial reduction in tumor cell adhesion to VCAM-1 coated micro-channels was observed when the adhesive capacity of miR-126 over-expressing cells was examined under shear stress using the Cellix's Microfluidic Platform. Using in situ hybridization on tissue microarrays containing melanoma tissue, miR-126 expression was evident in the tumor vasculature whereas melanoma cells did not appear to express miR-126. Analysis of the degree of vascular staining revealed a significant association between lower vascular miR-126 expression and lower T-stage. In addition, high vascular miR-126 scores were significantly associated with prolonged overall survival, in particular in high grade tumors (T-stages 3 and 4). Overall, miR-126 over-expression was shown to trigger a less aggressive phenotype in melanoma cells in vitro. Nonetheless, its clinical relevance in melanoma may primarily be mediated by the tumor vasculature. Depletion of miR-126 has previously been linked to a number of tumor relevant phenotypes, including inflammation. Vascular up-regulation of the miR-126 target protein VCAM-1 may mediate increased tumor infiltration of lymphocytes and macrophages, which are known to play a crucial role in tumor development and prognosis. This renders miR-126 an exciting target for closer investigation with regard to its role in the melanoma microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4366. doi:1538-7445.AM2012-4366
Abstract 4424: Roles of the primary bile acid receptor FXR in liver repair and tumorigenesis
Authors: Meng Zhipeng , Wang Xiaoqiong , Huang Wendong 
Published: August 2012

Abstract
Bile acids promote processing of dietary fat and regulate glucose homeostasis in liver through its receptor, FXR. In our study, we demonstrate that bile acid/FXR signaling also plays a role in the tissue homeostasis and repair as well as hepatocarcinogenesis. Either decreased bile acid level or loss of FXR leads to impaired liver regeneration after carbon tetrachloride-induced liver injury or 70% partial hepatectomy, which indicates that FXR is an essential liver protector by regulating liver cell proliferation and death. Indeed, FXR-/- mice spontaneously develop liver cancer when they are aged due to their chronic liver injury and deregulated repair. In addition, FXR expression is down-regulated in human liver tumors compared with non-tumor regions, and the hepatocarcinogenesis in FXR-/- mice can recapitulate the process of human liver cancer initiation and progression. Therefore, FXR-/- mice provide a unique animal model for liver cancer study. For instance, we generated IFNα-/-FXR-/- mice to clarify the tumor suppressor role of the cytokine IFNα, the function of which was ever under debate. FXR-/- mice can be also used to identify or predict more differentially expressed genes in human liver cancer. For example, we found that one liver-rich miRNA, miR-194, which is down-regulated in the liver tumors of FXR-/- mice, is an important liver epithelial cell marker and prevents cancer metastasis, which has not been described before. In conclusion, ablation of FXR increases susceptibility to liver injury and tumorigenesis, and the FXR-/- mice provide a unique animal model for human liver cancer study.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4424. doi:1538-7445.AM2012-4424
Abstract 4429: An investigation on p21-activated protein kinase 1 inhibitor, IPA-3, in hepatocellular carcinoma
Authors: Wong Leo LY , Lam Ian , Wong Tracy Y N , Lai Benny WL , Zhou Yuan , Hung Red , Ching Wilson YP 
Published: August 2012

Abstract
Background: Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to metastasis and tumor recurrence. However, apart from Sorafenib, there is no proven effective systemic chemotherapy for HCC yet. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is commonly found in HCC, which is coupled with a more aggressive tumor behavior. In this study, we examined the effect of an allosteric inhibitor of PAK1, IPA-3, on hepatocarcinogenesis. Methods: Human HCC line H2M was treated with various dosages of IPA-3 or vehicle control in order to measure the phospho-PAK1 level. The cells were also subjected to different functional assays, including proliferation assay, transwell assay and colony formation assay, to examine the anti-cancer effect of IPA-3. Tumor xenografts in nude mice were used to examine the in vivo activity of IPA-3. Results: Pretreatment with IPA-3 dose-dependently suppressed fetal bovine serum (FBS)-, and tumor necrosis factor (TNF)-α-induced PAK1 activity. The inhibitory effect was causally accompanied with suppression on cell migration, and enhancement of cell spreading. Furthermore, IPA-3 treatment on HCC cell line demonstrated a suppression of cell growth. The concomitant increase in apoptosis and delay in DNA synthesis had suggested a mechanism explaining the inhibition of HCC proliferation. In vivo, intraperitoneal administration of IPA-3 to subcutaneous xenograft mouse model significantly reduced the tumor growth rate. Conclusion: Taken together, these data showed that IPA-3 restrains cancer cell tumorigenicity and metastasis, thus, suggesting the potential use of IPA-3 in cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4429. doi:1538-7445.AM2012-4429