bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4757: The ALK-F1174L mutation accelerates MYCN-driven tumorigenesis in a murine transgenic neuroblastoma model
Authors: George Rani E. , Luther William , Ahmad Zahida , Cullis Elizabeth R. , Webber Hannah , Rodig Scott , Pearson Andrew DJ , Chesler Louis 
Published: June 2012

Abstract
Activating mutations in the anaplastic lymphoma receptor tyrosine kinase gene (ALK) have been identified in neuroblastoma and represent a novel therapeutic target in this childhood tumor of the sympathetic nervous system. The ALK-F1174L mutation, in particular, occurs at a higher frequency in tumors with MYCN gene amplification, is associated with a worse prognosis and with resistance to pharmacologic ALK inhibitors in adults with ALK-translocated cancers. To investigate the role of mutated ALK in MYCN-driven neuroblastoma, we generated transgenic mice that overexpress ALK-F1174L in neural crest-derived cells under the control of the tyrosine hydroxylase (TH) promoter, and performed genetic crosses against TH-MYCN transgenic mice. Doubly transgenic TH-ALK-F1174L/TH-MYCN animals developed aggressive tumors of the adrenal glands and abdominal and thoracic sympathetic ganglia, with 100% penetrance and a very short latency (31 days). In contrast, TH-MYCN littermates failed to develop tumors by this time. Furthermore, TH-ALK-F1174L hemizygote or homozygote animals failed to initiate tumors in the absence of MYCN expression. On histologic examination, ALK-F1174L/MYCN tumors were stroma poor and displayed undifferentiated small round blue cells with numerous apoptotic figures and scattered mitoses, and exhibited strong expression of both MYCN and aberrant ALK-F1174L transcripts and protein. Taken together, our studies demonstrate that the ALK-F1174L mutation plays a potent and significant role in the genesis of neuroblastoma, cooperating with MYCN to drive tumor formation. To our knowledge, this is the first mouse model available for investigations into the role of mutant ALK in neuroblastoma, especially its interaction with MYCN, and should provide a valuable new tool for development of ALK-targeted therapeutics in neuroblastoma.
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 4757. doi:10.1158/1538-7445.AM2011-4757
Abstract 4766: Negative control of glutaredoxin activity by Smad3 contributes to transforming growth factor-beta1-induced apoptosis of hepatoma cells
Authors: Kim Byung-Chul , Jeon Woo-Kwang , Park Seong-Ji , Jang Hyung-Ju 
Published: June 2012

Abstract
Although reactive oxygen species (ROS) has been established as important signaling molecules in transforming growth factor-beta1 (TGF-β1)-mediated apoptosis, its underlying molecular mechanisms are not well understood. Here, we demonstrate that TGF-β1 induces apoptotic cell death through decreasing the expression and activity of glutaredoxin (Grx), a thiol antioxidant enzyme, in hepatoma cells. Down-regulation of Grx by TGF-β1 was highly dependent on Smad3, a major TGF-β signaling transducer. Western blot analysis and chromatin immunoprecipitation (ChIP) assay revealed that endogenous Smad3 physically interacts with histone deacetylase 1 (HDAC1) and its co-repressor, mSin3A in response to TGF-β1 stimulation and this complex binds to Grx1 promoter region -1872/-1662 bp containing two CAGA boxes. Deletion or mutation of these sites abolished binding of Smad3 to Grx1 promoter and subsequent down-regulation of Grx1 promoter activity in TGF-β1-stimulated hepatoma cells. Notably, hepatoma cells which stably express hepatitis B virus X (HBx) displayed increased Grx activity and level of Grx protein, and showed resistance to TGF-β1-induced apoptosis. Importantly, HBx inhibited binding of Smad3 to Grx1 promoter by inducing phosphoprylation of serine 208 in linker region of Smad3. Expression of a mutant Smad3 in which linker phosphorylation sites were ablated caused a marked attenuation in inhibition by HBx of TGF-β1-induced apoptosis. Finally, elevated levels of Grx and phosphorylated Smad3 at linker regions were observed in the hepatocellular carcinoma (HCC) tissues compared to normal tissues. Taken together, these findings suggest that Smad3 is a transcriptional repressor of Grx and increased Smad3 phosphorylation at linker regions in HCC may intercept the tumor suppressor function of TGF-β through transcriptional activation of Grx, thereby providing new mechanistic insight into the development of anti-cancer drug-resistant HCC.
This work was supported by the “Human Resource Development Center for Economic Region Leading Industry” Project, the Ministry of Education, Science & Technology (MEST), and the National Research Foundation of Korea (NRF).
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 4766. doi:10.1158/1538-7445.AM2011-4766
Abstract 4772: A novel agonist antibody to human death receptor 4, AY4, induces apoptotic cell death in head and neck cancer through ROS generation: in vitro and in vivo
Authors: Kim Chul-Ho , Lee Bok-Soon , Kang Sung Un , Hwang Hye Sook , Sung Eun-Sil , Kim Yong-Sung , Koh Yoon Woo , Hong Hyun Jun , Ryu Mi Ran , Kim Jae Wook 
Published: June 2012

Abstract
Background : The proapoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors death receptor (DR) 4 and DR5 are attractive targets to develop the receptorspecific agonistic monoclonal antibodies (mAb) as anticancer agents because of their tumor-selective cell death-inducing activity. Here, we describe the characterization of a novel agonistic mAb (AY4) against human DR4 and apoptosis through reactive oxygen species (ROS) production in head and neck cancer model.
Methods : The effects of AY4 in head and neck cell lines (KB, SNU899, HN9, FaDu) was studied on apoptosis using MTT assy, TUNEL, Annexin V assay and western blotting and was examed on the production of reactive oxygen species with DCFDA staining, intracellular signaling and animal model. In addition, we analyzed the anticancer effect of AY4 in nude mice xenograft model. In addition, drug toxicity (embryotoxicity and neurotoxicity) of AY4 were investigated in vivo zebrafish model.
Results: The DR4 was expressed in head and neck cancer cell lines by Flow cytometry (FACS) and western blotting. AY4 inhibited cell growth in KB and HN9 excluding SNU899 and FaDu and caused cell death via caspase-dependent apoptosis. The apoptotic cell death by AY4 decreased by N-acetylcysteine (NAC), an antioxidant, suggesting ROS generation involved in the cell death. Moreover, NAC and AY4 cotreatment augmented the reduced expression of antiapoptotic molecules, Bcl-XL and XIAP. In vivo administration of AY4 significantly inhibited tumor growth of head and neck cancer preestablished in athymic nude mice. In addition, in a zebrafish model used for toxicity testing, a considerable dose of AY4 did not result in embryotoxicity or neurotoxicity.
Conclusion : Our results demonstrates the effect of AY4 on apoptosis and tumor inhibition via ROS production and provide potential use of AY4 as an anticancer therapeutic agent in head and neck 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 4772. doi:10.1158/1538-7445.AM2011-4772
Abstract 4797: A member of the SLC25 family is epigenetically inactivated in human gliomas and suppresses cell growth in vitro
Authors: Waha Anke , Felsberg Jörg , Simon Matthias , Hartmann Wolfgang , Pietsch Torsten , Waha Andreas 
Published: June 2012

Abstract
In a genome-wide screen using DMH (differential methylation hybridization) we have identified a CpG rich fragment upstream of the coding region of a member of the solute carrier family 25 (SLC25) that showed hypermethylation in gliomas compared to normal white matter controls. Pyrosequencing analysis was performed to confirm the methylation status of this gene in 76 gliomas and 7 glioma cell lines. Hypermethylation was detected in 14% of primary glioblastomas, 62% of secondary glioblastomas, 27% of anaplastic astrocytomas, 0.7% low-grade diffuse astrocytomas and in 71% of glioma cell lines. None of three investigated white matter samples showed hypermethylation of the investigated region. Hypermethylation of the SLC25 member was significantly more frequent in secondary glioblastomas compared to primary glioblastomas (P = 0.0066). Furthermore, the investigation of matched low grade and high grade glioma tissues revealed that this hypermethylation was associated with progression. Expression of the SLC25 member was investigated by real-time reverse transcription-PCR and found to be down regulated in primary and secondary glioblastomas as well as in anaplastic and low-grade astrocytomas when compared to white matter and total brain tissue. After treatment of glioma cell lines with 5-aza-2’-deoxycytidine, the transcription was restored. In functional investigations overexpression of exogenous SLC25 family member in glioblastoma cell lines lead to a significant reduction in focus formation.
In summary, we describe for the first time the epigenetic silencing of a nuclear encoded member of the mitochondrial transporter family (SLC25) in high grade malignant human brain tumors and provide functional proof for its growth suppressive activity on glioma cells in vitro.
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 4797. doi:10.1158/1538-7445.AM2011-4797
Abstract 4799: Promoter methylation of leukemia inhibitory factor receptor gene in colorectal carcinoma
Authors: Chang Xiaofei , Cho Yong G. , Park Il-Seok , Shao Chunbo , Ha Patrick , Pai Sara I. , Sidransky David , Kim Myoung S. 
Published: June 2012

Abstract
Aberrant methylation of gene promoters and corresponding loss of gene expression plays a critical role in the initiation and progression of colorectal cancer. An IL-6-type cytokine receptor, leukemia inhibitory factor receptor (LIFR), is a component of cell-surface receptor complexes for multifunctional cytokines such as LIF. Herein, we report that LIFR is methylated in human colon cancer. LIFR promoter was methylated in primary tumor tissues with high frequency (65%, 52/80). Quantitative methylation-specific PCR (TaqMan-MSP) demonstrated differential promoter methylation of LIFR in primary colorectal cancer tissues as compared to normal colon tissues (5%, 4/80). LIFR methylation was not detectable in 13 normal colon mucosa samples obtained from patients without cancer. The mRNA expression of LIFR was significantly down-regulated in colon cancer tissues as compared to corresponding normal tissues. A strong expression of LIFR protein was observed in all non-malignant normal and adjacent normal colon mucosa tissues whereas down-regulated LIFR protein expression was observed in primary tumors. These results implicate that cancer-specific methylation and a specific decrease of LIFR expression are a common inactivation event in colon cancer development.
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 4799. doi:10.1158/1538-7445.AM2011-4799
Abstract 486: A cancer stem cell population from a head and neck cancer show epithelial to mesenchymal transition properties and resistance to treatment
Authors: Roberg Karin B. , Fleur Linnea La 
Published: June 2012

Abstract
Mortality in head and neck squamous cell carcinoma (HNSCC) is high due to the emergence of therapy resistance which led to local and regional recurrences that may originate from resistant cancer stem cells (CSCs). The aim of the present study was to identify cells with CSC characteristics in a HNSCC cell line and evaluate differences in CSC proteins, invasion, migration and in treatment sensitivity to radiation, cisplatin and cetuximab (a antibody blocking epithelial growth factor receptor, EGFR) between subpopulations of cancer cells.
A HNSCC cell line established from a larynx cancer at the division of otorhinolaryngology at Linköping University Hospital was used in passages 8-15. Cells were cultured in Keratinocyte Media supplemented with 1% fetal calf serum. Subpopulations of cells were detected after direct immunofluorescense staning of surface CD44 and EGFR. Three different populations (CD44high/EGFRlow, CD44high/EGFRhigh and CD44low/EGFRhigh) were sorted for further investigations using a BD FACSAriaTM II Cytometer.
Culturing of sorted cells demonstrated diverse morphology between the populations, where CD44high/EGFRlow cells displayed a spindle shaped morphology compared to CD44low/EGFRhigh.
The subpopulations sensitivity to radiation (4Gy), cisplatin (2μg/ml, 1h) or cetuximab (30nM) was analysed 10 days after sorting by a crystal violet assay. Here, CD44high/EGFRlow cells showed the lowest sensitivity to both radiation and cisplatin. A real time PCR array was performed in order to screen for differences in gene expression between the subpopulations. Comparison of the cells with a high contra low CD44 surface expression, showed a change in mRNA levels in 19 genes, 14 up regulated and 5 down regulated. Of these 19 differently expressed genes 13 can be associated to an epithelial to mesenchymal transition (EMT) phenotype (VIM, MMP2, TIMP1, TWIST1, COL3A1, CDH1, CDH2, ITGA5, FN1, FOXC2, WNT5A, WNT5B and SPARC). Two stem cell marker genes (NANOG and SOX1) were slightly up regulated in the CD44high/EGFRlow population compared to CD44low/EGFRhigh. These populations ability for migration and invasion should now be investigated as well as differences in proliferation and clonogenic efficiency.
We here identify, in a recently established HNSCC cell line, subpopulations of cells using markers suggested to characterize CSCs. More importantly, the CSC-like subpopulation displayed a lower sensitivity to radiation and cisplatin compared to the control population.
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 486. doi:10.1158/1538-7445.AM2011-486
Abstract 4861: Identification of premalignant bladder markers using DNA microarray analysis of the UPII-SV40Tag model for invasive bladder UCC
Authors: Stone Randolph , Sabichi Anita , Gill Jennifer , Lee I-Ling , Cvek Urska , Trutschl Marjan , Adegboyega Patrick , Dai Michael , Loganantharaj Rasiah , Clifford John 
Published: June 2012

Abstract
Urothelial cell carcinoma of the bladder (UCC) ranks 5th in incidence of all cancers in the developed world, yet the mechanisms of its origin and progression remain poorly understood. A few urine-based tests for screening and surveillance are commercially available for bladder cancer, but there are no reliable non-invasive methods for detecting premalignant UCC. In order to determine molecular mechanisms involved in early UCC development and to identify new biomarkers for detection, diagnosis and prognosis of UCC, a transgenic mouse model for invasive bladder cancer (UPII-SV40Tag mice) was analyzed by DNA microarray technology. Genes that are differentially expressed between the bladders of UPII-SV40Tag mice and their age-matched wild type (WT) littermates at 3, 6, 20 and 30 weeks of age were identified. The ages selected correspond to premalignant, carcinoma in-situ, and early and later stage papillary UCC, respectively. Approximately 1,900 unique genes were differentially expressed (≥ 3-fold difference at one or more time points) between WT and UPII-SV40Tag urothelium during the time course of tumor development. A high proportion of cell cycle regulatory genes and proliferation signaling genes were more strongly expressed in the UPII-SV40Tag bladder urothelium. Several of the genes upregulated and downregulated in UPII-SV40Tag urothelium were tested as biomarkers for premalignancy, including autocrine motility factor (AMFR), hyaluronan-mediated motility receptor (Hmmr), proliferating cell nuclear antigen (PCNA), Rac GTPase activating protein 1 (RacGAP1), superoxide dismutase 3 (SOD3), collagen 1a2 (Col1a2), and others. These tests were performed by analyzing urine samples from a recently completed Phase II, randomized, placebo controlled chemoprevention trial (N01 CN85186, PI: A. Sabichi) that was designed to test whether celecoxib can prevent recurrence in patients successfully treated by transurethral resection (TUR) for non-muscle invasive bladder cancer. Positive markers, Hmmr and RacGAP1, and a negative marker, Col1a2, have been identified in patient urine samples that show promise for detecting UCC recurrence. We are currently attempting to determine the biological function of Hmmr, and RacGAP1 in bladder premalignancy.
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 4861. doi:10.1158/1538-7445.AM2011-4861
Abstract 4875: Combining immunohistochemistry and proteomics for improved antibody validation in complex FFPE tissues
Authors: Schuster Claudia , Hlubek Falk , Malinowsky Katharina , Liebmann Sibylle , Berg Daniela , Wolff Claudia , Reu Simone , Neumann Jens , Faber Claudius , Hoefler Heinz , Kirchner Thomas , Becker Karl-Friedrich 
Published: June 2012

Abstract
Personalized cancer treatment strategies depend on comprehensive and detailed characterization of individual human cancers. Translation of biomarker research into successful and tailored medical therapy at tumor and patient level require the identification and development of informative biomarkers that could be used to improve early diagnosis and prognosis. In clinical pathology, particularly IHC evaluation of biomarkers in tissue is considered as gold standard for diagnostic and therapeutic decisions, having a direct influence on patient management and therapeutic treatment. Although antibody-based approaches are established and successfully integrated into both clinical and research applications, for personalized treatment regimens new demands have been placed on the quality, reproducibility and accuracy of antibody-based assays. There is an ongoing debate on implementation and standardization of validation guidelines to provide for reliable and reproducible antibody-based tools in clinical management and basic research.
To overcome variations of epitope specificity in immunohistochemistry, we introduce a novel approach combining extraction of immunoreactive proteins from FFPE tissue with Western Blot analysis and IHC using the same archival tissue of interest for antibody validation. This tandem application allows for specific characterization of the antigen, taking advantage of the main properties of both technologies: localization of the protein of interest in tissue sections stained by IHC and specification of the biochemical identity by molecular weight analysis in immunoblot experiments. We assessed a panel of antibodies used in both, academic research as well as routine diagnostics for their usability across various validation platforms. While a significant proportion of the antibodies tested showed reliable specificity in both assays, some proved to be unsuited for dual application in IHC and WB, failing in either assay. The results presented here, reflect the heterogeneity in antibody specificity and emphasize the advantage of combining a series of suitable methods to ensure reproducibility and specific epitope detection. Based on our results presented here, we propose an improved step by step strategy to validate antibody immunoreactivity and control for variability across protocols.
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 4875. doi:10.1158/1538-7445.AM2011-4875
Abstract 4887: Automated imprint cytology evaluation for surgical margin determination
Authors: Ruidiaz Manuel E. , Cortes-Mateos Maria J. , Sandoval Sergio , Wang-Rodriguez Jessica , Kummel Andrew C. , Blair Sarah L. 
Published: June 2012

Abstract
Background: Breast conservation therapy (BCT) has been shown to have equal survival efficacy to total mastectomy and provides improved cosmesis. This has resulted in BCT being the preferred treatment of choice for localized tumors. BCT, however, results in about 25-50% of procedures with positive margin status which most likely require a second surgery to remove the remaining tumor mass. These second surgeries inhibit the healing process, reduce cosmesis and increase the risk of complications. Intra-operative determination of margin status has been previously demonstrated using imprint cytology (IC) of tumor margin faces with 96% sensitivity and 100% specificity, but this method requires an experienced cytopathologist and is prone to error if not done meticulously due to the difficulty of searching for cancer cells on large slides. Therefore the requirement for an automated imprint cytology analysis system is acute. Methods: Hematoxylin and eosine (H&E) stained imprint cytology specimens were scanned at 40X on an iScan Coreo Au (BioImagene, Inc., Sunnyvale, CA). Resultant digital images were used to train a linear discriminant algorithm to classify between cancer cells, white blood cells, and debris/junk particles. A unique combination of shape, color and local area descriptors was applied to allow for automated discrimination in a fast parallelized fashion to facilitate intra-operative use. The 16 specimen training set as determined by permanent section consisted of 5 positive, 3 close and 8 negative margins. The resulting classifier was then used on a separate testing set of 8 positive cases (46 IC specimens) as previously determined by permanent section (6 cases) or manual imprint cytology (2 cases) evaluation. Results: Automated evaluation of 46 IC specimens yielded 9 positive specimens in 4 cases. Of the 6 positive permanent section specimens, 2 were confirmed by automated analysis. 2 cases that were deemed negative by permanent section but positive by manual permanent section had 100% agreement. On aggregate, a 50% positive margin identification rate was observed. Conclusion: Automated margin analysis has an enhanced ability to reduce the number of second surgeries by identifying positive margins during the initial surgery. The ability to quickly determine margin status is necessary for intra-operative use and we believe that by taking advantage of the iScan Coreo Au slide scanner's ability to change magnification while scanning will provide us with the necessary analysis times. In the future we will integrate this advanced analysis system into an automated intra-operative evaluation tool.
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 4887. doi:10.1158/1538-7445.AM2011-4887