bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-111: Overexpression of esophageal squamous cell carcinoma (ESCC)-associated genes located within the homogeneously staining region (HSR) in chromosome 17p
Authors: Liu Christina D. , Pak K. C. , Hu L. , Guan X.y. , Tsao George S.W. , Law S. , Lam K Y. , Tang Johnny C. O. 
Published: February 2011

Abstract
The homogeneously staining region (HSR) has been shown to contain amplified genes that give selective advantages to the progression of cancer-cell growth. In this study, fluorescent in situ hybridization and array comparative genomic hybridization analysis were conducted on SLMT-1 (an ESCC cell line of Hong Kong Chinese origin) and revealed a HSR which was derived from chromosome 17p13.3. To identify the potential novel oncogene(s) with overexpression in ESCC, the overexpression study of the non-tumor suppressor genes within the region 17p13.3 was conducted in 15 ESCC cell lines by utilizing reverse transcription and multiplex PCR analysis. Eight non-tumor suppressor genes within this region were studied and three genes Timm22, JC-1 and JC-2 showed high percentages of overexpression compared with the non-tumor esophageal epithelial cell line NE1. Forty-six percent (7/15) of cell lines showed overexpression for Timm22 and both JC-1 and JC-2 were overexpressed in seventy-three percent (11/15) of ESCC cell lines. Further investigation on the JC-1, which showed the highest overexpression rate among the cell lines, was performed for its oncogenic properties. The entire coding sequence of JC-1 cloned into the mammalian expression vector pcDNA3.1(-) was transfected into mouse fibroblast NIH-3T3 cells. The JC-1-transfected NIH-3T3 cells showed an enhanced growth rate as determined by MTS assay, ncreased ability to form foci under anchorage dependent growth and increased migration rate in vitro. Thus, the results of the present study contribute to the investigation of potential novel oncogenes with overexpression in ESCC and may enrich our understanding of molecular pathogenesis of ESCC in the long run.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-111.
Abstract LB-127: Synthetic lethal RNAi screen of the human kinome with cytarabine (AraC) in leukemia cells
Authors: Hagelstrom R. Tanner , Bogenberger James , Buechel Megan , Bhagavatula Keerthi , Azorsa David O. , Tibes Raoul 
Published: February 2011

Abstract
Cytarabine is the backbone of therapy for acute myeloid leukemia (AML) patients, yet due to a high incidence of relapse and treatment-related complications novel, less toxic treatment regimens incorporating AraC need to be designed. To increase the therapeutic effect of cytarabine we developed and performed an RNAi synthetic lethal screening assay using siRNA, targeting 572 human kinases in combination with AraC in human myeloid cell lines TF-1 and THP-1. Several genes that enhance the effectiveness of cytarabine were identified. Among the top candidate genes, a trend became apparent in which several key regulators of the cell cycle as well as DNA repair genes where among the strongest sensitizers (CHEK1, PKMYT, CDC2, AURKB and ATR). The effectiveness of targeting these genes in combination with AraC was verified using a highly robust siRNA drug-dose response assay (siDDR) that validated CHEK1 as strong sensitizer, PKMYT as moderate sensitizer, and did not confirm CDC2 or AURKB as sensitizers. Since CHEK1 is emerging as a potential treatment target in combination chemotherapy in solid tumors, we obtained two commercially available CHEK1 inhibitors, PD 407824 and SB 218078 (both Tocris). PD 407824 strongly sensitized to AraC in the range of 2 to 10 fold decrease in several lines (MV 4;11, THP-1, HL60, HEL, ML-2) whereas in a few no sensitization was observed (MDS-L, U937). Calcusyn software was utilized to ensure the effect was more than simply additive in effect. Less effect was observed for SB 218078, which was surprisingly found to be antagonistic in some lines (TF-1, U937, ML-2, HL-60). Both compounds have slightly different target spectrum's that include CHEK1 plus other kinases. Interestingly, the sequence of addition of the compounds dramatically affected the outcome, with the greatest effects seen when CHEK1 inhibitors were added before AraC. In cases where AraC was added first or simultaneously, the effect was less pronounced or was not seen at all. Herein we present the “first-in-class” human kinome synthetic lethal screen in leukemia suspension cells in combination with AraC. In this unbiased functional genomics screen a strong convergence of hits emerged around G2/M cell cycle and DNA repair control. This information can immediately inform clinical drug development, channel resources and serve to direct development of new therapies in acute myeloid leukemias combining AraC with the first clinical available CHEK1 inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-127.
Abstract LB-128: Synthetic lethal RNAi screening identifies inhibition of Bcl-2 family members as sensitizers to 5-Azacytidine in myeloid cells
Authors: Bogenberger James , Shi Chang-Xin , Hagelstrom Tanner , Gonzales Irma , Choudhary Ashish , Tiedemann Roger , Azorsa David , Stewart Keith , Tibes Raoul 
Published: February 2011

Abstract
In order to identify novel targets and clinically exploitable vulnerabilities, we performed high-throughput RNA-interference (RNAi) synthetic lethality screening using myeloid cell lines TF-1 and ML-2 in combination with the hypomethylating agent 5-Azacytidine. A custom small interfering RNA (siRNA) library targeting nearly 1000 cancer-associated genes, including the human kinome, was utilized. Bcl-XL emerged as the strongest 5-Azacytidine sensitizing target in the erythroid cell line TF-1 but not in ML-2 cells. Additional siRNA sequences targeting Bcl-XL were transfected into a panel of myeloid cell lines and tested in drug dose response experiments using a ten-point serial dilution of 5-Azacytidine. The erythroid differentiated myeloid cell lines TF-1 and HEL both exhibited a 3 to 4-fold reduction in the IC50 of 5-Azacytidine upon knockdown of Bcl-XL, whereas IC50 values for non-erythroid, myeloid cell lines ML-2, THP-1 and MDS-L were unchanged. Furthermore, we tested lentiviral delivery of short-hairpin RNA (shRNA) targeting Bcl-XL in additional cell lines. Lentiviral knockdown of Bcl-XL confirmed 2 to 3-fold 5-Azacytidine sensitization in TF-1 and HEL cells while U937, HL-60, ML-2, THP-1 and MDS-L were not sensitized by Bcl-XL knockdown. Interestingly, while Bcl-XL knockdown with shRNA potentiated the effects of 5-Azacytidine in TF-1 and HEL, Bcl-XL knockdown alone resulted in considerable reductions in cell viability in TF-1 and HEL cells. These results demonstrate erythroid lineage-specific responses to Bcl-XL knockdown and suggest that Bcl-XL may represent an erythroid lineage-specific therapeutic vulnerability. To begin to explore this possibility we examined the putative BH3 mimetics Gossypol, Obatoclax and ABT-737 with 5-Azacytidine drug dose response experiments in myeloid cell lines. Neither Gossypol nor Obatoclax potentiated the effects of 5-Azacytdine. In striking contrast, ABT-737 resulted in a 2 to 4-fold reduction in the IC50 of 5-Azacytidine in all cell lines tested to date (TF-1, HEL, ML-2 and THP-1). ABT-737 sensitization to 5-Azacytidine was dose dependent. Furthermore, Combination Index (CI) values calculated with Calcusyn software demonstrate synergy between ABT-737 and 5-Azacytidine at clinically relevant concentrations. These results suggest that inhibition of anti-apoptotic Bcl-2 family members with a BH3 mimetic may represent an effective strategy for 5-Azacytidine combination therapy that can be directly translated into design of combination clinical trials in patients with myeloid leukemias.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-128.
Abstract LB-13: The role of p38/MAPK14 in Sonic Hedgehog-driven CGNP proliferation
Authors: Cemile Guldal G. , Mainwaring Lori , Parathath Susana , Kenney Anna M. 
Published: February 2011

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). The rapid proliferation stage of CGNPs has led to speculation that they are the cells of origin for some classes of medulloblastoma, the most common solid pediatric tumor. 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. We are currently investigating the role of oxidative stress and MAPK14 in CGNP proliferation by over-expressing and knocking down MAPK14 in CGNPs under oxidative stress conditions. Preliminary data suggests that knocking down MAPK14 reduces CGNP proliferation. Elucidating the role of MAPK14 pathway in CGNP proliferation will not only help us understand normal cerebellum development but may also lead to possible therapies for diseases where constitutive Shh signaling has been shown to play a role such as some classes of medulloblastoma and Gorlin's syndrome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-13.
Abstract LB-131: Mathematical model for tumor growth
Authors: ji Jiang , tu Guangde , zou Mei 
Published: February 2011

Abstract
Cancer is a leading cause of morbidity and mortality among humans worldwide. Theoretical studies could provide biologists with complementary and valuable insight into the mechanisms that may control the development of solid tumors. Based on our studies on membrane formation kinetics, a novel growth model is established for solid tumor development, which is consistent with the experimental data. According to the concept of the proliferation-active cells in the tumor tissue, two parameters, the effective cell division cycle for mitosis and the effective infiltration distance relevant to the nutrient support, are introduced in the model. The two parameters introduced can be further applied when the drug effects were considered. We have reviewed over 200 literatures and selected more than 50 of them having experimental data from different cell lines for theoretical studies. The growth curves generated by our model are consistent with many experimental data including lung cancer, breast cancer, liver cancer, ovarian cancer and colon cancer. Thus, the model obtained is very important not only for cancer research but also for searching anti-cancer drug and therapies.
In the figure below, we have displayed growth curves for colon carcinoma cell line. The dash lines are simulation curves of the model and the dots are the corresponding experimental data.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-131.
Abstract LB-134: Analysis of restored FFPE samples on high-density SNP arrays
Authors: Pokholok Dmitry K. , Le Jennie M. , Steemers Frank J. , Ronaghi Mostafa , Gunderson Kevin L. 
Published: February 2011

Abstract
Millions of Formalin Fixed Paraffin Embedded (FFPE) cancer tissue samples currently present in the US and worldwide provide an enormous, invaluable repository to the discovery of biomarkers in cancer research, drug development, diagnosis and treatment of diseases. However, the processes of fixation and storage of FFPE samples lead to degradation and base modification with chemical residues. This degraded FFPE DNA is inefficiently amplified in the Infinium® whole genome amplification (WGA) step leading to poor performance in the Infinium® assay.
In this study, FFPE DNA (100 ng input) was restored through a treatment with DNA polymerase, DNA repair enzyme, ligase, and modified Infinium® WGA reaction conditions. Canonical genotype cluster files were generated by creating artificially degraded Coriell DNAs and processing the samples through the restoration process and Infinium® assay. Results of genotyping on high density HumanCytoSNP-12 BeadChip®, featuring approximately 300k SNPs indicated that even highly degraded samples which show initial call rates of 40-70% can be successfully restored to a state that achieved call rates of greater than 90%, at a concordance greater than 99.0%, and associated standard deviation of log intensity less than 0.4. In general, over 80% of FFPE samples, which passed a QC assay metric were successfully restored and genotyped. Infinium® genotyping of restored DNA from a collection of tumor FFPE samples confirmed the presence of genomic aberrations around known cancer genes. Finally, we further demonstrated that paired sample analysis using canonical genotype clusters provide improved precision in CNV and LOH analysis compared to single sample analysis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-134.
Abstract LB-143: Sustained siRNA delivery by mesoporous silicon particles
Authors: Tanaka Takemi , Lingegowda Mangala , Nieves-Alicea René , Vivas-Mejia Pablo E. , Lopez-Berestein Gabriel , Sood Anil K. , Ferrari Mauro 
Published: February 2011

Abstract
RNA interference (RNAi) is a powerful approach for silencing genes associated with a variety of pathologic conditions; however, in vivo RNAi delivery has remained a major challenge due to lack of safe, efficient, and sustained systemic delivery. Here, we report on a novel approach to overcome these limitations using a multistage vector comprised of mesoporous silicon particles (S1MP) loaded with neutral nanoliposomes (DOPC) containing siRNA targeted against the oncoprotein, EphA2 that is overexpressed in a majority of cancers, including ovarian. Our delivery methodology resulted in sustained EphA2 gene silencing for at least 3 weeks in two independent orthotopic mouse models of ovarian cancer following a single intravenous administration of S1MP loaded with EphA2-siRNA-DOPC. Furthermore, a single administration of S1MP loaded with-EphA2-siRNA-DOPC substantially reduced tumor burden, angiogenesis and cell proliferation as compared to a non-coding control siRNA alone (SKOV3ip1: 54%, HeyA8: 57%), with no significant changes in serum chemistries or in pro-inflammatory cytokines. In summary, we have provided the first in vivo therapeutic validation of a novel, multistage siRNA delivery system for sustained gene silencing with broad applicability to pathologies beyond ovarian neoplasms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-143.
Abstract LB-144: In vivo detection of bone metastases in a mouse model by positron emission tomography (PET) with [F-18]-labeled tyrosine derivative (D-FMT)
Authors: Zitzmann-Kolbe Sabine , Strube Anne , Frisk Anna-Lena , Käkönen Sanna-Maria , Tsukada Hideo , Hauff Peter , Berndorff Dietmar , Gekeler Volker , Graham Keith 
Published: February 2011

Abstract
Objective: Detection and localization of metastatic lesions in advanced stages of cancer is still a difficult obstacle for diagnosis and subsequent treatment decisions for an optimized cancer patient management and therapy control. Whole body molecular imaging applying positron emission tomography (PET) allows the sensitive detection of radioactive labeled molecules, which specifically accumulate in tumor tissue. This offers a promising tool to assess the stage of the disease comprehensively. At present [F-18]-fluorodeoxyglucose (FDG) is the mostly used PET-tracer in oncology. However, FDG has the disadvantageof limited specificity by accumulating also in inflammatory cells due to their increased glucose metabolism. To overcome this problem, amino acids have been radiolabeled to study their potential imaging characteristics. D-[F-18]-fluoromethyl tyrosine (D-FMT, (R)-2-amino-3-(4-[F-18]fluoromethoxy-phenyl)-propionic acid) has shown good uptake into HeLa tumors in nude mice with no accumulation in sterile induced inflammation sites. The aim of this study was to investigate if D-FMT can also be used to image bone metastases besides primary soft tissue tumors.
Methods: Human 786-O/luciferase renal cell adenocarcinoma cells were injected intracardially, which gave rise to the formation of several bone metastases. The radiosynthesis of D-FMT was carried out using an indirect labeling method via the [F-18]-fluoromethyl bromide synthon. Micro-PET imaging was performed 51 and 65 days after tumor cell inoculation.
Results: The formation of metastases was monitored using bioluminescence imaging indicating the presence of tumor cells in the regions of hind limbs, forelimbs, spine and skull. A bone scan with [F-18]-fluoride confirmed skeletal metabolic activity at sites of osteolytic bone metastases. The i.v. application of [F-18]-D-FMT showed a very specific accumulation of the amino acid tracer in these bone metastases and, together with the low background, allowed very good imaging of these lesions. Based on the PET scan of [F-18]-D-FMT, sites of accumulation were excised. All imaged metastases could be verified histologically.
Conclusion: These data suggest D-FMT as a new potential imaging tracer for the detection of primary tumors as well as bone metastases. In addition, the sensitivity of this tracer suggests the possibility for substantial benefit in detecting soft tissue metastases as well.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-144.
Abstract LB-149: Identification of novel genes that cooperate with increased eIF4E expression to generate medulloblastoma using the Sleeping Beauty transposon system
Authors: Mainwaring Lori A. , Kenney Anna 
Published: February 2011

Abstract
Medulloblastoma is a malignant brain tumor that arises in the cerebellum of young children and occasionally is observed in adults. Increasing evidence suggests that different cell populations represent distinct cells of origin for the various medulloblastoma subtypes, and that these subtypes can be associated with aberrant activation of specific signaling pathways. Current mouse models recapitulate the Shh pathway driven tumors however few models are available to study other medulloblastoma subtypes as genetic events that drive tumorigenesis remain unknown. To address this problem we used the Sleeping Beauty transposon system to uncover novel mutations that contribute to medulloblastoma. Based on earlier work in normal CGNPs, we found that the translation initiation factor eIF4E is critical for regulating CGNP proliferation and the mRNA translation machinery is uniformly upregulated across medulloblastoma subtypes. Using a mouse model wherein eIF4E is ubiquitously over-expressed under control of the -actin promoter (T-Eif4e) we investigated cerebellum development and found that the CGNPs have increased proliferation in vitro in the absence of Shh as well as an expanded proliferative zone in vivo; however these mice do not develop medulloblastoma. Because eIF4E is an oncogene and been shown to cooperate with other known oncogenes in different cell types to accelerate tumorigenesis, we investigated whether eIF4E can cooperate with other mutated genes to generate medulloblastoma. Using a CGNP-specific promoter to drive transposase expression (“Math1-SB”), we crossed these mice with two different lines that carry the Sleeping Beauty transposon (T2/Onc 68 or T2/Onc 76) on different chromosomes. The progeny were then crossed with the T-Eif4e mice and observed for medulloblastoma occurrence; no tumors arise as a result of Math1-SB-mediated transposase activity alone. However, compared to the latency of tumors generated in SmoA1 mice, which have constitutive activation of the Shh pathway, tumors in T-eIF4E/Math1-SB/T2Onc animals arose earlier and were highly proliferative based on Ki-67 staining. They also expressed Otx2, which is associated with a medulloblastoma subtype that does not contain Shh or Wnt pathway mutations. Sequencing of the tumors to identify the genes whose activity is induced (novel oncogenes) or repressed (novel tumor suppressors) by transposon insertion will reveal genes that cooperate with eIF4E to induce medulloblastoma, and may lead to development of new mouse models for medulloblastoma as well as increased insight into genetic events contributing to these tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-149.