bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5297: Dual-modality imaging of hepatocellular carcinoma
Authors: Corn David , Jesberger Jack , Kolthammer Jeffrey , Flask Christopher , Lee Zhenghong 
Published: June 2012

Abstract
Choline compounds are linked to malignancy since elevation of the intensity of choline peak reflects increased biosynthesis of membrane phospholipids and can be a marker for cellular proliferation. Positron Emission Tomography (PET) images an injected tracer dose (nM∼pM) of [11C]-choline while Proton MR Spectroscopy (1H MRS) can characterize endogenous choline-containing compounds usually in the mM range. There have been studies on brain and prostate cancers with both imaging modalities although correlation between the results from PET and MRS is inconsistent. The transient radiolabeled choline metabolism measured by PET is different from the relative steady total choline contents measured by MRS. However, it begs the question of whether the two imaging modalities are measuring the same metabolic pathways of choline in cancer. For primary Hepatocellular Carcinoma (HCC), there have been [11C]-choline PET studies, both pre-clinical and clinical, showing focal uptake. Likewise, there have been 1H-MRS studies of choline with animals and humans showing significantly high choline levels in HCC. So far, there is no comparison study reported to link the two measurements in HCC.
This study was conducted with a woodchuck model of hepatitis viral infection-induced HCC, which is regarded as a naturally occurring animal model of human HCC with similar pathology and clinical behavior. The original objective of the study was to examine the effects of animals being fed and fasted on PET scans using [11C]-choline. MRI and MRS were added and performed immediately before PET imaging. Experiments were first performed with animals at the fed state using a 4T MR scanner with a human head coil. Dynamic PET images were then generated from a nearby clinical PET/CT scanner right after, spanning 50 minutes starting from [11C]-choline injection. Time-activity curves and tracer contrast uptake between focal uptake in HCC and that in the surrounding hepatic tissues were calculated in liver regions. The same animals were scanned again four days later following the exact same procedure, except that the animals were fasted over night. The results from PET imaging with [11C]-choline showed that the dietary state of fed or fast had little impact on radio-choline uptake in HCC while the results from 1H MRS of choline found similar choline/lipids ratios in HCC regardless of whether the animal was fed or fasted. These results are very promising for correlating the two measurements although further experiments are needed to confirm that the two imaging modalities are measuring related lipid metabolic pathways in HCC involving choline. This work is supported in part by NCI grants R01 CA095307 and U24 CA110943.
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 5297. doi:10.1158/1538-7445.AM2011-5297
Abstract 5307: VEGF downregulation by HSP90 inhibitor NVP-AUY922 visualized with 89Zr-bevacizumab PET in triple negative breast cancer (TNBC)
Authors: van Scheltinga Anton Terwisscha , Hooge Marjolijn Lub-de , Kosterink Jos , Timmer-Bosscha Hetty , Akimov Mikhail , de Vries Elisabeth , Schröder Carolien 
Published: June 2012

Abstract
Zirconium-89 (89Zr) labeled bevacizumab visualizes tumor vascular endothelial growth factor (VEGF) excretion in vivo, and can therefore serve as a potential biomarker for targeted drugs affecting VEGF levels. TNBC is more dependent upon alternative routes for their maintenance, such as angiogenesis, than hormone receptor or HER2 positive breast cancer. HSP90 inhibitors are known to impact the angiogenesis pathway via degradation of HSP90 client proteins such as HIF1α and VEGFRs, and in vitro studies have shown that breast cancer cells (including TNBC) are sensitive to these compounds. The aim of this study was to image modulation of VEGF expression in response to HSP90 inhibition with NVP-AUY922, a highly potent non-geldamycin HSP90 inhibitor, in a mouse model with a TNBC xenograft.
Methods: Three groups of animals were used in this study, a control (n = 6), treated (n = 7) and placebo (n = 6) group. Twenty-two days after inoculation of TNBC cell line MDA MB-231, all mice received co-injection of 89Zr-bevacizumab and Indium-111 (111In) labeled IgG as aspecific control. VEGF-PET was performed 144 h after tracer injection. Ex vivo biodistribution studies were performed in the control group after the first scan week, for the treatment and placebo group after the second scan week, which was after 3 weeks of treatment. The control group received no treatment, the treatment and placebo group received respectively 50 mg/kg NVP-AUY922 or vehicle every-third-day (q3d) administrated intraperitoneally. Treatment effect was verified with histological response.
Results: VEGF-PET showed a decreased 89Zr-bevacizumab tumor uptake of 44% (P = 0.0021) after 3 weeks NVP-AUY922 treatment compared to the baseline scan. Placebo treated mice showed no significant difference in bevacizumab uptake. These in vivo imaging data were supported by ex vivo biodistribution data. IgG tumor uptake was in all groups consistent, indicating that there was no influence on tumor perfusion due to the anti-angiogenic treatment. VEGF downregulation in the tumors was shown by immunohistochemistry of VEGF-A.
Conclusion: NPV-AUY922 downregulates VEGF in a TNBC mouse model. VEGF-PET using 89Zr-bevacizumab can be used in vivo to monitor downregulation of VEGF excretion in response to HSP90 inhibition, and can therefore potentially serve as biomarker for early HSP90 inhibition effect in TNBC.
Supported by a grant of the Dutch Cancer Society.
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 5307. doi:10.1158/1538-7445.AM2011-5307
Abstract 5337: The role of Eya3 as a target of EWS/Fli1 in Ewing's sarcoma
Authors: Robin Tyler , Reaves Lisa , Mckinsey Erin , Jedlicka Paul , Ford Heide 
Published: June 2012

Abstract
Ewing's sarcoma is an aggressive pediatric bone cancer most commonly affecting patients between 10 and 20 years of age. The vast majority of Ewing's sarcomas harbor a characteristic translocation between chromosomes 11 and 22, encoding the EWS/Fli1 fusion protein. Fli1 is an Ets transcription factor with a DNA-binding domain, whereas the EWS portion of the fusion contributes a transcriptional activation domain. EWS/Fli1 acts as a potent oncogenic transcription factor that is critical in the development of Ewing's sarcoma. EWS/Fli1 knockdown and rescue microarray data suggest that Eya3 may be a downstream target of EWS/Fli1, which we have validated using EWS/Fli1 overexpression and knockdown systems. Eya3 is important in DNA repair, and can interact with the Six family of homeoproteins as a bipartite transcription factor. The Six-Eya complex promotes proliferation and survival to facilitate the proper development of many tissues, but these features can also lead to aggressive cancers when re-expressed in adult tissues. We have shown that Eya3 knockdown in the human tumor-derived Ewing's sarcoma cells line, A673, decreases the rate of proliferation of these cells. Additionally Eya3 knockdown sensitizes Ewing's sarcoma cells to chemotherapeutics currently used to treat Ewing's sarcoma: doxorubicin, etoposide, and vincristine. Furthermore, clonal isolates of A673 Eya3 knockdown cells, expressing very low levels of Eya3, morphologically resemble their presumed cell of origin, the mesenchymal stem cell. These data suggest that Eya3 is an important target of EWS/Fli1 that may serve as a clinically significant novel therapeutic target for the treatment of Ewing's sarcoma patients.
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 5337. doi:10.1158/1538-7445.AM2011-5337
Abstract 5350: Distinction of childhood soft tissue sarcomas with high metastatic potential by miRNAs
Authors: Herrmann Delia , Armeanu-Ebinger Sorin , Warmann Steven W. , Bonin Michael , Leuschner Ivo , Brücher Björn , Fuchs Jörg , Seitz Guido 
Published: June 2012

Abstract
Background: Advanced stage alveolar (RMA) and embryonal rhabdomyosarcoma (RME) as well as malignant rhabdoid tumor (MRT) have a poor prognosis. Novel treatment approaches based on an improved understanding of metastatic invasion are required. Aberrant microRNA (miRNA) expression is found in cancer progression and metastatic invasion and may help to identify novel targets. The aim of this study was to identify specific miRNA expression patterns in pediatric soft tissue sarcomas.
Methods: We analyzed the expression of 743 miRNAs in 5 RMA, RME, and MRT formalin fixed tissue samples and in the rhabdomyosarcoma (RMS) cell lines Rh30 and RD using an Illumina BeadArray. Differentially expressed miRNAs between RMS and MRT specimens were identified on the basis of the cubic spline algorithm using BeadStudio Software. Selected target miRNAs were transfected with mimic or inhibitor oligonucleotides. Functional analysis was monitored by western blotting, flow cytometry, and migration assays.
Results: Principal component analysis as well as Spearman's rank correlation on the set of differentially expressed miRNAs showed tissue-specific clustering. A review of the literature revealed 23 miRNAs promoting and 46 miRNAs suppressing metastatic invasion. Eight miRNAs regulating migration in both directions were also described.
In our study, metastatic invasion associated miRNAs miR-9* and miR-221 were overexpressed in RMS tissue samples compared to MRT. miR-200c, which inhibits metastatic invasion, was lower expressed in RMS than in MRT. Transient transfection of RMS cells with a miR-200c mimic resulted neither in a reduction of the direct target ZEB1 nor in an increase of the ZEB1-repressed ectopic E-cadherin expression. Migration of RMS cells after induction of miR-200c was not decreased. Furthermore, inhibition of miR-9* and miR-221 in RMS cell lines did not influence migration characteristics.
Conclusions: Pediatric RMS and MRT can be distinguished by their specific miRNA expression pattern. These might also help for an optimized risk stratification of these tumors. A modulation of the metastatic invasion was not possible by the investigated miRNAs. Therefore, regulation of migration seems to be controlled by multiple miRNAs.
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 5350. doi:10.1158/1538-7445.AM2011-5350
Abstract 5351: Prevalence and function of p53 mutations among children with adrenocortical carcinoma (ADCC)
Authors: Wasserman Jonathan D. , Novokmet Ana , Eichler-Jonsson Claudia , Malkin David 
Published: June 2012

Abstract
Adrenocortical carcinoma (ACC) is a rare tumor in children, affecting 0.4 per million children worldwide. Incidence in adults is approximately 5-fold higher and may represent a distinct genetic and biologic entity. Mortality rates among patients with ACC are high and treatment options are limited. Previous studies have suggested that a majority of children who develop ACC possess germline mutations in the p53 tumor suppressor gene. In this study we sought to characterize the prevalence and mutational spectrum of p53 among a large multi-center cohort of children with ACC. We further compared the specific mutations found in these children with mutations found in individuals with the Li-Fraumeni syndrome, a familial cancer predisposition syndrome which is strongly associated with germline p53 mutation.
Among 58 independent pedigrees assessed for p53 mutation, 29 (50%) carried a heterozygous mutation in p53. No mutation was identified more than once among this cohort. This is in contrast to families with the LFS, where 6 “hotspot” mutations are disproportionately over-represented, combined accounting for 20% of patients with identified p53 mutations. Missense mutations were noted in 28/29 individuals, with a single intragenic deletion identified in the remaining individual. Mutations were found predominantly within the DNA-binding domain (26/29 (90%)). One mutation was identified in the trans-activation domain and two in the oligomerization domain.
In the course of this analysis, we identified several novel p53 mutations among children with ACC. These mutations were functionally characterized in vitro based on the ability of mutant p53 to activate transcription of known p53 target genes including those involved in DNA damage repair, cell-cycle arrest and apoptosis. Dominant-negative activity of these mutations was also assessed. Several of the novel mutations demonstrated either full p53 function or partial loss-of-function. The association of these seemingly milder mutations with adrenal tumorigenesis suggests that adrenal tissues may be more sensitive to partial decrease in p53 function than other LFS-affected tissues and that other predisposing or disease-modifying genetic alterations may exist to propel these cells towards a transformed fate.
Further efforts to identify disease modifying loci, as well as pathogenic loci in children with wild-type p53 genes are underway via genome-wide analysis.
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 5351. doi:10.1158/1538-7445.AM2011-5351
Abstract 5415: Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas
Authors: Sasaki Tsuyoshi , Tazawa Hiroshi , Hasei Jo , Kunisada Toshiyuki , Yoshida Aki , Morimoto Yuki , Urata Yasuo , Nouso Kazuhiro , Ozaki Toshifumi , Fujiwara Toshiyoshi 
Published: June 2012

Abstract
Purpose: Bone and soft tissue sarcomas frequently occur in young children and show aggressive progression, resistance to conventional chemotherapy and poor prognosis, indicating a requirement for novel antitumor therapy to improve the clinical outcome. Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor, but not of normal, cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that non-epithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear if OBP-301 is cytopathic for non-epithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells.
Experimental Design: The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bones (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1 and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1 and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified-OBP-301, (OBP-405), was used to confirm an antitumor effect on OBP-301-resistant sarcomas.
Results: OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR-expressing OUMS-27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression, not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells.
Conclusions: We showed that OBP-301 has antitumor effects on both non-ALT-type and ALT-type sarcoma cells through upregulation of human telomerase reverse transcriptase mRNA. Furthermore, coxsackie and adenovirus receptor-negative sarcoma cells were efficiently killed by fiber-modified OBP-301-derived-OBP-405 through virus-integrin binding. A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas.
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 5415. doi:10.1158/1538-7445.AM2011-5415
Abstract 5416: The low-molecular-weight compound MS-444 selectively targets cancer cells via inhibition of the mRNA stability factor HuR
Authors: Blanco Fernando F. , Meisner Nicole-Claudia , Dixon Dan A. 
Published: June 2012

Abstract
Colorectal cancer (CRC) is the third most common cancer among American adults and a leading cause of cancer-related mortality. The initiation and progression of colorectal tumorigenesis is characterized by genetic alterations that promote aberrant expression of oncogenic and tumor-promoting factors. In normal cells, the mRNAs of these inflammation- and cancer-associated genes are targeted for rapid decay through AU-rich elements (ARE) present in the mRNA 3’UTR. However, loss of ARE-mediated mRNA decay is a characteristic feature contributing to pathogenic gene overexpression in colorectal cancer. Our prior work identified enhanced expression of the RNA-binding protein HuR to occur during colon tumorigenesis and HuR overexpression is correlated with poor clinical prognosis. In this capacity, HuR acts as a mRNA stability factor by promoting ARE-containing mRNA stabilization. Therefore, HuR has emerged as a novel pharmacological target with potential selectivity for cancer cells. This was examined by treating HuR-overexpressing CRC cell lines HCT116, SW480, RKO, and HT-29 with the small molecule inhibitor of HuR MS-444. Growth inhibition was observed in all CRC lines with IC50 values of 7-12 µM and cancer cell selectivity was observed with 4- to 5-fold increased MS-444 IC50 in non-transformed intestinal and colonic epithelial cells. HuR is predominantly nuclear in non-transformed cells, whereas in CRC cells aberrant cytoplasmic HuR trafficking is observed indicating that cytoplasmic localization is a necessary component for HuR-mediated ARE-mRNA stabilization and cancer cell survival. In HCT116 cells treated with MS-444, complete inhibition of cytoplasmic HuR was observed along with induction of apoptosis. Similarly, long-term siRNA-mediated knockdown of HuR in HCT116 cells resulted in cellular apoptosis, and cells with attenuated levels of HuR exhibited a 5-fold higher sensitivity to MS-444 treatment. Expression profiling revealed increased expression of many pro-apoptotic proteins to be present in colon cancer cells resulting from MS-444 treatment. The expression of Fas ligand, a TNF superfamily member, is significantly increased, accompanied by elevated expression of caspase 8 and cell death effectors such as Bax and Bid. These results indicate that MS-444 treatment triggers a Fas-dependent signaling cascade mediated through cellular caspases, thereby resulting in cell death. Taken together, these findings indicate that small molecule-based inhibition of HuR results in selective cancer cell death while also indicating that overexpression of HuR is a necessary component for colorectal tumor cell survival.
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 5416. doi:10.1158/1538-7445.AM2011-5416
Abstract 5453: Drug transport in peritoneal tumors during intraperitoneal therapy – evaluation by computational model
Authors: Gao Yue , Guo Peng , Lu Ze , Tsai Max , Wientjes M. Guillaume , Au Jessie L-S. 
Published: June 2012

Abstract
Clinical studies have established that the efficacy of intraperitoneal paclitaxel therapy is dependent on the tumor size, producing survival advantage in patients with small tumors (&lt;1 cm diameter) but not in patients with larger tumors. This study was to investigate the mechanisms of this observation. We developed computational models to examine the effects of tumor size, drug binding (to extracellular proteins), tumor heterogeneity, and drug absorption on drug interstitial transport. The required model parameters were obtained from the literature. The models were used to simulate the drug penetration in small (0.3 cm) and larger (1 cm) tumors. Model performance was evaluated by comparing the simulated results to lab-generated experimental data using paclitaxel in mice bearing peritoneal metastases of ovarian tumors. The experiments measured drug concentration vs tumor penetration depth using autoradiography. The validated models were then used to generate penetration kinetic data for tumors of different sizes. The simulated penetration kinetics was subsequently compared to the pharmacodynamic data obtained from the literature (i.e., the C×T50 that produced 50% inhibition of tumor growth). The penetration kinetic models described the interstitial paclitaxel transport by both diffusion and convection, and the drug absorption into tumor vasculature by diffusion. The model-predicted concentration-penetration depth profiles were in general agreement with the experimental profiles (average deviation of 13.7%), indicating good model performance. The simulated drug C×T exceeded the C×T50 value at depth of up to 3 mm (from all sides of the outer tumor perimeter), indicating that for a spherical tumor of 1 cm diameter, 6.4% of the tumor (volume) would receive less than the therapeutic exposure, C×T50. Additionally, doubling the tumor diameter to 2 cm increased the subtherapeutic tumor volume fraction by nearly 5-times (34.3%). We have developed computational models to depict interstitial drug transport in peritoneal tumors during intraperitoneal therapy. These models provide quantitative measures of the effect of tumor size on local drug exposure for the tumor, and have the potential of predicting the tumor pharmacokinetics-pharmacodynamics for a given treatment.
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 5453. doi:10.1158/1538-7445.AM2011-5453