bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3651: Foxp3 expression correlates with survival in urothelial carcinoma of the bladder
Authors: Zhang Hanwei , Wang Xiaoyan , Seligson David , Pantuck Allan , Chin Arnold I. 
Published: August 2012

Abstract
Introduction and Objective The transcription factor Forkhead box p3 (Foxp3), originally described during the development of CD4+CD25+ T regulatory cells, has recently been implicated in divergent roles in human prostate, breast, pancreatic cancer, and melanoma. Here, we investigate the inducibility of Foxp3 in bladder cancer models and assess the prognostic role of Foxp3 in patients with bladder cancer. Methods Foxp3 expression in the human bladder cancer cell line SW780 was examined in in vitro cultures by flow cytometry and in in vivo subcutaneous implanted tumor models in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice by immunohistochemistry. Proliferation and invasion of SW780 cells in the absence of Foxp3 was performed by transfection of siRNA in vitro. Correlation of Foxp3 expression to urothelial carcinoma grade, stage, recurrence-free survival, and overall survival was examined in a human tumor microarray from a cohort of 280 patients by Cox proportional hazards regression and Kaplan-Meier analysis. Results Foxp3 expression correlates to higher cellular proliferation in vitro and in vivo. Knockdown of Foxp3 in SW780 cells resulted in decreased proliferation as well as invasion in vitro. Foxp3 expression increases with higher T stage, but not grade, as expression in adjacent normal bladder, Tis, Ta-1, T2-4, and lymph node metastasis was 1.2%, 3.8%, 15.2%, 26.5%, and 23.4% respectively, suggesting higher expression in muscle invasive and lymph node metastatic disease, but not carcinoma in situ. Using a cutoff of 10%, Foxp3 expression negatively correlates with survival following radical cystectomy with a median survival of 9.3 vs 2.8 years and a 10-year survival probability of 47% vs 27%. Conclusions This work implicates Foxp3 as novel transcription factor driving proliferation and tumor invasion in urothelial carcinoma. Expression of Foxp3 correlates with T stage and is a novel predictor of overall survival following radical cystectomy. Future studies will need to understand the mechanistic regulation of Foxp3 expression, as well examine Foxp3-mediated gene expression in urothelial carcinoma. Foxp3 expression may improve selection of patients to 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 3651. doi:1538-7445.AM2012-3651
Abstract 3661: Notch2 and Six1 are upregulated during progression of early-stage lung adenocarcinoma and define its unfavorable subset at advanced stages
Authors: Mimae Takahiro , Okada Morihito , Hagiyama Man , Miyata Yoshihiro , Tsutani Yasuhiro , Inoue Takao , Aogi Kenjiro , Murakami Yoshinori , Ito Akihiko 
Published: August 2012

Abstract
Lung adenocarcinoma (LA) often manifests as tumors with mainly lepidic growth (LG) pattern in which cancer cells replace alveolar cells, and is diagnosed, depending on the size of invasive foci, as in situ, minimally invasive, or invasive LA. This suggests that a subset of LAs undergoes malignant progression in this order. The present study examines how transcriptional aberrations during the early-stage of LA cells define the clinical phenotypes of advanced tumors. First, we comprehensively searched differentially expressed genes between preinvasive and invasive cancer cells in a single minimally invasive LA using laser capture microdissection and DNA microarrays, and successfully identified two transcription factors Notch2 and Six1 to be up-regulated in the invasive cancer cells from all of five minimally invasive LA tumors. These two molecules appeared to coordinately contribute to LA progression by inducing epithelial-mesenchymal transition and nuclear atypia, because exogenous Notch2 in NCI-H441 lung epithelial cells caused nuclei to enlarge and transactivated Six1, vimentin, and the TGF-β signal transducers Smad3 and Smad4. We then immunohistochemically stained 64 advanced LA tumors, and found that a third of them were double positive for Notch2 and Six1 in the invasive, but not in the LG component. The invasive potential was higher and 2-year disease-free survival rates were lower in tumors that were double-positive, than double negative in both components. These results suggested that paired up-regulation of Notch2 and Six1 during early LA progression persists in a considerable subset of advanced LAs and confers a more malignant phenotype on the subset.
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 3661. doi:1538-7445.AM2012-3661
Abstract 3668: Inhibition of HSP90 with NVP-AUY922 induces a synergistic effect in HER2-amplified, trastuzumab-resistant breast and gastric cancer
Authors: Wainberg Zev A. , Rogers Amy , O'Brien Neil , Anghel Adrian , Desai Amrita , Kalous Ondrej , Conklin Dylan , Akimov Mikhail , Finn Richard S. , Slamon Dennis J. 
Published: August 2012

Abstract
Background: Heat Shock Protein 90 (HSP90) enables the activation of a large number of client proteins of which the most clinically validated is HER2. NVP-AUY922 is a a highly potent, non-geldamycin HSP90 inhibitor that has shown preliminary activity in HER2 positive metastatic breast cancer. To explore its potential clinical utility specifically in HER2 amplified gastric and breast cancers, we evaluated the effect of AUY922 alone and in combination with trastuzumab in both trastuzumab-sensitive and resistant in vitro and in vivo models. Methods: A panel of 16 human gastric and 45 breast cancer cell lines, with 3 and 13 HER2-amplified lines respectively, were exposed in vitro to AUY922 over various concentrations to generate dose response curves. In both breast and gastric cancer, we used cell lines and xenograft models with conditioned trastuzumab-resistance to investigate the efficacy of AUY922 alongside trastuzumab. In all in vivo experiments, trastuzumab was dosed at 10 mg/kg (IP; twice/week) and AUY922 at 50 mg/kg, (IP; 5 days on, 2 days off). Effects of this combination on downstream markers (HER2, AKT, ERK) were analyzed via western blot. Results: AUY922 was found to have potent anti-proliferative activity in the low nanomolar range (&lt; 40 nM) for 59 of the 61 gastric and breast cancer cell lines tested. Additionally, in both gastric and breast cancer, HER2-amplified cells expressed greater sensitivity to the compound when compared to the HER2-negative cells. In conditioned trastuzumab-resistant cell line models, AUY922 continued to have potent activity and exhibited a synergistic effect with trastuzumab. The in vitro combination also induced greater decreases in HER2, induced a G0/G1 cell cycle arrest, and increased the rates of apoptosis. In a conditioned trastuzumab-resistant gastric cancer in vivo model (N87-Res), the combination of AUY922 and trastuzumab showed greater anti-tumor efficacy than either drug alone. Conclusions: These data suggest that AUY922 in combination with trastuzumab has unique efficacy in trastuzumab-resistant models. The combination of HSP90 inhibitors and trastuzumab represents a novel approach to the treatment of HER2 amplified cancers. Clinical trials combining AUY922 and trastuzumab in HER2 amplified breast and gastric cancers are currently ongoing.
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 3668. doi:1538-7445.AM2012-3668
Abstract 3673: Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect.
Authors: Tobias Edward S. , Yeap Phey M. , Mavraki Eleni , Fletcher Alexander , Freel Marie E. , Cooke Alexander , Bradshaw Nicola , Murday Victoria A. , Davidson Rosemarie , Perry Colin , Lindsay Robert S. 
Published: August 2012

Abstract
In SDHD mutation families, paragangliomas and pheochromocytomas usually occur only after paternal transmission of the mutation. This important but unexplained parent-of-origin effect is not due to imprinting of SDHD itself, as was initially suspected, since SDHD is biallelically expressed in several tissues. In clinically affected individuals who possess a paternally inherited SDHD mutation, there is loss of the entire maternal chromosome 11 in tumour DNA, implying that tumorigenesis requires loss of not only maternal (wild type) SDHD but also a further, imprinted, tumor suppressor gene (TSG). We report the second case of an SDHD-related tumor (a pheochromocytoma in a 33 year old woman possessing the common pathogenic mutation, p.Pro81Leu) occurring after maternal transmission. It is the first reported investigation of tumor DNA in this situation. Tumor DNA revealed loss of heterozygosity (LOH) at paternal 11q23 causing loss of the wild-type SDHD allele and also LOH affecting maternal 11p15, including H19. These two LOH regions were separated by a region exhibiting clearly retained heterozygosity, containing SDHAF2 (a recently reported paraganglioma TSG), which therefore appears uninvolved here. This case provides strong molecular evidence that the tumorigenic requirement for maternal 11p15 loss (in addition to inactivation of both SDHD alleles) drives the observed parent-of-origin effect. Thus, SDHD-related tumorigenesis most likely involves a “three-hit” mechanism that includes (as one of the hits) loss of an imprinted (paternally silenced and maternally active) TSG from chromosome 11, such as H19). Tumor formation more commonly results from paternal inheritance of SDHD mutations, as the necessary loss of both the wild type SDHD allele and maternal 11p15 can then occur by a single event (loss of maternal chromosome 11). These findings have important implications regarding the clinical management of carriers of maternally inherited SDHD mutations, who we confirm can develop pheochromocytomas, and the understanding of the parent-of-origin effect.
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 3673. doi:1538-7445.AM2012-3673
Abstract 3676: The hypoxia-activated pro-drug tirapazamine suppresses outgrowth of colorectal liver metastases following radiofrequency ablation
Authors: Govaert Klaas M. , Nijkamp Maarten W. , Emmink Benjamin L. , Steller Ernst J.A. , Minchinton Andrew I. , Kranenburg Onno , Rinkes Inne H.M. Borel 
Published: August 2012

Abstract
Background Radiofrequency ablation (RFA) is a common procedure for the management of colorectal liver metastases. RFA-generated lesions are surrounded by a rim of hypoxia that is associated with aggressive outgrowth of intrahepatic micrometastases. Hypoxia-activated pro-drugs such as tirapazamine (TPZ) are designed to selectively kill tumour cells under hypoxic conditions. Therefore we hypothesised that TPZ may have therapeutic value in limiting hypoxia-associated tumour outgrowth following RFA. Methods Murine C26 and MC38 colorectal cancer cells were grown under hypoxia and normoxia in vitro and were treated with different concentrations of TPZ. Apoptosis and cell cycle distribution were assessed by western blot and FACS analysis. Proliferative capacity was tested by colony formation assays. Mice harbouring microscopic colorectal liver metastases were treated with RFA, followed by a single injection of TPZ (60 mg/kg) or saline. Tumour load was assessed morphometrically 7 days later. Results TPZ induced apoptosis of colorectal tumour cells under hypoxia in vitro, which completely abolished clone-forming capacity. Under normoxia, TPZ caused a G2 cell cycle arrest from which cells recovered partly. This reduced, but did not abolish, colony-forming capacity. A single dose of TPZ largely prevented accelerated outgrowth of hypoxic micrometastases following RFA. TPZ administration was associated with minimal toxicity. Conclusions TPZ kills colorectal cancer cells in a hypoxia-dependent manner and potently suppresses hypoxia-associated outgrowth of liver metastases with limited toxicity. This warrants further studies to assess the potential value of TPZ, or other hypoxia-activated pro-drugs, as adjuvant therapeutics following RFA treatment of colorectal liver metastases.
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 3676. doi:1538-7445.AM2012-3676
Abstract 3680: Drug screening for glioblastoma patients
Authors: Jiang Pengfei , Mukthavaram Rajesh , Summitt IlaSri , Chao Ying , Gallagher Matthew , Kim Ryan , Pastorino Sandra , Kesari Santosh 
Published: August 2012

Abstract
The modest benefits of chemotherapy for Glioblastoma (GBM) patients’ makes it urgent to find potent drugs or combinations that can inhibitor tumor cell growth and proliferation. We have devised drug screening based on the NIH clinical collection compounds. This collection included 446 compounds that all have history of use in human clinical trials. The positive compounds can be rapidly entered into clinical trials for GBM. After found 22 drugs/compounds that can inhibit U87 cell proliferation and we tested 15 available positive drugs with A172, LN443, U118 cell line. After confirming in established serum-grown cell lines, we tested 8 FDA approved drugs in GBM primary cells with stem cell like features isolated from fresh brain tumor tissue samples and cultured in stem cell media. The various drug responses amongst the different patients’ primary cells suggested that we may be able to personalize drugs to optimize outcomes. In addition, we found that certain combinations of FDA approved drug had significantly enhanced activity against GBM cells in vitro when compared to the same agents used alone. Our work reveals that screening drugs and combinations for GBM patient may have clinical implications.
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 3680. doi:1538-7445.AM2012-3680
Abstract 3682: Overexpression and cell proliferation-regulating function of CRKL protein in gastric cancer
Authors: Natsume Hiroko , Shinmura Kazuya , Tao Hong , Suzuki Masaya , Goto Masanori , Yamada Hidetaka , Maeda Matsuyoshi , Konno Hiroyuki , Nakamura Satoki , Sugimura Haruhiko 
Published: August 2012

Abstract
Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. To identify previously undiscovered amplified genes in gastric cancer, a genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers. Twenty-two genes (including ERBB2) in five highly amplified chromosome regions (with a copy number of more than 6) were identified. Particular attention was paid to the CRKL gene, which has not been previously characterized in gastric cancer and the product of which is an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains. A relatively high CRKL copy number was confirmed in the MKN74 gastric cancer cell line using fluorescence in situ hybridization, and a high level of CRKL expression was also observed in the cells. The RNA-interference-mediated knockdown of CRKL in MKN74 disclosed the ability of CRKL to upregulate gastric cell proliferation. An immunohistochemical analysis revealed that CRKL protein was overexpressed in 24.4% (88/360) of the primary gastric cancers that were analyzed. Finally, we showed that MKN74 cells with CRKL amplification were responsive to the dual Src/BCR-ABL kinase inhibitor BMS354825, likely via the inhibition of CRKL phosphorylation, and that the proliferation of MKN74 cells was suppressed by treatment with a CRKL-targeting peptide. These results suggested that CRKL protein is overexpressed in a subset of gastric cancers, that it regulates gastric cell proliferation, and that it has the potential to be a molecular therapy target for gastric 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 3682. doi:1538-7445.AM2012-3682
Abstract 3694: Role of the inflammatory response in pancreatic cancer treatment
Authors: Cantoria Mary Jo , Dragovich Tomislav , Meuillet Emmanuelle 
Published: August 2012

Abstract
Pancreatic adenocarcinoma is an aggressive malignancy, often diagnosed late in the course of the disease, and very difficult to diagnose and treat. To date, systemic treatment for pancreatic cancer, either a single agent or combinations of agents, has shown only modest benefits; however, growing understanding of the molecular pathogenesis of pancreatic cancers, and the complex heterogeneous signals associated with them, may help to target these pathways specifically and improve patient outcome. There is evidence for a significant role of cyclooxygenase (COX)-2 and COX-2-generated prostaglandin (PG) E2 (PGE2) during pancreatic tumorigenesis. COX-2 has therefore become a potential chemotherapeutic target for pancreatic cancer. Clinical trials combining Gemcitabine and Celecoxib [1] or Gemcitabine+ Irinotecan and Celecoxib [2] have not shown a significant benefit from celecoxib but there were relatively few patients treated and they were not selected or stratified based on biomarkers. We have measured the levels of 4 cytokines, including Interleukin (IL)-6, IL-1α, Tumor Necrosis Factor (TNF)-α and Interferon (IFN)-α in patient blood samples at day 0, day 29 and day 50 following the combination Gemcitabine - Celecoxib treatment. For all samples analyzed and averaged, we show an increase in plasma TNF-α (by 1.37 fold) and IL-1α (by 2 fold) concomitantly with a dramatic increase in IFN-γ (by 7 fold on day 29, by 3 fold on day 50) and stable IL-6 using the Meso Scale Discovery multiplex platform. One patient had a stable profile of all 4 cytokines and was shown to have partial response to the treatment. All others exhibited a strong variation in their cytokines during the treatment and did exhibit progression of the disease. Although the number of patients enrolled in the trial [1] was low, these results showed an interesting trend. These findings provide a basis for investigating further the inflammation-linked pathways along the COX2/mPGE-S1/EP4/IL-6 axis in pancreatic cancer cells and animal models of pancreatic cancers which will be subjected to the comparative treatment. [1]. Dragovich et al., Am. J. Clin. Oncol. 31:157-162 (2008) [2]. Lipton et al., J. Clin. Gastroenterol. 44:286-288 (2010)
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 3694. doi:1538-7445.AM2012-3694
Abstract 3698: ODSH, a heparin derivative, enhances the efficacy of gemcitabine in a refractory human pancreatic tumor xenograft model
Authors: Marcus Stephen G. , Quintana-Diez Pedro M. , Gately Stephen , Gonzales Paul , Chavira Bernardo , Von Hoff Daniel D. 
Published: August 2012

Abstract
ODSH, a new chemical entity, is 2-0, 3-0 desulfated heparin, a desulfated heparin analog that has been shown to bind to the receptor for advanced glycation endproducts (RAGE). This interaction prevents RAGE from binding to a principal ligand, HMGB1, as well as to other ligands including S-100 calgranulin, which attenuates the activation of RAGE. RAGE activation is known to induce resistance to chemotherapy and promote pancreatic tumor cell survival. We have shown, in vivo, an increase in response with gemcitabine when combined with ODSH. ODSH was tested alone and in combination with standard of care agent, gemcitabine, against BxPC-3 human pancreatic tumor xenograft model. Single agent ODSH and gemcitabine treatment showed an 18.8% and 16.8% decrease in tumor weight, respectively. The combination regimen of ODSH and gemcitabine increased tumor growth inhibition to 37.9%. This decrease was statistically significant (P&lt;0.05) compared to ODSH and gemcitabine treatments alone according to Student's t-test. We believe this is a novel approach to treat metastatic pancreatic cancer. ODSH has already shown a favorable safety profile in Phase I and II studies. A clinical trial with ODSH treatment in combination with gemcitabine+nab-paclitaxel in newly diagnosed patients with metastatic pancreatic cancer is underway.
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 3698. doi:1538-7445.AM2012-3698
Abstract 3699: Adnab-9: A prospective stool biomarker for pancreatic ductal adenocarcinoma
Authors: Weinstein Douglas , Rambus MaryAnn , Levi Edi , Yuan Mei J. , Lawson Michael J. , Tobi Martin 
Published: August 2012

Abstract
Sporadic pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer and with no proven screening strategies. Adnab-9, a monoclonal antibody to constituents of human colonic adenomas has been shown to be prognostic in IPMN and diagnostic in gastric and colorectal cancer or adenomas (CRN). In this study, we retrospectively and prospectively evaluated the diagnostic potential of Adnab-9 in the stool of two distinct PDA populations. Methods: As proof of principle, 249 Chinese patients submitted stool for screening. Retrospectively, 15 patients had PDA and 80 patients without cancer served as controls. Adnab-9 stool reactivity was determined by ELISA. Prospectively, 1132 American CRN screening program patients submitted stool. Six patients developed PDA over five years of follow-up. 11 Patients free of any significant CRN or other cancer but deceased due to other causes, served as controls. An additional four patients with a known family history of PDA also prospectively submitted stool for Adnab-9. Results: The prospective study results are summarized in the Table. Table: Prospective Study Data for Adnab-9 stool antibody as a biomarker of PDA. The pilot study in Chinese PDA patients found that 12 of 15 patients had stool Adnab-9 ELISA positivity compared to 10 of 80 controls (OR 28, CI 6.7-116.8, P&lt;0.0001). 4 of 6 prospective American study PDA patients had either stool ELISA or Western blot positivity for Adnab-9 compared to 1 of 11 controls (OR=20, CI 1.4-287.6, P&lt;0.03). 2 of 4 patients with family history of PDA had stool positive by Adnab-9 ELISA or Western blot. Conclusions: Our study suggests that Adnab-9 stool tests may be an effective PDA diagnostic marker. Based on previous data in CRC and IPMN, Adnab-9 appears to bind Paneth-like cells, which we and others have shown to be cancer-associated and the likely source of the stool antigen. Future prospective studies are needed to confirm the diagnostic efficacy of Adnab-9 stool testing in PDA.

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 3699. doi:1538-7445.AM2012-3699