tbuckley/cabot-search huggingface dataset:
Abstract 2727: Clinical significance of PTEN in UTUC
Authors: Liang-Chen Li, Cheng-Keng Chuang, Hung-Ying Chiang, Ying-Tzu Chen, Po-Hung Lin, Kai-Jie Yu, See-Tong Pang, Wen Hui Weng*
Journal: Cancer Research (2017)

Abstract Upper tract urothelial carcinoma (UTUC) is a rare malignancy accounts for about 5% of all urothelial tumours. The cancer cells start in the layer of tissue urothelium, and found in the renal pelvis, renal calyces or ureters. When compare the UTUC to the bladder urothelial carcinoma, the pathological and clinical findings are often look and act alike. Previous studies indicated that deletion of phosphatase and tensin homologue (PTEN) gene is common to be found in bladder cancer. As known tumor suppressor gene PTEN is located on chromosome ten and considered as an important negative regulator for the PIP3/Akt signaling pathway to promote cell proliferation and inhibit apoptosis. Thus, this study we aimed to determine clinical significance of PTEN in UTUC. We collected sixty-eight formalin-fixed paraffin-embedded (FFPE) UTUC samples, the tumor stage was according to American Joint Committee on Cancer (AJCC) with Ta (n=15), T1 (n=11), T2 (n=10), T3 (n=18), T4 (n=7) and seven patients with unknown; in which male no.32, female no.36; the median age is 68 y/o (range 40-85 y/o). Fluorescence in situ hybridization (FISH) was performed to exam the PTEN gene copy number or gene structure alterations of UTUC; besides, immunohistochemistry (IHC) analysis were used to observe the PTEN protein expression in the tumor. Our results showed PTEN mutations were observed in twenty-two tumors with heterozygous PTEN deletion; one tumor with homozygous PTEN deletion, and three tumors with PTEN monosomy. Further, heterozygous PTEN deletion was shown significantly associated with stage of pTa, pT1 and pT2 (P=0.048) and history of smoking (P=0.030). The IHC results showed lower expression level was common to be observed in the tumor area. Our findings suggest loss of PTEN is associated with the low-risk group of UTUC but not the high-risk group, the unknown mechanisms between these two subtypes might be existed. Besides, smoking could also as a factor highly emerge from genetic alterations in UTUC. In conclusion, PTEN genomic loss might act a predictive indicator of classification of UTUC, however, the clinical treatment could be different due to the underlying diversity of the molecular activities. Citation Format: Liang-Chen Li, Cheng-Keng Chuang, Hung-Ying Chiang, Ying-Tzu Chen, Po-Hung Lin, Kai-Jie Yu, See-Tong Pang, Wen Hui Weng*. Clinical significance of PTEN in UTUC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2727. doi:10.1158/1538-7445.AM2017-2727
Abstract 2181: Antibody-conjugated nanoparticles for targeting metastatic triple-negative breast cancer
Authors: Vidhi Khanna, Stephen Kalscheuer, Ameya Kirtane, Jayanth Panyam
Journal: Cancer Research (2017)

Abstract Early detection and the availability of new treatments have improved the survival rates of patients presenting with local or regional breast cancer to as high as 99% and 85%, respectively. On the contrary, patients with metastatic disease have a dismal 5-year survival rate of 17%. Thus, there is an urgent need for treatment strategies directed towards metastasis. Our lab has developed antibodies (Clone 6 and AM6) capable of recognizing tumor cells that have undergone epithelial-to-mesenchymal transition (EMT), a key step in the generation of circulating tumor cells and metastasis. The goal of the current study was to determine whether we use these antibodies as targeting ligands for directing anticancer drug-loaded polymeric nanoparticles to metastatic triple negative breast cancer cells as a novel therapeutic option. Polymeric PLGA nanoparticles loaded with paclitaxel, a chemotherapeutic agent, were functionalized with the antibodies using thiol-maleimide chemistry. We optimized the conjugation reaction in order to achieve maximal cell uptake of nanoparticles without compromising antibody binding. In vitro studies were carried out in an MDA-MB-231 derivative cell line with enhanced lung metastatic potential as well as a melanoma metastatic cell line M12. Clone 6 nanoparticles and AM6 nanoparticles showed significant improvement in cellular uptake as well as retention. A competition experiment confirmed target-mediated uptake of nanoparticles. Cytotoxicity studies showed improved cell kill using Clone 6 nanoparticles and AM6 nanoparticles. Based on these promising in vitro results, we are currently carrying out in vivo studies in mice. The development of a targeted drug delivery system for the treatment of metastatic triple negative breast cancer can significantly enhance the survival rate for patients who often have a life-expectancy of less than one year. Citation Format: Vidhi Khanna, Stephen Kalscheuer, Ameya Kirtane, Jayanth Panyam. Antibody-conjugated nanoparticles for targeting metastatic triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2181. doi:10.1158/1538-7445.AM2017-2181
Comparison of three methods to detect mutations in the PI3K oncogene in FFPE cancer samples
Authors: J. Rodgers, C. Murray, N. Leaves
Journal: Journal of Clinical Oncology (2009)

e22212 Background: PI3Kinase is an important target for new oncology therapies, since it is central to several cell signalling pathways associated with proliferation and survival. Many pharmaceutical companies have PI3K inhibitors in their drug development pipelines all of which are in early phase trials. Activating mutations in exons 9 and 20 of the PI3KCA oncogene have been observed in a number of important cancer types including: gastrointestinal, breast, liver, lung and genito-urinary cancers. The presence of such mutations may prove useful as companion diagnostic biomarkers for prediction of response to therapy. Methods: Source BioScience (Nottingham, UK) tested three different methods for the detection of PI3K mutations in archival tumour samples, in their CPA and GLP accredited laboratories. Eighty formalin-fixed paraffin-embedded (‘FFPE') samples from histologically confirmed breast cancer samples were tested by the new DxS P13K Mutation Test Kit using real-time PCR, by pyrosequencing (Qiagen), and by conventional bidirectional capillary sequencing. Tumour content was evaluated by pathology review. Results: The results of the comparison showed that the DxS test using rtPCR technology was easy to perform, convenient and robust. The DxS test had a high degree of sensitivity provided there was more than 20% tumour content in the test sample as determined by histology and pathology review. Conclusions: In conclusion, the DxS test is a valuable tool for detecting PI3K mutations in FFPE samples from breast cancer patients. No significant financial relationships to disclose.
Abstract 4460: TET1 over expression contributes to lung cancer malignancy
Authors: Piotr Teodor Filipczak, Shuguang Leng, Carmen S. Tellez, Steven A. Belinsky
Journal: Cancer Research (2017)

Abstract Epigenetic alterations are a leading cause of lung carcinogenesis and malignancy. While the role of enzymes catalyzing cytosine-guanine (CpG) island methylation and chromatin modifications has been extensively studied, the role of the recently discovered demethylating enzymes represented by ten-eleven translocation methylcytosine dioxygenases (TETs) remains unknown. The goal of this study was to investigate the expression and functional significance of the TET1 gene in non-small cell lung cancer (NSCLC). QRT-PCR revealed 2- to 30-fold over expression of TET1 in 52% of squamous cell carcinoma (SCC) and 40% of adenocarcinoma (AdC) tumors compared to paired normal lung tissue. This result was validated using The Cancer Genome Atlas (TCGA) database with TET1 over expressed in 72% of SCCs and 53% of AdCs. Elevated levels of TET1 transcript were associated with increased protein levels in NSCLC cell lines compared to normal human bronchial epithelial cells (HBECs). A reporter assay analysis defined the promoter region critical for elevated transcription of the TET1 gene using lung cancer cell lines, and studies to identify the transcription factors underlying the increase in expression are underway. Transient knock down of TET1 expression in NSCLC cell lines caused global changes in the transcriptome, reduced cell proliferation, colony formation, and inhibited growth of tumor xenografts in nude mice. Cellular senescence mediated by p21 signaling and associated with β-galactosidase activation was identified as one mechanism underlying growth inhibition. This study suggests that TET1 may function as an oncogene contributing to the lung cancer malignant phenotype and thus, could serve as a potential new target for treatment. (Supported by R01 CA183296) Citation Format: Piotr Teodor Filipczak, Shuguang Leng, Carmen S. Tellez, Steven A. Belinsky. TET1 over expression contributes to lung cancer malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4460. doi:10.1158/1538-7445.AM2017-4460
Abstract 5787: Validation of spheroids with long-term incubation for high-throughput screening
Authors: Jesse J. Parry, Steven M. Garner, Lee R. Cavedine, Alyssa M. Cracchiolo, Brogan A. Epkins, Samantha C. Burkart, Timothy J. Sindelar, Charles R. Wageman, Usha Warrior, Alastair J. King
Journal: Cancer Research (2017)

Abstract The OncoPanel™ service has established 100 genomically-characterized human tumor cell lines as targets for the screening of compounds in 3D spheroid models. We sought to (1) expand the cell line capability of the service and (2) validate the cell lines in a long-term (10-day) assay. For the cell line expansion, cells were plated at two densities in 384-well, spheroid-promoting plates, and were incubated for 3 days to allow formation of spheroids. The growth media were then removed and replaced with media containing the hypoxia probe, Lox-1. Twenty-four hours later, the ability to form spheroids was determined by bright-field, high-content imaging, and fluorescent detection of the Lox-1 probe in the hypoxic core of the spheroids. Cells were then seeded in assay plates at pre-determined densities, along with a time zero (T0) plate, and were incubated for 4 days to allow spheroid formation. Spheroid formation was verified by bright-field, high-content imaging, as previously mentioned. The growth media were removed and replaced with fresh media, followed by the addition of staurosporine over a range of 10 concentrations, using acoustic liquid transfer. At this time, the T0 plate was processed for subsequent doubling calculations. The assay plates were incubated for 10 days, re-imaged, and the spheroids were lysed using CellTiter-Glo® 3D viability reagent. Data were analyzed as the relative cell count, where the measured bioluminescence intensity was transformed to percent of control, as compared with a vehicle-treated control. Cellular response parameters were calculated using nonlinear regression to a sigmoidal single-site dose response model. A vehicle CV of &amp;lt;30% was required, as one criterion, for each cell line to pass quality control. Based on our tests of spheroid formation in the expansion cell lines, we have added 36 cell lines to the spheroid- or loose aggregate-forming cell line panel, with 20 cell lines validated in the long-term assay. Through the use of high-throughput screening and high-content imaging, we can verify and validate spheroid formation and growth in a 384-well format, with which we can test agents for drug discovery projects and provide value for potentially greater therapeutic outcomes. Citation Format: Jesse J. Parry, Steven M. Garner, Lee R. Cavedine, Alyssa M. Cracchiolo, Brogan A. Epkins, Samantha C. Burkart, Timothy J. Sindelar, Charles R. Wageman, Usha Warrior, Alastair J. King. Validation of spheroids with long-term incubation for high-throughput screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5787. doi:10.1158/1538-7445.AM2017-5787
Abstract 2741: Assessing the utility of circulating tumor DNA as a surveillance tool for sarcomas and Li-Fraumeni syndrome using a pre-clinical model
Authors: Sangeetha Paramathas, Nathan Lewis, Tanya Guha, Zainab Motala, David Malkin
Journal: Cancer Research (2017)

Abstract Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome commonly characterized by the presence of inherited mutations in the tumor suppressor gene TP53. This leads to an early onset of a wide spectrum of tumors in multiple organ systems. Current surveillance protocols for early tumor detection include biochemical screening, MRI and ultrasound scans, colonoscopy and mammography (for adults). While early detection is associated with improved survival, the complexity of testing, potential to ‘misdiagnose’ tumors (false positive/negative) and requirement for multiple imaging modalities makes clinical surveillance challenging to implement and interpret. Liquid biopsies are a recently described diagnostic and prognostic tool that takes advantage of analyzing circulating tumor DNA - fragmented genomic material that are released into the blood from dying tumor cells. In this proof-of-principle study, we use mouse xenograft tumor models to assess the dynamic relationship between tumor burden and ctDNA concentrations, as well as resolve the sensitivity of capturing the presence of lesions in their earliest stages of growth. Longitudinal analyses of ctDNA from serially collected blood were performed on mice with xenografts of rhabdomyosarcoma (Rh4 and Rh30), osteosarcoma (HOS) and non-small cell lung carcinoma (H1975) of both localized and simulated metastatic tumors. We characterized ctDNA using droplet digital PCR (ddPCR) for known gene mutations that were specific for the cancer cell lines used. We observe obvious increases in ctDNA with increased tumor burden and a complete clearance of ctDNA after tumor resection. In addition, using the metastatic model, we have conducted synchronized imaging and blood-based biopsies to determine the smallest lesion able to be detected in the blood by ctDNA. These studies provide the foundation for early tumor detection with ctDNA in Trp53 mutant mice that develop spontaneous tumors analogous to LFS. This model will help further our understanding on the utility of ctDNA as a surveillance and diagnostic tool for LFS as well as assess its potential for clinical use. Citation Format: Sangeetha Paramathas, Nathan Lewis, Tanya Guha, Zainab Motala, David Malkin. Assessing the utility of circulating tumor DNA as a surveillance tool for sarcomas and Li-Fraumeni syndrome using a pre-clinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2741. doi:10.1158/1538-7445.AM2017-2741
Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site
Authors: E Hadzijusufovic, K Albrecht-Schgoer, K Huber, G Hoermann, F Grebien, G Eisenwort, W Schgoer, S Herndlhofer, C Kaun, M Theurl, W R Sperr, U Rix, I Sadovnik, B Jilma, G H Schernthaner, J Wojta, D Wolf, G Superti-Furga, R Kirchmair, P Valent
Journal: Leukemia (2017)
Abstract 4428: A miRNA signature linked to human environmental risk defined from carcinogen-induced and genetically-driven colon carcinogenesis models
Authors: Ying-Shiuan Chen, Rong Wang, Wan-Mohaiza Dashwood, Christiane Löhr, David E. Williams, Emily Ho, Susanne Mertens-Talcott, Roderick H. Dashwood
Journal: Cancer Research (2017)

Abstract Heterocyclic amines (HCAs) produced during high-temperature cooking have been studied extensively in terms of their genetic effects, but recent work has implicated epigenetic mechanisms involving non-coding RNAs. We reported that colon tumors induced in the rat by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) have altered microRNA (miRNA) signatures linked to dysregulated pluripotency factors, such as c-Myc and Krüppel-like factor 4 (Klf4). The corresponding miRNAs prioritized from PhIP-induced colon tumors were examined in other target organs from a one-year carcinogenicity bioassay, and compared with miRNAs dysregulated in the Apc-mutant polyposis in rat colon (Pirc) genetic model. Multiple let-7 family members were downregulated in colon, skin, lung, small intestine, and Zymbal’s gland tumors, and were associated with Myc and Hmga2 upregulation. A “PhIP miRNA signature” with the profile mir-21high | mir-126low | mir-29low | mir-215low | mir-145low was linked to reduced expression of Klf4 in multiple target organs of the rat, and was predictive of poor prognosis in human pan-cancer and colorectal cancer datasets (https://cancergenome.nih.gov/). Findings from The Cancer Genome Atlas suggested that PhIP signature miRNAs might serve as an arbiter of HCA exposure, defining a subset of human tumors linked to environmental carcinogen exposure. We conclude that future studies should examine the miRNA signatures of other HCAs, and determine their possible predictive value for human risk assessment. This work was supported in part by NIH grants CA090890, CA122959, ES00210, and ES023512, the John S. Dunn Foundation, and a Chancellor’s Research Initiative. We are most thankful to Robert Hawk for providing a graduate student fellowship in aid of Y-S Chen. Citation Format: Ying-Shiuan Chen, Rong Wang, Wan-Mohaiza Dashwood, Christiane Löhr, David E. Williams, Emily Ho, Susanne Mertens-Talcott, Roderick H. Dashwood. A miRNA signature linked to human environmental risk defined from carcinogen-induced and genetically-driven colon carcinogenesis models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4428. doi:10.1158/1538-7445.AM2017-4428
Abstract 186: Increased STIM1 Expression Results in Altered Calcium Handling and Heart Failure
Authors: Robert N Correll, Sanjeewa A Goonasekera, Jop H van Berlo, Adam R Burr, Federica Accornero, Allen J York, Michelle A Sargent, Steven R Houser, Jeffery D Molkentin
Journal: Circulation Research (2015)

Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor that partners with Orai1, resulting in store-operated Ca2+ entry (SOCE) that is important for maintaining endoplasmic reticulum (ER) Ca2+ homeostasis. STIM1 is expressed in the heart and upregulated during disease, but its role in disease progression is unclear. In this study we used transgenic mice with STIM1 overexpression in the heart to model the known increase of this protein in response to cardiac disease. We found that STIM1 transgenic myocytes showed elevated Ca2+ entry following store depletion and STIM1 co-localized with the type 2 ryanodine receptor (RyR2) in the sarcoplasmic reticulum (SR). In addition, STIM1 transgenic mice exhibited sudden cardiac death as early as 6 weeks of age, while mice that survived past 12 weeks developed cardiac hypertrophy that progressed to heart failure, pulmonary edema, activation of the fetal gene program, alterations in mitochondrial structure, and reduced ventricular functional performance. When pre-symptomatic STIM1 transgenic mice were subjected to disease stimuli including pressure overload stimulation or neurohumoral agonist infusion, they showed greater pathology compared to control mice. STIM1 elevation also disrupted normal Ca2+ handling in cardiac myocytes, which showed spontaneous Ca2+ transients that could be inhibited by the SOCE blocker SKF-96265, as well as increased diastolic Ca2+ levels and elevated Ca2+ spark frequency. In keeping with this increase in Ca2+ cycling we also found that STIM1 elevation resulted in an increased baseline activity of cardiac nuclear factor of activated T-cells (NFAT) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). This increased CaMKII activity did not, however, translate into additional RyR2 phosphorylation, suggesting that the augmented Ca2+ spark frequency observed was likely due to an elevation in SR Ca2+ load. Our results suggest that increased STIM1 expression elicits augmented Ca2+ entry, SR Ca2+ load and Ca2+ spark frequency, that leads to mitochondrial pathology and the induction of Ca2+ sensitive hypertrophic signaling pathways that contribute to cardiac disease.
Abstract 3252: Synthesis of N-substituted [Benzoylamino]-3-Ethyl-1,2,3,6-tetrahydropyridines as potential anti-cancer agents
Authors: Elizabeth Henderson, Madhavi Gangapuram, Suresh Eyunni, Kinfe Redda, Tiffany Ardley
Journal: Cancer Research (2017)

Abstract Chronic inflammation is believed to promote cancer through cellular and genomic damage. Inflammation creates a microenvironment within the tissue that enhances cell proliferation. In 2016, American Cancer Society estimates that 1,685,210 new cancer cases are expected to be diagnosed in the United States. Cyclooxygenase (COX) is an enzyme found to play an essential role in inflammation and converts arachidonic acid to prostaglandin-like molecules. The three isomers of COX are COX-1, COX-2, and COX-3. COX-2 has been found to be up-regulated in inflammation and some cancers, such as breast cancer and prostate cancer. Tetrahydropyridines (THPs) developed by our research group were effective in inhibiting inflammation, COX, and the growth of some breast cancer cells. Previous research has shown that pharmacological activities of the THP derivatives depend greatly on the nature and position of the substituents on the THP ring structure. Here, we present the synthesis of a series of novel THP derivatives. 3-Ethylpyridine is reacted with O-mesitylenesulfonylhydroxylamine (O-MSH) to furnish N-amino-3-ethylpyridinium mesitylenesulfonate. The reaction of N-amino-3-ethylpyridinium mesitylenesulfonate with substituted acid chlorides gives the stable crystalline pyridinium ylides. A sodium borohydride reduction of ylides furnishes the target compounds, N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines. Five novel N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines were synthesized, purified, and characterized. The evaluation of these compounds cytotoxicity studies on MCF-7 estrogen receptor positive breast cancer cells, MDA-MB-231 estrogen receptor negative breast cancer cell lines, and Ishikawa cells, using the CellTiter-Glo (CTG) luminescent cell viability assay is underway. This research was supported by the National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number 8 G12MD007582-28. Citation Format: Elizabeth Henderson, Madhavi Gangapuram, Suresh Eyunni, Kinfe Redda, Tiffany Ardley. Synthesis of N-substituted [Benzoylamino]-3-Ethyl-1,2,3,6-tetrahydropyridines as potential anti-cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2017-3252