bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4012: GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft.
Authors: Fu Junsheng , Rodova Mariana , Roy Sanjit K. , Shankar Sharmila , Srivastava Rakesh K. 
Published: August 2014

Abstract
Multiple lines of evidence suggest that the Sonic Hedgehog (Shh) signaling pathway is aberrantly reactivated in pancreatic cancer stem cells (CSCs). The objectives of this study were to examine the molecular mechanisms by which GANT-61 (Gli transcription factor inhibitor) regulates stem cell characteristics and tumor growth. Effects of GANT-61 on CSC's viability, spheroid formation, apoptosis, DNA-binding and transcriptional activities, and epithelial-mesenchymal transition (EMT) were measured. Humanized NOD/SCID/IL2Rgammanull mice were used to examine the effects of GANT-61 on CSC's tumor growth. GANT-61 inhibited cell viability, spheroid formation, and Gli-DNA binding and transcriptional activities, and induced apoptosis by activation of caspase-3 and cleavage of Poly-ADP ribose Polymerase (PARP). GANT-61 increased the expression of TRAIL-R1/DR4, TRAIL-R2/DR5 and Fas, and decreased expression of PDGFRα and Bcl-2. GANT-61 also suppressed EMT by up-regulating E-cadherin and inhibiting N-cadherin and transcription factors Snail, Slug and Zeb1. In addition, GANT-61 inhibited pluripotency maintaining factors Nanog, Oct4, Sox-2 and cMyc. Suppression of both Gli1 plus Gli2 by shRNA mimicked the changes in cell viability, spheroid formation, apoptosis and gene expression observed in GANT-61-treated pancreatic CSCs. Furthermore, GANT-61 inhibited CSC tumor growth which was associated with up-regulation of DR4 and DR5 expression, and suppression of Gli1, Gli2, Bcl-2, CCND2 and Zeb1 expression in tumor tissues derived from NOD/SCID IL2Rγ null mice. Our data highlight the importance of Shh pathway for self-renewal and metastasis of pancreatic CSCs, and also suggest Gli as a therapeutic target for pancreatic cancer in eliminating CSCs.
Citation Format: Junsheng Fu, Mariana Rodova, Sanjit K. Roy, Sharmila Shankar, Rakesh K. Srivastava. GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4012. doi:10.1158/1538-7445.AM2013-4012
Abstract 4014: The therapeutic potential of ICG-001 and β-catenin specific RNAi in liver cancer development.
Authors: Kassa Anketse D. , Medina Vivian G. , Zeng Ni , He Lina , Nguyen Cu , Smbatyan Goar , Rieger Megan , Kahn Michael , Stiles Bangyan L. 
Published: August 2014

Abstract
Liver cancer is one of the most common malignant tumors. It is reported to be the third most lethal malignancy worldwide. Recent studies including our own identified CD133+ cell population as the tumor initiating cells for liver cancer. Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome ten) is aberrantly expressed in liver cancers. Liver specific Pten (Pm) null mice develop liver cancer following an extensive phase of chronic lipid accumulation and demonstrate escalating levels of hepatic injury markers from 6-12M, prior to hepatic progenitor cell proliferation. Concomitantly, expression of mRNA levels for Wnt ligands and receptors also increased progressively. Wnt/β-Catenin signaling pathway has various roles in regulating embryonic development and tumorigenesis. In Pten null liver progenitor cell line and tissues; we observed high levels of βcatenin, a downstream target component of the Wnt signaling pathway compared to control cells.
In this study, we investigate the role of the Wnt/β-Catenin pathway in the activation of hepatic progenitor cells in the Pten deletion liver cancer model using two methods: a novel Wnt/β-Catenin inhibitor ICG-001 and β-Catenin specific RNAi. ICG-001 is a small molecule, which specifically inhibits β-Catenin/CBP interaction. Coactivator CBP/β-Catenin/T cell factor (TCF) mediated transcription has been reported as critical for stem cell/progenitor cell proliferation.
ICG-001 significantly attenuates the proliferation of hepatic cancer stem cells in vitro and in vivo. Our preliminary results demonstrate inhibition of Wnt/β-Catenin pathway using sh-β-Catenin in vitro can effectively inhibit the proliferation of CD133+ hepatic cancer stem cells.
These observations indicate that Wnt/β- Catenin pathway likely mediates proliferation of hepatic cancer stem cell. Targeting this pathway using ICG-001 and/or β-Catenin directed shRNA holds promise for the treatment and eradication of liver cancer.
Citation Format: Anketse D. Kassa, Vivian G. Medina, Ni Zeng, Lina He, Cu Nguyen, Goar Smbatyan, Megan Rieger, Michael Kahn, Bangyan L. Stiles. The therapeutic potential of ICG-001 and β-catenin specific RNAi in liver cancer development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4014. doi:10.1158/1538-7445.AM2013-4014
Abstract 4020: Genome-wide analysis of stepwise hepatocarcinogenesis using next generation sequencer.
Authors: Midorikawa Yutaka , Takayama Tadatoshi , Yamamoto Shogo , Ueda Hiroo , Sonoda Kotaro , Takane Kiyoko , Tsuji Shingo , Nagae Genta , Tatsuno Kenji , Morgan Margaret , Wheeler David , Aburatani Hiroyuki 
Published: August 2014

Abstract
Early hepatocellular carcinoma (HCC) originates from the hepatocytes of chronic liver disease and develops into classical HCC. To identify sequential genomic changes in multistep hepatocarcinogenesis, we analyzed fusion genes and mutations using next generation sequencer about 40 early and 80 advanced HCCs. First, exome sequence showed that base sequence aberrations were more frequent in advanced HCC than early HCC, and mutations including TP53 (24%), CTNNB1 (24%), and ARID1A (16%) were recurrently observed in both early and advanced HCCs. Consistent with our previous report homozygous deletions near CSMD1 and CDKN2A were also found in 8 and 5 cases, respectively, only in advanced HCC. Next, we detected 4 types of fusion gene, including interchromosomal (translocation), intrachromosomal (deletion), intrachromosomal (translocation), and inversion by RNA sequencing. We also found that every HCC harbored 2 to 5 fusion genes, which were more frequent in advanced than early HCC, although there were no recurrent rearrangements in neither advanced nor early HCCs. Especially chromathripsis, in which 10 to 100 rearrangements were localized in the specific genomic regions and genomic features imply chromosome breaks occur in one-off crisis, was the event observed only in advanced HCC. Taken together, genomic changes were more frequent in advanced HCC, suggesting early HCC originates in the chronic liver disease and progresses into advanced HCC with genomic aberrations.
Citation Format: Yutaka Midorikawa, Tadatoshi Takayama, Shogo Yamamoto, Hiroo Ueda, Kotaro Sonoda, Kiyoko Takane, Shingo Tsuji, Genta Nagae, Kenji Tatsuno, Margaret Morgan, David Wheeler, Hiroyuki Aburatani. Genome-wide analysis of stepwise hepatocarcinogenesis using next generation sequencer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4020. doi:10.1158/1538-7445.AM2013-4020
Abstract 4025: Data-driven computational modeling to identify biomarkers of response to lenvatinib (E7080) in melanoma.
Authors: Kadowaki Tadashi , Funahashi Yasuhiro , Matsui Junji , Pavan Kumar , Sachdev Pallavi , O'Brien Jim , Xing Heming , McDonagh Paul D. , Khalil Iya , Kurzrock Razelle , Hong David S. , Nemunaitis John 
Published: August 2014

Abstract
Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. Anti-tumor activity has been observed in melanoma patients in Phase I studies. We applied an integrative supercomputer-driven analysis approach to identify biomarkers of lenvatinib treatment response in melanoma patients.
Methods: Clinical data sets including tumor response data (RECIST), progression free survival (PFS), pharmacokinetic parameters (PK) and molecular data sets including baseline tumor gene expression (Affymetrix U133Plus2) and BRAF and NRAS mutational status, were collected from 18 patients with metastatic melanoma who received lenvatinib 10 mg orally twice daily in 28-day cycles. These clinical and molecular data sets were used to generate computational models developed using REFS (Reverse Engineering and Forward Simulation) modeling platform, which utilizes Bayesian network inference and simulations. Simulations were performed to identify biomarkers of lenvatinib treatment response. These potential predictive biomarkers were then tested for their ability to predict response to lenvatinib in preclinical models.
Results: Using a model comprising gene expression, mutational status and PK data, REFS identified a panel of 18 potential predictive biomarkers of lenvatinib treatment response. Identified biomarkers were able to predict up to 89% of the observed variance in the tumor response data. A total of 32 identified genes including 6 candidate predictive biomarkers (TARBP2, CACNA1, C7ORF, RAP2A, SHMT1, IL22RA2) were further validated in a preclinical melanoma model system (n=12) and tissue bank samples with matched normal adjacent tissue (n=21). Expression of 14 genes correlated with relative tumor volume (r&gt;0.35 or r&lt;-0.35) in the preclinical model and expression levels of 19 genes were found to be higher in tumor compared to normal tissue (FC&gt;2).
Conclusions: Potential predictive biomarkers of lenvatinib treatment response in melanoma patients were identified by computational modeling and validated in a preclinical model system and tumor tissue bank samples. The identified biomarkers will be tested for their predictive value in an ongoing Phase 2 trial.
Citation Format: Tadashi Kadowaki, Yasuhiro Funahashi, Junji Matsui, Kumar Pavan, Pallavi Sachdev, Jim O'Brien, Heming Xing, Paul D. McDonagh, Iya Khalil, Razelle Kurzrock, David S. Hong, John Nemunaitis. Data-driven computational modeling to identify biomarkers of response to lenvatinib (E7080) in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4025. doi:10.1158/1538-7445.AM2013-4025
Abstract 4033: Gene expression of EdU proliferating cells made possible with improved click chemistry.
Authors: Clarke Scott T. , Cheng Angie , Rukavishnikov Aleksey , Yan Michelle , Singh Upinder , Gee Kyle , Magdaleno Susan 
Published: August 2014

Abstract
Gene expression profiling of cancer cells has become increasingly common over the past five years. Especially important is identifying changes in gene expression caused by drug treatment leading to side populations with altered pathways. These populations can escape drug treatment and lead to recurrence. Characterizing gene expression of proliferating cells requires a method of identifying proliferation while simultaneously maintaining high quality RNA. Typically, cells are screened in a drug panel in the presence of tritiated thymidine or BrdU to identify the drug resistance in the proliferating population. Proliferation detection with these methods is neither rapid nor does it yield high quality RNA for profiling. A new proliferation method based on click chemistry using an alkyne modified thymidine analog (EdU), which can be used to rapidly identify replicating cells appears ideally suited for this application; however, copper used for the catalysis of the click reaction causes undesired degradation of RNA. Recent improvements to the copper based click reaction are presented here whereby the copper is tightly controlled, resulting in higher quality RNA useful for sequencing.
In this study we demonstrate gene expression changes in the proliferating population of a drug resistant cancer cell line compared to the parental cell lines. Proliferating cells were identified using an improved click reaction comprising of a copper(I) ligand combined with a picolyl modified dye azide detection reagent. Total RNA from these cells was isolated and gene expression was assessed by targeted RNA sequencing using an RNA Apoptosis panel and an RNA Cancer panel using proton based sequencing technology.
Use of an improved copper “safe” click reaction for detection of nascent DNA, allows for detection of incorporated click analog for measuring proliferation and subsequent isolation of high quality RNA for use in sequence analysis.
Citation Format: Scott T. Clarke, Angie Cheng, Aleksey Rukavishnikov, Michelle Yan, Upinder Singh, Kyle Gee, Susan Magdaleno. Gene expression of EdU proliferating cells made possible with improved click chemistry. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4033. doi:10.1158/1538-7445.AM2013-4033
Abstract 4043: The role of CD63/Timp1/β1 integrin complex in cell survival.
Authors: Pinto Mariana T. , de Melo Fabiana Henriques Machado , Jasiulionis Miriam Galvonas 
Published: August 2014

Abstract
Although malignant melanoma is the less frequently diagnosed skin cancer, it shows a poor prognosis due its chemoresistance and metastasis development. One of the acquired abilities of transformed cells is anoikis resistance and this property is closely related to metastasis formation. In our laboratory, we developed a model that allows us to study different steps of melanocyte malignant transformation. Melan-a melanocytes surviving after 1, 2, 3 and 4 deadhesion cycles showed modified morphology and independent PMA growth and have been named 1C, 2C, 3C and 4C cells, respectively. Different melanoma cell lines were established after submitting 4C spheroids to limiting dilution. Previous data from our group demonstrated increased expression of Timp1 and resistance to anoikis during the malignant transformation of melanocytes. Melan-a melanocytes overexpressing Timp1 acquire anoikis-resistant phenotype. In our laboratory, we observed interaction between CD63, Timp1 and β1-integrin in the 4C, 4C11- and 4C11+ cell lines established after cycles of anchorage impediment. This seems to be the first study describing the interaction between Timp1, CD63 and β1-integrin in tumor cells. However, it is unclear how Timp1 modulates resistance to anoikis. Therefore, our aim is to analyze the role of Timp1 in the context of Timp1/CD63/β1-integrin complex and the signaling pathways involved in the acquisition of anoikis resistance. Supported by CAPES and FAPESP.
Citation Format: Mariana T. Pinto, Fabiana Henriques Machado de Melo, Miriam Galvonas Jasiulionis. The role of CD63/Timp1/β1 integrin complex in cell survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4043. doi:10.1158/1538-7445.AM2013-4043
Abstract 4046: Estrogen receptor-α coordinates the unfolded protein response,autophagy, and reactive oxygen species generation to regulate breast cancer survival.
Authors: Clarke Pamela A. , Cook Katherine , Hu Rong , Schwartz Jessica L. , Abu-Asab Mones , Warri Anni , Clarke Robert 
Published: August 2014

Abstract
Of the almost 240,000 new breast cancers diagnosed in 2011 within the USA, approximately 70% of these cases express the estrogen receptor-α (ER). ER targeted therapies such as tamoxifen (TAM) or faslodex (ICI) are often used to treat this breast cancer subtype. However, the curative potential of these interventions is frequently limited in patients due to resistance. Understanding how antiestrogen resistance occurs could lead to improved approaches to eradicate ER+ breast cancers. Increased unfolded protein response (UPR, an endoplasmic reticulum stress pathway) or autophagy (a “self” eating process used to clear dysfunctional protein or organelles) was previously shown to promote antiestrogen resistance in ER+ breast cancer. Using the antiestrogen sensitive MCF7-LCC1 (LCC1) and resistant MCF7-LCC9 (LCC9) cell lines, we determined the effect of antiestrogens and ERα on autophagy and UPR signaling. Suprisingly, ablation of ERα through RNAi potentiated LCC1 to antiestrogen-mediated cell death and resensitized LCC9 cells to endocrine therapy. While ICI stimulated both autophagy and UPR signaling, RNAi knockdown of ERα in LCC1 and LCC9 cells inhibited ICI-mediated UPR signaling and concurrently stimulated autophagy. Furthermore, we showed that ERα knockdown stimulated ROS production and potentiated the cell death response to antiestrogen therapy. ERα knockdown, but not ICI treatment, reduced nuclear Nrf2 (a UPR-induced antioxidant signaling protein) and increased cytosolic KEAP1 (an inhibitor of Nrf2), which may lead to the observed increase in ROS production. Autophagy inhibition through ATG7 silencing increases cell death and apoptosis in LCC1 ERα knockdown cells, showing that autophagy induction by antiestrogens is prosurvival in this context. These data suggests that UPR and autophagy stimulated by antiestrogen therapy results from two different mechanisms of ER regulation. We show that antiestrogens promote the accumulation of ERα in the cytosol that is associated with increased UPR signaling, while the inhibition of ERα promotes prosurvival autophagy. The inherent stimulation of resistance mechanism signaling through antiestrogen treatment suggests that combining autophagy or UPR inhibitors with anti-estrogens may greatly reduce the development of acquired antiestrogen resistance in breast cancer.
Citation Format: Pamela A. Clarke, Katherine Cook, Rong Hu, Jessica L. Schwartz, Mones Abu-Asab, Anni Warri, Robert Clarke. Estrogen receptor-α coordinates the unfolded protein response,autophagy, and reactive oxygen species generation to regulate breast cancer survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4046. doi:10.1158/1538-7445.AM2013-4046
Abstract 4048: Aggresome formation is regulated by RanBPM through an interaction with HDAC6.
Authors: Salemi Louisa , Almawi Ahmad , Lefebvre Karen , Schild Poulter Caroline 
Published: August 2014

Abstract
RanBPM (Ran-binding protein M, also called RanBP9) is a nucleocytoplamsic protein that has been implicated in a number of cellular processes including cell adhesion, migration and gene transcription. It has been hypothesized to be a scaffolding protein, but its function remains poorly understood. In previous studies we documented the relocalization of RanBPM from the nucleus to the cytoplasm in response to ionizing radiation (IR) treatment. Subsequent analysis showed that IR triggered cytoplasmic RanBPM relocalization in perinuclear dots or foci often located close to an invagination of the nucleus. Upon further investigation, the RanBPM aggregates were identified as aggresomes, which have not been previously documented to occur in response to IR. Aggresomes are aggregates of misfolded/ubiquitinated proteins resulting from improper protein assembly, aberrant modifications and/or environmental stress. These misfolded/ubiquitinated proteins are normally cleared by chaperone-mediated refolding or by proteasomal degradation through the ubiquitin-proteasome system. In conditions where these systems are impaired or overwhelmed, misfolded proteins accumulate in specific perinuclear structures called aggresome. Further analysis confirmed that the RanBPM foci were indeed aggresomes by assessing co-localization of RanBPM with HDAC6, which is required for aggresome formation. Further, we showed RanBPM also formed aggresome in response to treatment with the proteasome inhibitor MG132. To determine the effect of RanBPM downregulation on aggresome formation, we assessed aggresome formation by HDAC6 in RanBPM shRNA and control shRNA Hela and HEK cells. RanBPM downregulation resulted in significantly lower number of aggresomes both after MG132 and IR treatment, suggesting that RanBPM is essential in aggresome formation. Confocal microscopy analysis showed that RanBPM and HDAC6 co-localize within the aggresome and co-immunoprecipitation studies detected an interaction between the two proteins. Downregulation of RanBPM also resulted in decreased acetylated α-tubulin, suggesting that RanBPM regulates HDAC6 activity. Altogether these results suggest that RanBPM may regulate aggresome formation through an interaction with HDAC6. The molecular details of this regulation are currently under investigation.
Citation Format: Louisa Salemi, Ahmad Almawi, Karen Lefebvre, Caroline Schild Poulter. Aggresome formation is regulated by RanBPM through an interaction with HDAC6. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4048. doi:10.1158/1538-7445.AM2013-4048
Abstract 4070: β-arrestin-2 mediated regulation of plasminogen activator inhibitor Type 1.
Authors: Sobolesky Philip M. , Zhou Tanyau , Gorstein Arielle , Woolworth Julie A. , Moussa Omar 
Published: August 2014

Abstract
Several studies described the elevated levels of plasminogen activated Inhibitor-1 (PAI-1) protein in malignant tissues and indicated the potential use as a therapeutic target. In bladder cancer, higher levels of PAI-1 were found in tumor tissues compared to normal tissues. Urinary levels of PAI-1 protein in combination with other markers resulted in higher sensitivity and specificity in detecting bladder cancer. In human kidney mesangial cells, the thromboxane A2 (TP) receptor agonist stimulation increased PAI-1 mRNA and protein. Our lab indicated that TP receptor is highly expressed in bladder cancer tissues and inversely correlated with patients` survival. We also indicated the TPβ isoform can induce malignant transformation in immortalized non-transformed urothelial cells. Our published data indicated that U46619 dependent stimulation of cell migration is β-arrestin-2 dependent. The purpose of the current study is to investigate the mechanism whereby TP stimulation regulates PAI-1 expression. The protein levels of PAI-1 were found to be increased in bladder cancer cells following stimulation with TP agonist (U46619). Tetracycline inducible shRNA knock-down of β-arrestin-2 resulted in a significant reduction of PAI-1 protein, but not mRNA in bladder cancer cells and also resulted in a significant reduction of trans-well cell migration and invasion. Our data suggest that the agonist mediated increase in PAI-1 is regulated at the post-transcriptional level. The role of β-arrestin-2 KD on agonist dependent stimulation remains to be determined.
Citation Format: Philip M. Sobolesky, Tanyau Zhou, Arielle Gorstein, Julie A. Woolworth, Omar Moussa. β-arrestin-2 mediated regulation of plasminogen activator inhibitor Type 1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4070. doi:10.1158/1538-7445.AM2013-4070