bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3899: ROCK inhibitor as a differentiation-inducing agent to target glioma stem cells
Authors: Auffinger Brenda , Tobias Alex L. , Han Yu , Lesniak Maciej S. , Ahmed Atique U. 
Published: May 2015

Abstract
Only 3% of patients diagnosed each year with Glioblastoma Multiforme (GBM) survive longer than 5 years, making GBM one of the most lethal forms of human cancer. It has been proposed that GBMs are driven by a rare subset of tumor cells referred to as cancer stem cells (CSCs), which have the ability to resist conventional radio- and chemotherapy and initiate disease recurrence. Thus, the development of novel and effective therapeutic strategies targeting CSCs is required and should significantly improve the dismal prognosis for patients with GBM. A possible viable strategy to effectively target glioma stem cells (GSCs) is the use of bone morphogenetic proteins (BMPs) as differentiation inducers. Our results suggest that Rho-associated protein kinase (ROCK) could work as a pharmacological negative regulator of BMPs. Our preliminary data indicate that: i) Fasudil, a ROCK1 inhibitor, induces BMP2 and BMP4 expression both in vitro and in vivo in different human-derived glioma xenograft models; ii) Fasudil-induced BMPs can increase the expression of differentiation markers and decrease stemness in these glioma models; iii) temozolomide, a chemotherapeutic agent, converts glioma cells to a GSC phenotype, while Fasudil blocks this interconversion; iv) co-administration of Fasudil with temozolomide inhibits the invasive characteristics of GBM in an orthotropic glioma xenograft model; and v) the analysis of BMP expression in human-derived GBM samples from the Repository of Molecular Brain Neoplasia Database (REMBRABDT) reveals that patients with higher BMP2 expression survived four times longer than those with low or intermediate BMP2 expression (p&lt;0.001). Based on this, we propose that, by blocking ROCK signaling with the FDA approved pharmacological inhibitor Fasudil, one can modulate BMP expression in human-derived gliomas. Fasudil, therefore, may redirect cellular signals regulating GSCs' stemness, fate, and initiate their differentiation. Such an agent will allow us to develop a more effective anti-glioma therapy through its combination with other conventional anti-cancer drugs.
Citation Format: Brenda Auffinger, Alex L. Tobias, Yu Han, Maciej S. Lesniak, Atique U. Ahmed. ROCK inhibitor as a differentiation-inducing agent to target glioma stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3899. doi:10.1158/1538-7445.AM2014-3899
Abstract 391: Identification of a novel tumor-suppressor gene through methylome analysis in smoking-associated lung adenocarcinoma
Authors: Imoto Issei 
Published: May 2015

Abstract
Aberrant methylation of promoter DNA and transcriptional repression of specific tumor suppressor genes (TSGs) play an important role in carcinogenesis. In order to identify novel TSG candidates implicated in smoking-associated lung adenocarcinoma (AC), we performed genome-wide methylation profiling of six smoking-associated lung ACs with paired non-cancerous tissues using the single-CpG resolution Infinium array. After defining differentially methylated candidates including known targets in ACs, we analyzed gene expression using microarray/RT-PCR to identify genes potentially silenced by promoter methylation. Frequent hypermethylation and downregulation of candidates was further validated by pyrosequencing and RT-PCR/immunohistochemistry, respectively, in a larger set of ACs, and methylation dependency of silencing was determined by 5-aza-2-deoxycytidine treatment and promoter assay in AC cell lines. Through this approach, we identified one gene matching all of our selection criteria for a possible TSG (HSLAC1, Lab. name). Additionally, functional analyses supported a tumor-suppressive activity in vitro. Our results implicate HSLAC1 as a novel TSG for smoking-associated lung AC.
Citation Format: Issei Imoto. Identification of a novel tumor-suppressor gene through methylome analysis in smoking-associated lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 391. doi:10.1158/1538-7445.AM2014-391
Abstract 3910: Identification of lead organic compounds active against stem cell-like neuroblastoma cells by high throughput screening
Authors: Ikegaki Naohiko , Ratia Kiira , Hsiao Ruth , Limpar Mariko M. , Lomahan Sarah , Tang Xao X. 
Published: May 2015

Abstract
Cancer stem cells (CSCs) are plastic in nature, a characteristic that hampers cancer therapeutics. We previously reported the establishment of induced neuroblastoma (NB) stem cells (iCSC), which were stable stem cell-like NB cells in sphere culture. These cells recapitulated the in vivo histological phenotypes of Large-Cell NB (LCN), the most aggressive and deadly subset of NB, including vesicular nuclei and two to three prominent nucleoli (PNAS Vol. 110: 6097-102 2013). In addition to the LCN phenotype, high-level expression MYC or MYCN is the consistent feature of the iCSC xenografts grown in immune-compromised mice. The goal of this study is to identify lead organic compounds active against NB iCSCs by high throughput screening. By using MTS assays, the SKNAS iCSC and the parental monolayer cells were used to screen the Prestwick Chemical Library®, containing 1200 FDA-approved small molecules. Growth suppressive compounds were defined as they exhibited cell survival reduction of greater than 80% compared to DMSO control. There were unexplored compounds with significant antineoplastic activity among existing antibacterial, antifungal, antiprotozoal, and anthelmintic compounds. Among the compounds screened, we identified a dozen of small molecules that were preferentially growth suppressive to the SKNAS iCSC over the monolayer cells. The secondary MTS assay confirmed so far that Chlorhexidine (antiseptic), Benzethonium (antiseptic) and Digoxin (cardiac glycoside) were potential anti-NB iCSC agents: they were more effective in suppressing growth of the SKNAS iCSC than the monolayer cells. In addition, these compounds exhibited MYC destabilizing activity in the SKNAS iCSC. Notably, JQ1, the recently identified MYC destabilizer, was less effective than Chlorhexidine, Benzethonium and Digoxin in suppressing growth of SKNAS iCSC. The above three compounds also showed the MYCN destabilizing effect in another pair of MYCN-amplified SKNBE(2)C iCSCs and SKNBE(2)C monolayer cells. We are currently completing characterization of the small molecules identified with focus on their anti- iCSC growth and anti-MYC/MYCN effects. This study would reveal specific pathways that regulate biological activities of the CSCs. In addition, it is a promising approach that could lead to development of safe and effective anti-cancer therapeutics not only for NB but also other cancer types.
Citation Format: Naohiko Ikegaki, Kiira Ratia, Ruth Hsiao, Mariko M. Limpar, Sarah Lomahan, Xao X. Tang. Identification of lead organic compounds active against stem cell-like neuroblastoma cells by high throughput screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3910. doi:10.1158/1538-7445.AM2014-3910
Abstract 3917: Understanding the mechanisms driving pancreatic neuroendocrine tumorigenesis
Authors: Wasylishen Amanda R. , Lozano Guillermina 
Published: May 2015

Abstract
A recent exome sequencing study of pancreatic neuroendocrine tumors (PanNETs) provided valuable information about the genetic landscape of these cancers and for the first time implicated DAXX and ATRX loss in tumorigenesis. These interacting proteins are chaperones for the histone variant H3.3 and contribute to chromatin homeostasis and telomere maintenance. Mutually exclusive mutations in DAXX or ATRX occur in 43% of PanNETs. To understand how loss of these epigenetic regulators specifically contributes to tumorigenesis, we are developing genetically engineered mouse models of PanNETs. While a mouse with a conditional Daxx allele is publically available, subsequent sequencing and characterization revealed a mutant loxP site, which renders recombination extremely inefficient. We are, therefore, currently generating a new conditional Daxx allele, as well as using an existing conditional Atrx allele to specifically delete these genes in the endocrine pancreas. Cohorts of mice are being built and followed for developmental and tumor phenotypes. In addition, in vitro studies have also implicated a role for DAXX as a negative regulator of the p53 tumor suppressor pathway. Interestingly, p53 is rarely mutated in PanNETs. We are using a Daxx-null allele, generated using the existing conditional Daxx mouse, to investigate the relationship between DAXX and the p53 pathway in vivo. Combined, this work aims to generate and characterize mouse models which will lead to a better understanding of both the etiology of PanNETs and how loss of DAXX and ATRX contribute to tumorigenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Amanda R. Wasylishen, Guillermina Lozano. Understanding the mechanisms driving pancreatic neuroendocrine tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3917. doi:10.1158/1538-7445.AM2014-3917
Abstract 3925: The PIK3CA
H1047R mutation can initiate tumorigenesis in the colon
Authors: Pasch Cheri , Maher Molly , Deming Dustin 
Published: May 2015

Abstract
Background: Our understanding of how mutations within the intestinal epithelium result in tumor development and progression is continuously evolving. We have previously described the FC PIK3ca* murine colon cancer model which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K resulted in invasive mucinous adenocarcinomas in the proximal colon through a non-canonical mechanism. We sought to determine if the hotspot PIK3CA H1047R mutation, commonly found in human colorectal cancers, can also induce intestinal tumorigenesis.
Methods: Female FVB mice carrying a conditional PIK3CA H1047R mutation (PIK3CAH1047R) were crossed to B6 males carrying atransgene in which the fatty acid binding protein promoter is fused to Cre recombinase (FC). (FVB x B6)F1 FC PIK3CAH1047R progeny express this constitutively active form of PI3K in epithelial cells of the distal small bowel and colon. 22 F1 FC PIK3CAH1047R mice were examined. Necropsy was performed at approximately 200 days of age or once moribund.
Results: 50% of FC PIK3CAH1047R mice develop invasive adenocarcinomas within the colon. These cancers are highly mucinous and often penetrate through the serosal layer of the colon. These lesions can be found throughout the colon, but are more common proximally. No tumors were identified within the small intestine. These cancers can have associated invasion into the regional lymphatics and metastases to the mesentery. Interestingly these cancers have a minimal luminal component compared to the amount of submucosal extension. Precursor lesions are able to be identified and are not polypoid. These cancers demonstrate activation of the AKT signaling pathway, but do not demonstrate nuclear localization of β-catenin.
Conclusion: This is the first report of the hotspot PIK3CA H1047R mutation leading to intestinal tumorigenesis through a non-canonical mechanism, resulting in flat mucinous invasive adenocarcinomas.
Citation Format: Cheri Pasch, Molly Maher, Dustin Deming. The PIK3CAH1047R mutation can initiate tumorigenesis in the colon. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3925. doi:10.1158/1538-7445.AM2014-3925
Abstract 3977: Molecular reprogramming in high-risk progressive neuroblastoma
Authors: Pandian Vijayabaskar , Khan Faizan H. , Ramraj Satish K. , Aravindan Sheeja , Natarajan Mohan , Herman Terence S. , Aravindan Natarajan 
Published: May 2015

Abstract
High risk disease in infants with neuroblastoma significantly contributes to the pediatric cancer death. We investigated the molecular reprogramming in neuroblastoma cells that drives favorable neuroblastoma to aggressive disease. For this, multi-site aggressive tumors from animals that received parental (SH-SY5Y) cell xenotransplantation were assayed and compared to the animals with subtle non-metastatic xenografts. Establishment of highly malignant neuroblastoma cell line (NBP4) and its comparative (with SH-SY5Y) cytogenetic/phenotypic physiognomies were reported elsewhere. Ex vivo whole genome gene expression identified a total of 33 genes upregulated and another 33 genes downregulated (&gt;40 fold change) in NBP4 cells as opposed to parental SH-SY5Y cells. QPCR analysis revealed a conforming upregulation of SEMA3D, MEGF10, GRB10 and suppression of RD3 in multi-site aggressive tumors. Tissue microarray (72 core) constructed with aggressive multiple tumors and non-progressive controls coupled with immunohistochemistry showed robust levels of SEMA3D, GRB10, MEGF10 and complete loss of KCNQ2, KRTAP1-1 and RD3. Consistently, translational modifications of SEMA3D, GRB10, MEGF10, KCNQ2 and RD3 in multi-site aggressive tumors were validated with immunoblotting. More importantly, selective knockdown of KCNQ2 or KRTAP1-1 in parental SH-SY5Y cells robustly modified the cellular phenotype and significantly increased the tumorosphere formation. Conversely, discrete muting of GRB10, KIAA2022, MEGF10 or SEMA3D ex vivo (in aggressive NBP4 cells) endorsed the cellular differentiation, adherence and resulted in complete regulation of tumorosphere formation. Together, these data suggests that the milieu based molecular reprograming of the neuroblastoma cells drives the development of high-risk disease and further implies that GRB10, KIAA2022, MEGF10, SEMA3D, RD3 and KCNQ2 may concert and orchestrate the disease progression. Signal flow-through and molecular driver(s) that orchestrate favorable to high-risk disease are yet to be understood and are currently in progress in our laboratory.
Citation Format: Vijayabaskar Pandian, Faizan H. Khan, Satish K. Ramraj, Sheeja Aravindan, Mohan Natarajan, Terence S. Herman, Natarajan Aravindan. Molecular reprogramming in high-risk progressive neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3977. doi:10.1158/1538-7445.AM2014-3977
Abstract 398: Epigenetic changes in testis specific Y-like 5 gene in human prostate carcinoma: Gene expression analysis and its potential as a biomarker
Authors: Kumar Senthil R. , Bryan Jeffrey , Esebua Magda 
Published: May 2015

Abstract
INTRODUCTION
Testis specific Y-like protein (TSPYL-5) is a member of TSPY-L family of gene, whose functions are currently unknown. TSPYL-5 was reported to possess tumor suppressor function and a target for epigenetic silencing in human glioblastoma and colon carcinoma. The exact nature of TSPYL-5 gene expression and its epigenetic modification is not known in prostate carcinoma. We hypothesize that this gene could be expressed in prostate carcinoma cells and tissues and its methylation status could function as an epigenetic biomarker for aggressive prostate cancer phenotype.
MATERIALS AND METHODS
Human prostate carcinoma cells (PC3, DU145, LnCAP) was grown in DMEM-F12 media with 10% FBS at 37oC. Normal prostate epithelial cells (RWPE1-) were maintained in keratinocyte serum free media. Total RNA was extracted from the cells and converted to cDNA which served as a template for PCR amplification in the presence of TSPYL-5 gene primers. The amplified PCR products were analyzed by 2% agarose gel electrophoresis. Methylation-specific PCR (MSP) was performed with primers designed for the CpG island in the gene promoter to detect the methylation changes in the carcinoma cells.
RESULTS
Quantitative RT-PCR analysis of TSPYL-5 gene expression in different human prostate carcinoma cells lines identified 2-3 fold higher expression (P ≤ 0.005) in lines with metastatic propensity (PC3) compared to less aggressive ones. MSP analysis indicated differential promoter methylation of TSPYL-5 gene in carcinoma and normal prostate epithelial cells (RWPE1). Consistent methylation in LnCAP and DU145 cells was observed in our experiments and was associated with reduced expression of the gene.
CONCLUSIONS
Expression of TSPYL-5 is higher in human prostate carcinoma cells derived from more metastatic phenotype. This expression could be influenced by DNA methylation. It is not clear whether TSPYL-5 expression in prostate carcinoma cells could play a part in tumor suppressor function. Alternately, the presence of this gene may play alternate roles including treatment resistance and cell growth. Further, DNA methylation of the CpG island of TSPYL-5 could serve as a robust biomarker of aggressive phenotype in human prostate carcinoma.
Citation Format: Senthil R. Kumar, Jeffrey Bryan, Magda Esebua. Epigenetic changes in testis specific Y-like 5 gene in human prostate carcinoma: Gene expression analysis and its potential as a biomarker. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 398. doi:10.1158/1538-7445.AM2014-398
Abstract 3991: Increased expression of cancer stem cells markers (CD44, CD90 and CD133) contributes to disease progression and reduced survival in hepatoblastoma patients from Egypt: four years survival data
Authors: Zekri Abdel-Rahman N. , Bahnassy Abeer A. , Fawzy Mohamed , El-Wakil Mohamed , Abdel-Sayed Ahmed , Sheta Marwa E. 
Published: May 2015

Abstract
Background: Hepatoblastoma (HB) is an embryonal tumor of the liver that occurs in infants and young children. Complete surgical resection and cisplatin-containing chemotherapy are crucial for cure in HB. Cancer stem cells (CSCs) constitute a newly identified subpopulation, which may differentiate into heterogeneous progenies of malignant cells. The aim of this study is to assess the prognostic and predictive values of CSCs markers (CD133, CD90 and CD44) in a cohort of HB patients from Egypt.
Methods: Disease status was evaluated for 43 HB patients at the main checkpoints of therapy and during follow-up. Protein and RNA expressions of CD44, CD 90 and CD 133 were assessed by immunohistochemistry and quantitative real time (qPCR).
Results: OS for all patients at 4 years was 58.2. OS significantly correlated with disease stages (stage I&II versus III&IV 81.9% and 30%, p&lt;0.001); tumor response (p&lt;0.001); CD44, CD 90, CD 133 expression (p&lt;0.001) versus treatment modality (total surgical resection versus incomplete or no resection, 83.8% versus 25.2 %; p&lt;0.001). Reduced DFS was associated with CD44 and CD133 expression (p&lt;0.001) only.
Conclusion: Complete surgical resection and systemic chemotherapy significantly improve outcome in HB with a significantly higher survival rates among patients with early stage disease. Expression of CSCs markers (CD133, 44, and 90) can predict poor outcome in HB patients with reduced OS and DFS rates. However further studies are required to confirm their prognostic and potential targeted therapy value.
Citation Format: Abdel-Rahman N. Zekri, Abeer A. Bahnassy, Mohamed Fawzy, Mohamed El-Wakil, Ahmed Abdel-Sayed, Marwa E. Sheta. Increased expression of cancer stem cells markers (CD44, CD90 and CD133) contributes to disease progression and reduced survival in hepatoblastoma patients from Egypt: four years survival data. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3991. doi:10.1158/1538-7445.AM2014-3991
Abstract 4003: Clinical and biological significance of CXCR6 in lung cancer
Authors: Mir Hina , Gupta Pranav , Singh Rajesh , Sharma Praveen K. , Kaur Gurpreet , Ward Ashley B. , Grizzle William E. , Lillard James W. , Singh Shailesh 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer related deaths worldwide in both men and women. Metastasis is responsible for most lung cancer related deaths; therefore, a better understanding of the metastatic processes and therapies designed to prevent the spread of cancer cells are greatly needed. The specific mechanisms that promote metastases have not been fully elucidated. Among all known chemokine receptors involved in cancer progression, most cancer cells including lung cancer express CXCR4. Furthermore, involvement of CXCR4 and CCR7 in breast cancer and CXCR4, CCR9 and CX3CR1 in prostate cancer progression further indicates that multiple chemokine receptors are involved in dictating the multi-step process of metastasis. In this study, we show significantly higher expression of CXCR6 and CXCL16 in lung cancer tissues compared to normal matched tissues. Expression of CXCR6 was significantly higher in adeno- carcinoma compared to squamous cell carcinoma. It addition to these, serum levels of CXCL16, the only natural ligand for CXCR6, was also significantly higher in lung cancer patients compared to normal healthy donor. Furthermore, serum CXCL16 was also significantly higher in patients with adenocarcinoma compared to patients with squamous cell carcinoma. Impact of this chemokines-receptor axis was determined in lung cancer cell lines in vitro, which express CXCR6 and CXCL16. Like tissues, lung cancer cells showed higher expression of CXCR6 and CXCL16 compared to normal lung epithelial cells (NuLi-1). Interestingly, expression of CXCR6 was highest in cell lines derived form adenocarcinoma followed by cell lines from squamous cell carcinoma. Furthermore, we demonstrate that CXCR6 and soluble CXCL16 interaction plays a crucial role in lung cancer cells migration and invasion. The mechanism underlying these clinically and biologically important findings need to be further explored. Increased serum CXCL16 in lung cancer patients with metastatic disease required further validation as a potential therapeutic target and/or diagnostic marker for lung cancer.
Citation Format: Hina Mir, Pranav Gupta, Rajesh Singh, Praveen K. Sharma, Gurpreet Kaur, Ashley B. Ward, William E. Grizzle, James W. Lillard, Shailesh Singh. Clinical and biological significance of CXCR6 in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4003. doi:10.1158/1538-7445.AM2014-4003