bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3116: NF-κB2/p52 induces expression of inflammatory mediators in prostate cancer in vivo.
Authors: Nadiminty Nagalakshmi , Tummala Ramakumar , Lou Wei , Evans Christopher P. , Gao Allen C. 
Published: August 2014

Abstract
Introduction and objective: Inflammation plays a key role in the etiology of carcinoma of colon, cervix or liver, but PCa, in which inflammation has not been deemed to play a causative role, also display a pro-inflammatory gene profile. NF-κB is central to the induction of inflammation and the classical and alternative NF-κB activation pathways have been shown to modulate expression of inflammatory mediators. Here we explored the induction of markers of tumor-infiltrating inflammatory cells in two in vivo models overexpressing NF-κB2/p52.
Methods: LNCaP human PCa cells were infected with adenoviruses encoding empty vector or NF-κB2/p52 and injected s.c. into both flanks of nude mice. Gene expression of markers of inflammatory mediators such as macrophages, lymphocytes and dendritic cells was analyzed in the tumor tissues by qRT-PCR. In addition, whole prostates were collected from transgenic mice expressing NF-κB2/p52 in the prostate and RNA was analyzed for inflammatory markers. Expression of the cell surface markers was validated by immunohistochemistry in sections of whole prostates.
Results: The infiltration of host immune cells into the xenograft tissues was detected by expression of surface markers of cells of myeloid and lymphoid lineage. The expression of B220 (B cells), F4/80 (activated macrophages), Cd8A (CTL) was increased in p52-expressing xenografts compared to controls, indicating the presence of host-derived inflammatory cells in the xenografts. Expression levels of chemokines (Cxcl1), chemokine receptors (Ccr1, Ccr3) and pro-inflammatory cytokines (Il-6 and Tnf) were enhanced in the xenografts compared to the controls, indicating that expression of NF-κB2/p52 induces an inflammatory response in xenografts of human PCa cells.
Compared to littermate negative controls, expression of B220, F4/80, Cd8A and Cd208 was increased in transgenic mouse prostates expressing p52. Furthermore, expression levels of Cxcl1, Ccr1, Ccr3, Il-6 and Tnf were also enhanced compared to controls, indicating the induction of inflammation in mouse prostates by NF-κB2/p52.
Conclusions: Our previous studies have shown that NF-κB2/p52 plays an important role in the development of castration resistance in human PCa cells. In this study we showed that NF-κB2/p52 may induce an inflammatory response in xenografts of human PCa cells or in transgenic mouse prostates, and thereby promote tumor proliferation.
Citation Format: Nagalakshmi Nadiminty, Ramakumar Tummala, Wei Lou, Christopher P. Evans, Allen C. Gao. NF-κB2/p52 induces expression of inflammatory mediators in prostate cancer in vivo. [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 3116. doi:10.1158/1538-7445.AM2013-3116
Abstract 3130: Dependency on c-MYC in multiple myeloma.
Authors: Holien Toril , Våtsveen Thea K. , Hella Hanne , Waage Anders , Sundan Anders 
Published: August 2014

Abstract
The oncogene c-MYC is deregulated in multiple myeloma. Importantly, the activity of c-MYC is elevated in plasma cells in patients with myeloma compared to the premalignant state monoclonal gammopathy of undetermined significance, indicating a prominent role for c-MYC in myeloma pathogenesis. We earlier found the bone morphogenetic proteins induce apoptosis in myeloma cell lines and primary cells by SMAD-dependent downregulation of c-MYC. Repression of c-MYC by short hairpin RNA in myeloma cell lines has by others also been shown to induce apoptosis. We wanted to go one step further and study the role of c-MYC in primary myeloma cells. Transcriptional regulation by c-MYC requires heterodimerization of c-MYC and its obligate partner MAX. The small molecular inhibitor 10058-F4 disrupts the formation of such heterodimers and was used in vitro to test the dependency on c-MYC activity in primary myeloma cells and myeloma cell lines. The inhibitor induced apoptosis in a dose-dependent manner in the 22 primary samples tested. Apoptosis was induced in five of six cell lines tested. The sixth cell line, U266, does not express c-MYC, and was not sensitive to the inhibitor. Using the INA-6 myeloma cell line, we found that apoptosis induced by 10058-F4 correlated with downregulation of the anti-apoptotic protein Bcl-xL. We also found that apoptosis was induced by the inhibitor even in the presence of bone marrow stromal cells derived from myeloma patients. Our results further support that c-MYC is a potential target for therapy in multiple myeloma.
Citation Format: Toril Holien, Thea K. Våtsveen, Hanne Hella, Anders Waage, Anders Sundan. Dependency on c-MYC in multiple myeloma. [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 3130. doi:10.1158/1538-7445.AM2013-3130
Abstract 3131: Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation.
Authors: Gao Lina , Schwartzman Jacob , Gibbs Angela , Kleinschmidt Richard , Wilmot Beth , Bottomly Daniel , Coleman Ilsa , Nelson Peter , McWeeney Shannon , Alumkal Joshi J. 
Published: August 2014

Abstract
Prostate cancer is the most common cancer in men in the United States and the second leading cause of cancer death. The androgen receptor (AR) is the central signaling pathway in prostate cancer. Because of this, androgen deprivation therapy (ADT), which involves reducing levels of androgen ligands or interfering with binding of ligands to AR, has been the major therapeutic focus for the past 70 years. However, in many patients there is no benefit from ADT, and all prostate cancers eventually progress. At progression on ADT, the AR is ubiquitously expressed. For this reason, we contend that AR-dependent mechanisms are critical for prostate cancer progression after ADT. Indeed, recent work demonstrates that the AR can function independently of ligands to promote prostate cancer cell survival. However, specific ligand-independent AR target genes that account for this effect were not well-characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer progression, is a key ligand-independent AR target gene.
Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-tumor activity of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer - AR and c-Myc - and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control.
Citation Format: Lina Gao, Jacob Schwartzman, Angela Gibbs, Richard Kleinschmidt, Beth Wilmot, Daniel Bottomly, Ilsa Coleman, Peter Nelson, Shannon McWeeney, Joshi J. Alumkal. Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation. [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 3131. doi:10.1158/1538-7445.AM2013-3131
Abstract 3151: High-throughput RNAi screening identifies a novel metastatic melanoma drug target in the context of PTEN mutation.
Authors: Yin Holly , Chow Donald , Sereduk Chris , Aziz Meraj , Kim Seungchan , Brown Kevin M. , Trent Jeffrey M. 
Published: August 2014

Abstract
It has become increasingly important to identify targeted therapy in a defined molecular context. Here we will present our data which suggests TERT, a telomerase reverse transcriptase, serves as a novel drug target in melanoma in the context of PTEN mutation. PTEN is mutated in ∼15% of melanoma patients. Genomic RNA-interference (RNAi) technology was applied for synthetic lethality screens in an effort to identify the targets which upon knock-down significantly decrease cell viability specifically in the context of somatic mutations of the PTEN gene. We carried out such screen in a panel of 15 melanoma cell lines, including four PTEN mutated cell lines, against an siRNA library covering the kinome (∼700 genes with 4 siRNA per target) using CellTiter Glo as the endpoint to measure cell viability. Lethal genes, which decreased cell viability significantly upon knockdown, were initially identified for each cell line. Then the hit lists were compared between wild-type PTEN and mutant PTEN using a chi-square test, a statistical analysis. 29 gene candidates were selected for hit confirmation using the same set of siRNA, among which 24 genes were confirmed as potential PTEN synthetic lethal candidates, this results in a high confirmation rate of 83%. Based upon its association with melanoma risk (Law et al, J Invest Dermatol, 2012), We further validated TERT using a commercially available small molecule inhibitor. This inhibitor has significantly higherpotency in the PTEN mutant context (average IC50 of 0.34uM) compared to PTEN wild-type background (average IC50 of 0.75uM). This result both validates our RNAi screening results, but more importantly, this compound can serve as an initial structure scaffold for further optimization towards development as a novel drug for metastatic melanoma patients who carry PTEN mutations. Evaluation of more TERT inhibitors in a diverse panel of melanoma cell lines is presently underway.
Citation Format: Holly Yin, Donald Chow, Chris Sereduk, Meraj Aziz, Seungchan Kim, Kevin M. Brown, Jeffrey M. Trent. High-throughput RNAi screening identifies a novel metastatic melanoma drug target in the context of PTEN mutation. [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 3151. doi:10.1158/1538-7445.AM2013-3151
Abstract 3159: Modulating therapeutic targets in B-cell lymphoma: Loss-of-function RNAi screen for CD20 regulators.
Authors: Slabicki Mikolaj , Sellner Leopold , Jethwa Alexander , Boettcher Michael , Zenz Thorsten 
Published: August 2014

Abstract
The surface glycoprotein CD20 is expressed on healthy and malignant B-cells and can be therapeutically exploited by monoclonal antibodies (e.g. Rituximab, Ofatumumab, GA-101). Stem cells and pro-B-cells are lacking CD20 surface protein, which allows the reestablishment of B-cell populations after treatment. Other cell lineages do not express CD20. Rituximab has revolutionized clinical practice in the treatment of malignant B-cell lymphoma. However, refractory lymphoma cells can lose the expression of CD20 after Rituximab exposure and B-cell lymphoma with low CD20 surface expression may be less responsive to treatment. Despite the widespread use of CD20 antibodies across lymphoma subtypes, little is known about the endogenous regulation of CD20. It was shown that several chemical compounds may modulate the surface density of CD20 (e.g. histone deacetylase inhibitors), but the regulatory network controlling CD20 levels is not understood. We aim to dissect the CD20 regulatome and to exploit the findings for novel therapeutic strategies.
The CD20 regulatome is studied in a Burkitt lymphoma cell line (Raji) characterized by medium expression of CD20 in comparison to other lymphoma models. As a proof of principle, we were able to down-regulate the surface expression of CD20 assayed by FACS with four independent silencing triggers targeting CD20 mRNA. To discover novel regulators of CD20 expression, we performed an unbiased genome-wide RNAi screen. The screen hits are involved in diverse molecular mechanisms such as signaling, trafficking, chromatin remodeling and membrane composition.
The group of genes decreasing the expression of CD20 expression can provide an insight into the physiological and pathological machinery involved in CD20 trafficking and processing. The strongest hit in this group, next to CD20 knockdown, is potentially involved in the direct transport of CD20 to the cell surface. Clinically most relevant is the group of genes where silencing increases the expression of CD20. The two strongest hits in this category are a transcription factor and a gene involved in signaling. Detailed molecular characterization of several chosen hits is currently ongoing. Their inhibition may lead to increased sensitivity to anti-CD20 antibodies and thus provide starting points for rational drug design.
Citation Format: Mikolaj Slabicki, Leopold Sellner, Alexander Jethwa, Michael Boettcher, Thorsten Zenz. Modulating therapeutic targets in B-cell lymphoma: Loss-of-function RNAi screen for CD20 regulators. [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 3159. doi:10.1158/1538-7445.AM2013-3159
Abstract 3174: A real-time qPCR approach to detect fusions between the KIF5B and RET genes in non-small cell lung cancer.
Authors: Bell Katherine , Gaffney Dana , Martinez Gabriela , Platero Suso , Karkera Jayaprakash 
Published: August 2014

Abstract
Lung cancer is the leading cause of death in cancer worldwide. There are two major forms of lung cancer, including small cell lung cancer (SCLC) which accounts for approximately 20% of all lung cancers and non-small cell lung cancer (NSCLC) which accounts for approximately 80% of lung cancers. Around 25% of these lung cancer patients are never smokers and these cancers tend to be the result of single somatic mutation events. Several somatic events have been reported in NSCLC, including mutations in EGFR and KRAS along with an EML4-ALK fusion gene, however more than 40% of these cancers are the result of unknown genetic events. Recently several papers have reported a novel fusion gene resulting from a 10.6 Mb inversion on chromosome 10 which leads to a fusion between the KIF5B and RET genes. The RET gene is a well-known tyrosine-kinase proto-oncogene which has been linked to papillary thyroid carcinomas and its expression is generally very low in lung. RET tyrosine kinase stimulates autophosphorylation of the tyrosine kinase unit which activates several pathways including STAT3, RAS/ERK, MAPK, PI3K/AKT and SRC. In the KIF5B-RET fusion KIF5B retains its coiled-coil domain necessary for homodimerization and the RET retains its kinase function leading to aberrant activation of several kinase pathways. Several fusion genes between the exons of KIF5B and RET have been previously reported including KIF5B15:RET12, KIF5B16:RET12, KIF5B22:RET12, KIF5B23:RET12, KIF5B15:RET11, KIF5B24:RET8 and KIF5B24:RET11. In this study we developed a TaqMan qRT-PCR-based approach to evaluate the expression of these seven (7) KIF5B-RET fusion transcripts in 64 NSCLC fresh frozen biopsies, ranging from stage I to stage III, including 25 adenocarcinoma and 37 squamous cell carcinoma samples, respectively. Our findings confirm the presence of the fusion between KIF5B15 (exon 15) and RET12 (exon 12) at a frequency of 1.56% in all subtypes. The clinicopathological background of the KIF5B/RET fusion-positive patient agrees with previously reported trends for this fusion event consisting of a caucasian female, non smoker, with adenocarcinoma subtype. Although this percentage is relatively small, it still represents around 12,000 individuals worldwide that express this fusion transcript, presenting a promising biomarker for targeted therapeutics in the treatment of NSCLC disease.
Citation Format: Katherine Bell, Dana Gaffney, Gabriela Martinez, Suso Platero, Jayaprakash Karkera. A real-time qPCR approach to detect fusions between the KIF5B and RET genes in non-small cell lung cancer. [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 3174. doi:10.1158/1538-7445.AM2013-3174
Abstract 3185: The eSNV-Detect: a computational system to identify expressed single nucleotide variants from tumor transcriptomes.
Authors: Tang Xiaojia , Baheti Saurabh , Shameer Khader , Thompson Kevin J. , Kocher Jean-Pierre , Perez Edith A. , Thompson Aubrey E. , Kalari Krishna R. 
Published: August 2014

Abstract
MOTIVATION: Transcriptome sequencing (RNA-seq) is the most economical and information-rich next generation sequencing technology to study genomic medicine. Genomic features such as gene expression, transcript expression, fusion transcripts, long non-coding RNAs and expressed single nucleotide variants (eSNVs) can be obtained from RNA-seq data. There are several computational workflows to obtain gene counts, transcript counts and fusion gene candidates, but not a comprehensive system to identify expressed SNVs from RNA-sequencing data.
METHODS: We have developed a novel computational system (The eSNV-Detect) with parallel alignment strategies to identify expressed SNVs accurately from tumor transcriptome sequencing data. Sequence-based features like reads supporting reference allele, alternate allele, ratio of alternate reads to total read depth, base qualities, mapping qualities, forward strand and reverse strand supporting reads etc. along with a variety of databases such as dbSNP, 1000 genome, 5400 exome, refGene, avsift, ljb_phylop from UCSC were used to call SNVs from RNA-sequencing data. For the expressed SNVs detected in tumors, we can also identify the amino acid change and classify the protein domains using our method.
RESULTS: We have applied the eSNV-Detect method to call novel expressed SNVs in two tumors (one HER2 positive and one ER positive breast tumor). BWA and Bowtie were used to align the two breast tumors. Several filtering criteria's were applied to the tumors to remove any known (germ line) or low confidence SNVs. We randomly selected 83 and 31 eSNVs for the HER2 and ER positive tumors respectively and performed Sanger sequencing validation in tumor and matched normal tissues of the tumor. We were able to validate 81 out of 83 eSNVs in the HER2 tumor sample, and 29 out of 31 eSNVs in the ER positive tumor sample. Of the eSNVs that we validated 39/81 and 10/31 were localized to functional protein domains in HER2 and ER positive tumors respectively. We are also in the process of validating eSNVs detected from RNA-seq with the tumor and blood exome sequencing data we have for the same patients.
Citation Format: Xiaojia Tang, Saurabh Baheti, Khader Shameer, Kevin J. Thompson, Jean-Pierre Kocher, Edith A. Perez, Aubrey E. Thompson, Krishna R. Kalari. The eSNV-Detect: a computational system to identify expressed single nucleotide variants from tumor transcriptomes. [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 3185. doi:10.1158/1538-7445.AM2013-3185
Abstract 3194: Tristetraprolin controls the stability of uPA/uPAR mRNA through binding to the 3’UTR of uPA/uPAR mRNA in U87MG glioma cells.
Authors: Ryu Jinhyun , Choi Jungil , Lee Dong Hoon , Roh Gu Seob , Kim Hyun Joon , Cho Gyeong Jae , Choi Wan Sung , Park Jae-Yong , Park Jeong Woo , Kang Sang Soo 
Published: August 2014

Abstract
Malignant gliomas are one of the most common primary intrinsic brain tumors. In particular, glioblastoma multiforme (GBM), WHO grade IV, is highly invasive. Because of its high invasiveness, patients with unresectable GBM have a poor prognosis and have median survival of only a few months. The invasiveness of glioma depends on proteolysis of the extracellular matrix, a complex event occurring through the surrounding tissue during tumor cell invasion. Urokinase plasminogen activator (uPA) and its specific receptor (uPAR) play a major role in the infiltrative growth of glioblastoma. Tristetraprolin (TTP or ZFP36) is a tandem CCCH zinc-finger RNA-binding protein that regulates the stability of certain AU-rich element (ARE) mRNAs. Recent work reports that TTP is deficient in many cancer cells when compared with normal cell types. Moreover, the lack of TTP is associated with a variety of cancer-related processes. In the present study, we investigated the post-transcriptional regulation of uPA/uPAR expression by the tristetraprolin (TTP) in U87MG human glioma cells. Here, we showed that the overexpression of TTP decreased the stability of uPA/uPAR mRNA and the expression level of uPA/uPAR protein. uPA/uPAR mRNA include AU-rich elements (AREs) within the 3’-untranslated region, and TTP destabilized a luciferase mRNA containing uPA/uPAR AREs. In addition, TTP inhibits cell invasion in U87MG glioma cells. Present study demonstrates that TTP suppress the progression of glioma through the regulation of uPA/uPAR mRNA stability.
Citation Format: Jinhyun Ryu, Jungil Choi, Dong Hoon Lee, Gu Seob Roh, Hyun Joon Kim, Gyeong Jae Cho, Wan Sung Choi, Jae-Yong Park, Jeong Woo Park, Sang Soo Kang. Tristetraprolin controls the stability of uPA/uPAR mRNA through binding to the 3’UTR of uPA/uPAR mRNA in U87MG glioma cells. [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 3194. doi:10.1158/1538-7445.AM2013-3194
Abstract 3196: Androgen receptor 3’ untranslated region (UTR): a conundrum and a significant therapeutic opportunity.
Authors: Shukla Girish C. , Sikand Kavleen , Ebron Jey S. 
Published: August 2014

Abstract
Master transcriptional regulator Androgen Receptor (AR) remained a fascinating and an enigmatic molecule, particularly in Prostate cancer biology. Major impetus in PCa research is currently focused on the development of new generation of therapeutics to target AR expression, especially in castration-resistant stage of the disease. 920 amino acid coding AR gene encompasses over 180 kilobase (kb) of X-chromosome containing eight exons that produces a nearly 10.7 kb AR mRNA. The fully processed mature AR mRNA account for only 26% of total coding capacity and most of the transcript codes for noncoding regions that includes 5’ and 3’ UTRs. However, functional roles of UTRs in AR gene expression, principally its regulatory involvement in development of CRPC remained indefinable. Our research is focusing on understanding the functional roles of 6.8 kb long AR 3’ UTR in AR gene expression and especially the molecular mechanism that revitalizes AR expression in CRPC. We have shown that a number of regulatory noncoding miRNAs play a critical 3’ UTR targeting role in AR gene expression and has potential therapeutic implications. Here we show a synergistic approach of targeting AR expression mediated via its 3’ UTR, using a miRNA cocktail combinatorial approach. In addition, we are investigating the potential functional association of 3’ UTR in AR gene expression and implication in PCa.
Citation Format: Girish C. Shukla, Kavleen Sikand, Jey S. Ebron. Androgen receptor 3’ untranslated region (UTR): a conundrum and a significant therapeutic opportunity. [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 3196. doi:10.1158/1538-7445.AM2013-3196
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.