bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-102: A pro-proliferative function of centriole duplication regulator, polo-like kinase-4 in human melanoma
Authors: Shabbir Maria , Nihal Minakshi , Singh Chandra K. , Longley B Jack , Ahmad Nihal 
Published: July 2016

Abstract
Malignant melanoma is one of the deadliest forms of skin cancer that remains resistant to existing therapeutic strategies. According to the SEER (Surveillance, Epidemiology, and End Results) program database of the National Cancer Institute, the 5-year survival rate for metastatic melanoma is a dismal 16%. Further, of the seven most common cancers in the USA, melanoma is the only neoplasm with constantly increasing incidence. Therefore, it is important to intensify our efforts to better-understand the genetics and biology of melanoma. This may lead to development of novel targets and biomarkers for management of this hard-to-treat neoplasm. This study was undertaken to determine the role and potential significance of polo-like kinase 4 (PLK4) in human melanoma. PLK4 is a serine/threonine kinase that has been shown to localize to centrioles and regulate centriole duplication during the cell cycle. While the potential role of PLK4 in cancer is beginning to be appreciated, there are evidence for its function as a tumor suppressor as well as tumor promoter. However, the role of PLK4 in melanoma is not known. Here, we employed in vitro and ex vivo experiments to determine the role of PLK4 in melanoma. Our data demonstrated that PLK4 was significantly overexpressed, both at mRNA and protein levels in human melanoma cells viz. A375, Hs294T, G361, 451Lu; when compared to the normal human epidermal melanocytes (NHEM). We also found a significant increase in PLK4 immunostaining in clinical melanoma tissues, compared to normal skin and nevus tissues. Further, treatment of melanoma cells with a selective small molecule PLK4 inhibitor, centrinone-B, was found to cause a significant decrease in the cell growth/viability and clonogenic survival in multiple melanoma cell lines. The observed anti-proliferative effects of centrinone-B were found to be accompanied with i) a G0/G1 phase arrest of cell cycle, and ii) induction of apoptosis, in human melanoma cells. Taken together, our study suggests a pro-proliferative role of PLK4 in human melanoma. Additional studies are ongoing in our laboratory to determine the functional significance of PLK4 in melanoma. We suggest that PLK4 should be further evaluated as a potential ‘druggable target’ and biomarker, for the management of melanoma.
Citation Format: Maria Shabbir, Minakshi Nihal, Chandra K. Singh, B Jack Longley, Nihal Ahmad. A pro-proliferative function of centriole duplication regulator, polo-like kinase-4 in human melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-102.
Abstract LB-103: Molecular exploitation of oncogenic stress in melanoma management
Authors: Kumar Raj , Ji Zhenyu , Miao Benchun , Njauw Ching-Ni Jenny , Tsao Hensin 
Published: July 2016

Abstract
Oncogenic B-RAF and N-RAS mutations are frequently reported in mitogen-activated protein kinase pathways of tumors. BRAF and NRAS mutations are found in more than 30% of all human tumors and 43% (88% V600E, 10% V600K) and 30% (48% Q61K, 40% Q61R) of malignant melanoma. These mutations were considered mutually exclusive except a few (0.7%) cases. BRAF and NRAS mutations are an important clinical marker and prognostic factor in metastatic melanoma. Recently developed BRAFV600E targeted therapies demonstrate significant clinical benefit but the targeted therapeutic options for NRAS-mutant melanomas are still under intense investigation. Importantly, BRAF and NRAS mutations are mutually exclusive, meaning that tumors are rarely found with these two mutations and are reported as lethal to the cancer cells. Hence, molecular behavior and interaction between BRAF and NRAS mutant proteins underline phenotypic complexity which is poorly understood. In the current study, we aimed to determine the translational significance of BRAF and NRAS mutations and their products in cell based studies with metastatic melanoma cell lines. Our lab sought to investigate the common molecular therapeutic target(s) of these genes, responsible for synthetic lethality. By using remote inducible expression system of BRAFV600E mutant gene in NRASQ61R mutant cell lines and vice versa. It is found that 25% (2/8) NRASQ61R mutant cell lines are sensitive to BRAFV600E and NRASQ61R mutation co-expression and have slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence, apoptosis and cell cycle arrest, more over rescued with BAP1 ectopic expression. While some NRAS mutant cell lines showed no lethal effect to BRAFV600E mutation expression which is well explained by human phospho-kinase array. These preliminary results suggest a complex interplay of tumor drivers (BRAF and NRAS) and passengers (X-factors) in cancer biology that need to be investigated in detail in melanoma.
Citation Format: Raj Kumar, Zhenyu Ji, Benchun Miao, Ching-Ni Jenny Njauw, Hensin Tsao. Molecular exploitation of oncogenic stress in melanoma management. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-103.
Abstract LB-104: Functional genomic screening identifies USP11 as a novel therapeutic target in breast cancer
Authors: O’Connor Darran , Dwane Lisa , O’Connor Aisling , Bernards Rene , Gallagher William 
Published: July 2016

Abstract
The estrogen receptor (ER) is the principal driver of growth and differentiation in breast cells and de-regulated receptor function is a key feature of almost 75% of breast cancers. Here, we investigated the role of de-ubiquitinating enzymes (DUBs), which act to remove ubiquitin moieties from proteins, in regulating the transcriptional activity of ER in breast cancer.
To identify DUBs involved in the regulation of ER transcriptional activity, we performed an RNAi loss-of-function screen using a library of shRNA vectors targeting all known human DUB genes (108 genes/432 shRNAs in total). We found that suppression of a number of DUBs markedly repressed or enhanced the activity of an estrogen-response-element (ERE) luciferase reporter to estradiol (E2). In particular, suppression of the BRCA2-associated DUB, USP11, was found to down-regulate ERα transcriptional activity (both in the presence and absence of E2), as demonstrated by a pronounced decrease in estrogen-response element (ERE) luciferase reporter activity. Subsequent validation of the screen using multiple individual hairpins and ZR-75-1 stable USP11 knockdown cells confirmed the suppression of ERE-reporter activity and further revealed a notable reduction in expression of the endogenous ER target genes TFF1 and PgR following USP11 knockdown. Growth assays and Western blot analysis also revealed a global decrease in cell survival, decreased ERK and AKT phosphorylation and increased sensitivity to DNA-damaging agents in USP11 knockdown cell lines.
In silico analysis of publically available breast cancer gene expression datasets revealed a highly significant association between high USP11 mRNA levels and poor prognosis. We observed a highly significant correlation between high expression of USP11 mRNA in ER positive patients and poor overall survival (OS)(HR 1.51, CI 1.07-2.14, p = 0.018) and distant metastasis-free survival (DMFS)(HR 1.35, CI 1.04-1.73, p = 0.023). This correlation was also significant in ER positive patients who had received endocrine therapy (OS, HR 3.4, CI 1.2-9.81, p = 0.014), DMFS, HR 2.16, CI 1.23-3.8, p = 0.0083). Tissue microarray validation using immunohistochemistry in an independent cohort (n = 144) confirmed USP11 as an independent marker of poor prognosis in ER+ breast cancer. These results suggest a role for USP11 in driving cellular growth and identifiy USP11 as a rationale and novel therapeutic target in breast cancer.
Citation Format: Darran O’Connor, Lisa Dwane, Aisling O’Connor, Rene Bernards, William Gallagher. Functional genomic screening identifies USP11 as a novel therapeutic target in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-104.
Abstract LB-105: High-throughput target identification using CRISPR/Cas9
Authors: Revankar Chetana M. , Braun Julia , Wong LaiYee , Wetter Justin , Yang Jian-Ping , Ravinder Namritha , Chesnut Jon , Piper David 
Published: July 2016

Abstract
One of the major challenges of the drug discovery process is the identification of novel, validated targets, whose pharmacological modulation may yield the desired therapeutic outcomes. The use of CRISPR (clustered regularly interspaced short palindromic repeat)-associated Cas9 nuclease and guide RNA can potentially impact the entire drug discovery process from generation of models based on clinical findings through to the target identification. The ability of CRISPR/Cas9, to efficiently and precisely edit a cell's DNA and introduce a complete genetic knockout, while minimizing off-target effects, offers an improved approach to target identification. Moreover, the ability to scale this approach through the generation of genome wide CRISPR libraries, coupled with the use of lentiviral delivery methods enables high-throughput (HTP) loss-of-function screens to be performed rapidly and identify genes whose activity is important for the specific endpoint being measured. For example, in this study, we have used CellSensor® cell lines targeting various signaling pathways (AP-1, c-Fos and NF-kB) to identify key targets critical to these pathways. Transcription factors like AP-1, c-Fos and NF-kB have shown to play an important role in cancer initiation and progression. Using the key signaling molecules along these pathways as controls we have data that supports HTP target identification. Furthermore, we will present our results from screening of a subset of a CRISPR library targeting 160 different kinases. Eventually, we plan to screen the entire CRISPR library targeting 750 kinases with 4 gRNA per gene against each of these signaling pathways. Similar screenings can be performed using other functional assay formats, like the cell health assays or high content imaging. These screenings can provide a wealth of data on the normal functioning of a target and in turn, should yield better validated targets for progression into full drug discovery. Ultimately, the hits from the HTP screenings can be followed up by using CRISPR technology to generate animal knockout models that would support translating the screen to the pre-clinical trials. This in turn could provide better correlation to the clinical setting and thereby reduce candidate drug attrition.
Citation Format: Chetana M. Revankar, Julia Braun, LaiYee Wong, Justin Wetter, Jian-Ping Yang, Namritha Ravinder, Jon Chesnut, David Piper. High-throughput target identification using CRISPR/Cas9. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-105.
Abstract LB-115: Mechanisms of acquired resistance to allosteric versus ATP-competitive AKT inhibition
Authors: Zimmerman Kristin M. , Lee Brian , Chung Wei-Jen , Gnad Florian , Lin Eva , Martin Scott , Lin Kui 
Published: July 2016

Abstract
The PI3K/AKT signaling pathway mediates a variety of cellular processes including metabolism, glucose uptake, angiogenesis, growth, survival and proliferation. Increased activity of this pathway is observed in many cancer types and is associated with tumor invasiveness, survival, and proliferation. Various regulators of this pathway are being investigated as therapeutic targets in oncology, including the AKT kinases. Two distinct classes of AKT inhibitors (AKTi) are being evaluated as therapeutic agents in the clinic: allosteric inhibitors (e.g. MK-2206) and ATP-competitive inhibitors (e.g. Ipatasertib/GDC-0068). In an effort to elucidate pathway alterations in response to these inhibitors and, ultimately, to improve therapeutic outcome, we are currently evaluating mechanisms of acquired resistance to both AKT inhibitor classes. The establishment of clonal cell populations resistant to either MK-2206 or GDC-0068 and subsequent characterization of alterations in these lines revealed various genetic and non-genetic variations associated with AKTi resistance. Here, we will present findings on biological mechanisms that contribute to acquired AKTi resistance in prostate and ovarian cancer cell line models.
Citation Format: Kristin M. Zimmerman, Brian Lee, Wei-Jen Chung, Florian Gnad, Eva Lin, Scott Martin, Kui Lin. Mechanisms of acquired resistance to allosteric versus ATP-competitive AKT inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-115.
Abstract LB-124: Preliminary anti-proliferative effect of ethanolic extracts of Xylopia aethiopica on prostate and breast cancer cell lines
Authors: Iweala Emeka E.J , Bankole Eunice W. 
Published: July 2016

Abstract
Xylopia aethiopica (African Pepper), a plant found throughout West Africa, has both nutritional and medicinal uses. The aim of this research was to study the preliminary anti-proliferative effects of ethanolic extracts of Xylopia aethiopica on prostate and breast cancer cell lines. Dried X. aethiopica fruits were extracted with 70% ethanol and tested against prostate(LNCaP) and breast cancer (MCF7 and MDA-MB231) cells’ viability in vitro using the MTT ((3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide) assay. The IC50 values for the extract were determined through linear regression using GraphPad Prism 6 software. The data obtained were expressed as mean ± SEM. Statistical analysis was carried out by one-way ANOVA followed by Dunnet's test (α = 0.05) to compare experimental means with controls. The data generated indicates that X. aethiopica fruits extract showed a dose-dependent anti-proliferative activity against LNCaP, MDA-MB231and MCF7 cancer cell lines after treatment for 48 and 72 hours. The extract induced a 16.96% and 93.5% inhibition on MDA-MB231 cells, 29.76% and 94.03% on the MCF7 cells and a 9.15% and 94.61% inhibition on the LNCaP cells at the lowest (1μg/ml) and highest (100μg/ml) dose respectively after 48 hours. The extract induced a 12.26% and 91.8% cell growth inhibition on the MDA-MB231 cells, 3.35% and 87.36% growth inhibition on the MCF7 cells and 2.28% and 92.42% cell growth inhibition on the LNCaP cells at the lowest (1μg/ml) and highest (100μg/ml) dose respectively after 72 hours. The IC50 was estimated to be 3.408μg/ml, 2.064μg/ml, 3.371μg/ml for MDA-MB231, MCF7 and LNCaP cells respectively. The data generated from this research indicates the anti-proliferative effects of ethanolic extract of X. aethiopica fruits on breast and prostate cancer cells. This can be seen from the inhibition of cell growth by this extract thus highlighting its potential as a therapy against breast and prostate cancer.
Citation Format: Emeka E.J Iweala, Eunice W. Bankole. Preliminary anti-proliferative effect of ethanolic extracts of Xylopia aethiopica on prostate and breast cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-124.
Abstract LB-129: Epigenetic regulators to predict docetaxel sensitivity; a guide for treatment choice
Authors: Gurard-Levin Zachary A. , Wilson Laurence OW , Pancaldi Vera , Postel-Vinay Sophie , Sousa Fabricio G. , Reyes Cecile , Marangoni Elisabetta , Gentien David , Valencia Alfonso , Pommier Yves , Cottu Paul , Almouzni Genevieve 
Published: July 2016

Abstract
The limited capacity to predict the response of a given patient to cancer therapy is a major hurdle in cancer management. To date, many standard-of-care chemotherapy agents act by directly binding or modifying DNA or indirectly during processes that rely on chromatin architecture, as exemplified with docetaxel. Therefore, alterations in chromatin organization may impact resistance mechanisms for these drugs. Here, we explore the mis-regulation of chromatin regulators—factors involved in the establishment and maintenance of functional chromatin domains—as a tool to predict the response to docetaxel. For a series of chromatin regulators, we exploit Affymetrix microarray and NanoString gene expression data generated from breast cancer patient derived xenograft (PDX) models, colorectal cancer organoids, and breast cancer patient samples treated with docetaxel. Random Forest classification reveals a limited set of chromatin regulators that readily distinguish docetaxel responders from non-responders. Since the candidate predictive factors feature key subunits of the chromatin remodeler SWI/SNF complex, we then explore the behavior of SWI/SNF subunits in the response to docetaxel in the large NCI-60 dataset and in cultured cells. All together, our results showcase the predictive value of chromatin regulators and reveal that the SWI/SNF chromatin remodeler associates tightly with docetaxel response in several settings. Our findings open avenues for applications as biomarkers, but also as therapeutic targets to sensitize patients towards docetaxel. These approaches offer a means to potentially combat drug resistance.
Citation Format: Zachary A. Gurard-Levin, Laurence OW Wilson, Vera Pancaldi, Sophie Postel-Vinay, Fabricio G. Sousa, Cecile Reyes, Elisabetta Marangoni, David Gentien, Alfonso Valencia, Yves Pommier, Paul Cottu, Genevieve Almouzni. Epigenetic regulators to predict docetaxel sensitivity; a guide for treatment choice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-129.
Abstract LB-137: IGF2BP1 and miR-34a genetic instability found in deadly neuroblastoma
Authors: Bell Jessica L. , Hüttelmaier Stefan 
Published: July 2016

Abstract
Chromosomal 17q21-ter gain in neuroblastoma is both a common and clinically significant occurrence. The oncogenic, insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) gene is located near the proximal edge of this region. We have previously reported that in 69 neuroblastoma samples, IGF2BP1 DNA copy number (increased in 84% of tumors), mRNA, and protein levels are significantly higher in stage 4 compared with stage 1 tumors. Moreover, clinical and experimental data pointed to a strong association of IGF2BP1 with the MYCN oncogene. From the late 1990s onwards, 17q gain and 1p deletions (either alone or both) have been speculated as essential precursors to the MYCN amplification. As the tumor suppressive, miR-34a is located within 1p and is known to directly target MYCN and putatively IGF2BP1 mRNAs (Targetminer website), in this study we analyzed the co-occurrence of IGF2BP1 gain, miR-34a loss and MYCN amplification) in 69 neuroblastomas. qPCR was utilized to assess copy number. Changes were found for IGF2BP1 (58 tumors), miR-34a (15) and MYCN (12). miR-34a was never completed deleted. Interestingly, in all (12/12) MYCN amplified tumors, miR-34a was partially lost. Whilst, IGF2BP1 was gained in 9/12 MYCN amplified tumors. IGF2BP1 and miR-34a were aberrant together only twice with the absence of MYCN amplification. Of the 17 patients that died, all but one had at least an IGF2BP1 or miR-34a change in copy number. This stage 4 patent also had low MYCN protein levels, comparable to the stage 1 patients, indicating an aggressive tumor not involving the MYCN pathway. may A second larger cohort is certainly required to confirm these important results. IGF2BP1 and miR-34a locus have aberrant copy numbers in the majority of neuroblastoma, most strikingly, in the patients that died. IGF2BP1 and miR-34a may just be representative DNA of the larger locus changes and not be the causative event in affected neuroblastoma, but because of their known roles in cancer, the above results are intriguing. Although further experimental data is required, we speculate that either IGF2BP1 or mir-34a oncogenic changes are required for the clonal expansion of MYCN amplified tumor cells in neuroblastoma, and that these factors are crucial in the ability for an increase in MYCN transcription to be oncogenic in neuroblastoma.
Citation Format: Jessica L. Bell, Stefan Hüttelmaier. IGF2BP1 and miR-34a genetic instability found in deadly neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-137.
Abstract LB-147: Simultaneous profiling of mRNA and protein in single human induced pluripotent stem cells
Authors: Liu Benjamin , Dakshinamoorthy Gajalakshmi , Gong Haibiao , Ooi Aik , Li Nianzhen , Unger Marc , Holcomb Ilona , Ramakrishnan Ramesh 
Published: July 2016

Abstract
The cancer stem cell theory proposes that a discrete, small number of “stem-cell-like” cancer cells are primarily responsible for driving cancer. Thus, future cancer treatments are likely to be developed by targeting these cancer stem cells. One approach to modeling cancer therapy utilizes induced pluripotent stem cell (iPSC) technology. While gene expression studies have measured differentiation propensities between different iPSC clones and compared protein coding gene profiles between iPSCs and embryonic stem cells (ESCs), relatively little is known about the expression characteristics of individual RNA transcripts and their corresponding protein within each single iPSC. In addition, studies of the dynamic interaction between RNA and protein during the cell differentiation stage remains rare. Here we present an integrated assay that simultaneously quantifies mRNAs and proteins of interest within single iPSCs. The C1™ system was utilized for individual cell capture, cell lysis, DNA template generation for protein detection and cDNA synthesis. Final products from each iPSC were quantified on the 96.96 Dynamic Array™ IFC on the Biomark™ HD system. PCR data were analyzed using the Singular™ Analysis Toolset. For each run, up to 5,000 data points for 52 protein targets and 2,880 data points for 30 RNA targets, in addition to control and reference assays, were simultaneously generated and analyzed in less than two days. Combined RNA and protein signatures of each iPSC were identified. By comparing these results to those obtained from non-induced fibroblast cells, we demonstrate that this method is capable of obtaining expression levels of both RNA and protein associated with pluripotency marker genes at a single-cell level. More interestingly, the profiling data also indicates changes of some key members (EGFR, TGFB1, EPCAM, etc.) of cancer related common signaling pathways. The current system significantly controls lab-specific differences in reprogramming processes, progenitor cells or cell culture and handling conditions. We believe this powerful method makes it a suitable approach of choice for providing new insights into cell differentiation, reprogramming and tumor progression, as well as cancer therapeutic targets research.
Citation Format: Benjamin Liu, Gajalakshmi Dakshinamoorthy, Haibiao Gong, Aik Ooi, Nianzhen Li, Marc Unger, Ilona Holcomb, Ramesh Ramakrishnan. Simultaneous profiling of mRNA and protein in single human induced pluripotent stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-147.