bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1852: Multiple PI3K pathway mutations predominate in low stage endometrial carcinomas
Authors: Roque Dario R. , Jeck Will R. , Hayes David N. , Dizon Arthur M. , Clark Leslie , Pierce Stuart , Wysham Weiya Z. , Castellano Tara , Gehrig Paola A. , Bae-Jump Victoria 
Published: July 2016

Abstract
Objectives: Endometrial cancers (ECs) frequently harbor mutations in PI3K pathway genes. Our objective was to determine the mutation frequency of the PIK3 pathway in the tumors of EC patients prospectively enrolled on an IRB-approved institutional tumor sequencing initiative (UNCseq) and correlate these with clinical factors.
Methods: Snap-frozen and FFPE tissue samples were collected from patients enrolled on UNCseq (NCT01457196). DNA was isolated using the Puregene DNA purification system, and Illumina libraries were prepared separately from tumor and a matched normal sample from each patient. Relevant targets, were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Samples were sequenced on Illumina HiSeq machines in a variety of formats. Statistical analysis of clinical correlates was performed in R (v 3.1.1).
Results: Data was collected from 109 EC patients. Thirty-six tumors (33.0%), 34 of which were endometrioid, had &gt;2 mutations between PIK3CA and PIK3R1. 20 patients had multiple PIK3CA mutations (18.3%) and 11 had multiple PIK3R1 mutations (10.1%). In all but 5 cases, multiple mutations of PIK3R1 or PIK3CA were coincident with PTEN mutation (p = 0.018). There were strong correlations between PI3K pathway mutations and tumor grade and stage. High stage tumors (stage &gt;2) were less likely (5/36) than stage 1 tumors (31/73) to have multiple PI3K mutations (p = 0.0056). Though not reaching significance, grade 3 tumors (8/37) were less likely than low-grade tumors (28/72) to demonstrate multiple PI3K mutations (p = 0.11). Of the 10 serous ECs, none exhibited multiple PI3K mutations.
Conclusions: There is a strong relationship between mutated PIK3 pathway genes and clinically relevant tumor biology in ECs. Multiple mutations in the PIK3 pathway are common, suggesting that PI3K pathway inhibition in EC may need to be directed against PIK3CA and PIK3R1 simultaneously. These multiply mutated tumors are strongly linked to lower stage and grade tumors with concurrent PTEN mutations. We posit that initially PTEN mutant clones may give rise to subclonal populations with various PI3K mutations which may be relatively indolent until additional driver mutations are acquired such that one subpopulation predominates, resulting in higher grade and stage ECs.
Citation Format: Dario R. Roque, Will R. Jeck, David N. Hayes, Arthur M. Dizon, Leslie Clark, Stuart Pierce, Weiya Z. Wysham, Tara Castellano, Paola A. Gehrig, Victoria Bae-Jump. Multiple PI3K pathway mutations predominate in low stage endometrial carcinomas. [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 1852.
Abstract 1900: MiR-222 accelerates the progression of inflammatory breast cancer by targeting tumor suppressor gene p27kip1 (CDKN1B)
Authors: Ogony Joshua Were , Hayes Erin , Knapp Jennifer , Lewis-Wambi Joan 
Published: July 2016

Abstract
MicroRNAs (miRNAs) are small non-coding RNAs about 18-22 nucleotides in length, whose main role is to regulate gene expression by altering mRNA stability and translation. MicroRNAs have been shown to play a role in many types of cancer, including breast cancer by targeting tumor suppressor genes such as p53, p27, PTEN, BRCA1, BRCA2 and many others. The goal of this study was to investigate the role of miRNAs in inflammatory breast cancer (IBC). IBC is the most aggressive and metastatic form of breast cancer, that is characterized by very rapid progression, poor prognosis, with a 5 year survival outcome of 30-40%. The mechanism that underlies the rapid progression of IBC is currently under intense investigation, and novel approaches are needed to better understand this disease. To understand the role that microRNAs might play in IBC, we conducted next generation sequencing of the miRNAs from two IBC cell line, SUM149 which is a triple negative IBC (ER-, PR-, HER2-), and SUM190 which is HER2 overexpressing, but ER and PR negative (ER-, PR-, HER2+). We found that 463 miRNAs were differentially expressed in the two cell lines, with 243 miRNAs being overexpressed in SUM149 compared to SUM190, while 220 miRNAs were overexpressed in SUM190. Notably, our qPCR analysis confirmed the raw read counts, showing that miR-155, miR-221, and miR-222 were overexpressed in SUM149 as compared to SUM190 cells by 15, 10, and 3 fold respectively. Furthermore, the inhibition of miR-222 in SUM149 resulted in significant reduction in cell proliferation, tumorsphere formation, and migration in these cells as compared to SUM190 cells. Our flow cytometry data showed that there was cell cycle arrest at the G1 phase in SUM149 cells due to miR-222 inhibition, while SUM190 cells showed little or no change. Additionally, Western blot and immunofluorescence analyses showed that the protein levels of p27, which is one of the targets of miR-222, significantly increased in SUM149 cells, but not in SUM190 cells when miR-222 inhibitor was used in these cells. These results suggest that miR-222 may accelerate the progression of some IBCs by targeting tumor suppressor genes, resulting in rapid cell proliferation, and may be a potential therapeutic target for triple negative inflammatory breast cancers.
Citation Format: Joshua Were Ogony, Erin Hayes, Jennifer Knapp, Joan Lewis-Wambi. MiR-222 accelerates the progression of inflammatory breast cancer by targeting tumor suppressor gene p27kip1 (CDKN1B). [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 1900.
Abstract 1938: The identification of p53 target genes and noncoding RNAs through the combined analysis of RNA-seq and ChIP-seq data
Authors: Idogawa Masashi , Ohashi Tomoko , Sasaki Yasushi , Tokino Takashi 
Published: July 2016

Abstract
p53 is inactivated in approximately half of human cancers. p53 execute various functions by modulating transcriptional regulation. To identify direct p53 transcriptional targets including non-coding RNAs, we performed gene expression analysis with next-generation sequencing (RNA-seq) in osteosarcoma U2OS cells treated with Nutlin-3a which activates endogenous p53. We identified 261 genes increased more than 4-fold and 373 long non-coding RNAs (lncRNAs) increased more than 2-fold. Next, we analyzed the data of chromatin immunoprecipitation with next-generation sequencing (ChIP-seq) and then searched for p53 binding sites in the whole human genome. p53 binding sites were located in the neighborhood of 126/261 (48.3%) genes including 28 known target genes and 122/373 (32.7%) lncRNAs including 7 lncRNAs we already identified in previous study. Recent reports have revealed that lncRNAs play an important role in various biological and pathological processes such as development, differentiation, stemness and carcinogenesis. Although all functions of lncRNAs have not been elucidated, many lncRNAs are involved in transcriptional regulation like transcriptional factors. Therefore, we performed a gene network analysis of cancer transcriptome including lncRNAs using public RNA-seq data of cancer tissues. As a result, we identified several hub lncRNAs which regulate the transcription of many downstream genes. Our results suggest that p53 and lncRNAs comprise a complex transcriptional network for various biological functions and tumor suppression.
Citation Format: Masashi Idogawa, Tomoko Ohashi, Yasushi Sasaki, Takashi Tokino. The identification of p53 target genes and noncoding RNAs through the combined analysis of RNA-seq and ChIP-seq data. [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 1938.
Abstract 1942: Change in serum microRNA expression during neoadjuvant chemoradiation for rectal cancer
Authors: Lim Stephanie H. , De Souza Paul , Chua Wei , Ng Weng , Harris Benjamin , Cowley Mark J. , Spring Kevin 
Published: July 2016

Abstract
Introduction
MicroRNAs (miRNA) expression may change with treatment and influence responses in locally advanced rectal cancer (LARC) making them potentially useful predictive and prognostic biomarkers. We investigated 112 miRNAs in serum during chemoradiation for LARC.
Methods
Twenty-one patients with LARC treated with neoadjuvant chemoradiation were prospectively recruited for the study. Serum was collected at three time-points: 1) at diagnosis (baseline), 2) at three weeks into treatment and 3) at completion of chemoradiation (pre-surgery). Serum was also collected from 10 healthy controls. RNA extraction was performed using the Norgen™ total RNA purification kit. Reverse transcription and pre-amplification were performed as per the Taqman™ OpenArray MicroRNA Panels manufacturer's instructions. miRNA array qPCR was performed on 112 miRNA targets using the QuantStudio™ 12K platform. Differentially expressed miRNAs were identified using the delta-delta-Ct method, using the endogenous U6 snRNA as the control. Analysis was performed in R, using paired t-statistics, and the Benjamini-Hochberg False Discovery Rate for multiple hypothesis testing adjustment, with a threshold q&lt;0.05 for significant differential expression. Enriched KEGG pathways were identified using DIANA, based on verified gene targets of each miRNA from Tarbase.
Results
We identified 12 miRNAs that were significantly differentially expressed between patients and matched controls. The strongest differences were observed between patient samples at baseline and completion of chemoradiation, where eight miRNAs decreased in expression: hsa-miR-101, hsa-miR-130a, hsa-miR-130b, hsa-miR-223, hsa-miR-27a, hsa-miR-628-5p, hsa-miR-630 and hsa-miR-720, all with fold change &gt; 3-fold. These genes are known to target key rectal cancer genes such as SMAD4, BCL2, MSH2 and TGFBR2. An additional three miRNAs changed significantly between baseline and week 3: hsa-miR-135b*, hsa-miR-375 and hsa-miR-629. All except hsa-miR-135b* became less abundant.
Conclusions
Ten differentially expressed miRNAs appear downregulated during chemoradiation in LARC. These miRNAs have been implicated in cell proliferation, the epithelial-mesenchymal transition and radiation resistance. Further work will be undertaken to understand the functional implications of these changes.
Citation Format: Stephanie H. Lim, Paul De Souza, Wei Chua, Weng Ng, Benjamin Harris, Mark J. Cowley, Kevin Spring. Change in serum microRNA expression during neoadjuvant chemoradiation for rectal 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 1942.
Abstract 1979: Comprehensive analysis of the dynamics of aberrant WNT signaling on global gene expression and higher order nuclear structure in human cells
Authors: Brown Markus , Wangsa Darawalee , Hu Yue , Ried Thomas 
Published: July 2016

Abstract
The organization of the genome in the nucleus is complex and dynamic. Features of the nuclear architecture, including the spatial arrangement of genomic sequences, the structure of chromatin, and the accessibility of regulatory DNA elements modulate nuclear processes such as gene transcription DNA replication, DNA repair, RNA processing, and mRNA transport. However, the interplay between nuclear architecture and gene expression is poorly understood. We propose to elucidate the impact of silencing the prominent transcription factor, TCF7L2, the major effector of the WNT signaling pathway, on the transcriptional equilibrium and nuclear architecture of the nucleus in human colorectal cancer cells. Our multidisciplinary approach combines targeted silencing of TCF7L2, 3D-FISH, RNA-seq, and Hi-C chromosome conformation capture, in parallel with mathematical modeling to delineate structure/function relationships in the interphase nucleus. This approach will elucidate the intricacies of a dynamic cellular signaling pathway in three-dimensional space.
Citation Format: Markus Brown, Darawalee Wangsa, Yue Hu, Thomas Ried. Comprehensive analysis of the dynamics of aberrant WNT signaling on global gene expression and higher order nuclear structure in human 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 1979.
Abstract 1986: CEBPD promotes stemness in the pathogenesis of gliomas
Authors: Wang Shao-Ming , Ko Chiung-Yuan , Wang Ju-Ming 
Published: July 2016

Abstract
Glioblastoma multiforme (GBM) is the most common and lethal type of brain tumor with a median survival of 12-15 months despite optimal therapy. Nowadays, an increasing number of studies has indicated the connection between malignancy and stemness. The molecular mechanisms controlling the stem cell-like properties and tumorigenic potential of glioblastoma stem cells (GSCs) remain less investigated. CCAAT/Enhancer binding protein delta (CEBPD) is a C/EBP family of transcription factors. In this study, CEBPD was highly expressed in GBM specimens and GBM patients with low levels of CEBPD show a significantly better overall survival. The transcription factor OCT4 is known to play an important role in maintaining stem cell self-renewal within the central nervous system (CNS) and this activity is present in gliomas as well. Further, our data showed that CEBPD contributes to stem-like characteristics and promoted cancer cells toward stem cell traits through direct activation of OCT4 gene expression. In conclusion, this study highlights the involvement of CEBPD in enchaining stem-cell property in GBM.
Citation Format: Shao-Ming Wang, Chiung-Yuan Ko, Ju-Ming Wang. CEBPD promotes stemness in the pathogenesis of gliomas. [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 1986.
Abstract 2009: Role of FOXO1 in oncogenic program of B cell precursor acute lymphoblastic leukemia (BCP-ALL)
Authors: Wang Fan , Ushmorov Alexey , Wirth Thomas 
Published: July 2016

Abstract
Although treatment of B cell precursor acute lymphoblastic leukemia (BCP-ALL) in children has shown eminent progress over the past decades, about 15% of patients can still not be cured, however. Therefore, new therapeutic strategies are warranted.
FOXO1 together with other transcription factors including EBF1, PAX5 and TCF3 plays a central role in differentiation of pre-B-cells. In cooperation with PAX5 and other B-cell transcription factors, FOXO1 induces expression of SYK, BLNK, RAG1, RAG2, AICDA and IL7RA genes. Of note, SYK and IL7RA signaling contribute to the oncogenic program of BCP-ALL, which utilize pre-B cell survival and proliferation program.
In this study, we demonstrate that FOXO1 is highly expressed in most of the BCP-ALL cell lines. By using immunofluorescence assays we show that FOXO1 is localized in the nucleus of BCP-ALL cells. Overexpression of constitutively active AKT1 (inactivating FOXO1) negatively regulates the growth of BCP-ALL cells. Inhibition of FOXO1 by shRNA results in cell death in the RS4;11 BCP-ALL cell line. BCP-ALL cells are more sensitive to growth arrest and apoptosis induced by a small molecular FOXO1 inhibitor AS1842856 than other classical Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. Gene expression profiling of BCP-ALL cells after treatment with the FOXO1 inhibitor for 24h shows the significantly down-regulation of FOXO target genes including VPREB3, IL1B, KLHL24 and BNIP3L. Interestingly, at the same time, some FOXO targets like NOXA, RUNX2 and PRDM1 were found upregulated, indicating a complex effect of the FOXO1 inhibitor.
We conclude that FOXO1 expression is critical for the BCP-ALL oncogenic program and its targeting represents a novel therapeutic approach.
Citation Format: Fan Wang, Alexey Ushmorov, Thomas Wirth. Role of FOXO1 in oncogenic program of B cell precursor acute lymphoblastic leukemia (BCP-ALL). [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 2009.
Abstract 2016: Paired box 2 promotes progression of endometrial cancer via cell cycle pathway
Authors: Wang Jieyu , Feng Weiwei , Yu Yinhua , Wong Kwong-Kwok , Jia Nan , Lyu Tianjiao 
Published: July 2016

Abstract
Human paired box 2 (PAX2) plays a key role in cell fate, early patterning and organogenesis. To investigate the function of PAX2 on the biological behavior of endometrial cancer and the regulation mechanism, stable knocking-down and over-expression PAX2 endometrial cancer cell lines were established. CCK-8 and transwell assays were applied to determine proliferation, invasion and migration ability. Cell cycle distribution was analyzed by flow cytometry. Nude mice were used for in vivo experiments and Affymetrix GeneChip® human Exon 1.0 ST arrays was used to screen the downstream target genes of PAX2. The upstream regulation mechanism of PAX2 was explored by dual luciferase reporter gene assay and bioinformatics analysis.Results showed that,no matter in vivo or in vitro,PAX2 significantly enhanced tumorigenicity and invasiveness of endometrial cancer cells, and promoted liver metastasis in vivo. In addition, PAX2 influenced the expression of cyclin-dependent kinase 1(CDK1) and YWHAZ, which play pivotal roles in cell cycle pathway. Knocking down CDK1 in PAX2 over-expressing cells attenuated cell viability.A myeloid zinc finger gene-1(MZF-1)binding site was found in a negative regulation region of PAX2 upstream and down-regulation of MZF-1 reduced the transcriptional activity of PAX2, as well as its protein level.Together, PAX2, through influencing the activity of CDK1 and YWHAZ, promotes proliferation,invasion and progression of endometrial cancer and can be regulated by MZF-1. PAX2 may be a target therapeutic site for endometrial cancer.
Citation Format: Jieyu Wang, Weiwei Feng, Yinhua Yu, Kwong-Kwok Wong, Nan Jia, Tianjiao Lyu. Paired box 2 promotes progression of endometrial cancer via cell cycle pathway. [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 2016.
Abstract 2056: Development of quaternary amine linkers for ADCs: Application to auristatin E and tubulysin
Authors: Burke Patrick J. , Hamilton Joseph Z. , Pires Thomas A. , Setter Jocelyn R. , Hunter Joshua H. , Cochran Julia H. , Toki Brian E. , Senter Peter D. , Lyon Robert P. , Jeffrey Scott C. 
Published: July 2016

Abstract
The recent clinical success of antibody-drug conjugates (ADCs) has spawned an increased effort to identify new technologies, and the development of new drug-linker chemistry is vital to expand the scope of conjugatable payloads. The tertiary amine functional group is a common structural motif present in many bioactive compounds, including antimitotics of the auristatin and tubulysin classes. Traditionally, conjugation of tertiary amines required drug derivatization or modification to remove an N-alkyl group, thus creating a readily conjugatable secondary amine. However, identifying appropriate modifications that do not compromise the activity of the drug is frequently time consuming and often unsuccessful. To eliminate the need for such structural modifications, we sought a method for stable conjugation and facile release through the tertiary amine functional group by creating linkers with a quaternary amine point of attachment. To validate the linker strategy, quaternary amine-based cleavable linkers bearing auristatin E were synthesized and evaluated as ADCs. The conjugates were stable in rodent plasma, and were potent and immunologically specific both in vitro and in vivo in a Hodgkin lymphoma xenograft model. A second application of this technology has been demonstrated with tubulysins, another class of potent antimitotics containing a tertiary amine at the N-terminus. A cleavable quaternary amine linker containing a tubulysin analog was synthesized and ADCs were prepared and evaluated. The tubulysin conjugates were potent and immunologically specific across a panel of cancer cell lines, including multiple MDR-positive lines. Furthermore, the tubulysin conjugate displayed ‘bystander activity’ in an in vitro co-culture assay. The quaternary amine linkers represent an advance in linker technology and will enable the evaluation of drug classes previously inaccessible as ADCs.
Citation Format: Patrick J. Burke, Joseph Z. Hamilton, Thomas A. Pires, Jocelyn R. Setter, Joshua H. Hunter, Julia H. Cochran, Brian E. Toki, Peter D. Senter, Robert P. Lyon, Scott C. Jeffrey. Development of quaternary amine linkers for ADCs: Application to auristatin E and tubulysin. [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 2056.