bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 154: Identification of TGFβ-regulated long noncoding RNAs in mammary epithelia: lncRNA-HIT mediated TGFβ-induced EMT and breast cancer metastasis
Authors: Richards Edward , Zhang Gu , Permuth-Wey Jennifer , Li Zhu-Peng , Challa Sridevi , Kong William , Su Dan , Coppola Domenico , Mao Wei-min , Sellers Thomas , Cheng Jin Q. 
Published: August 2015

Abstract
Background: Long noncoding RNAs (lncRNAs) are emerging as key regulators in various biological processes. Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by tumor cells to depart from the primary tumor site, invade surrounding tissue, and establish distant metastases. TGFβ signaling has been shown to be a major inducer of EMT and to facilitate breast cancer metastasis. However, the role of lncRNAs in this process remains largely unknown.
Methods: Genome-wide lncRNA profile was performed using NCode™ Mouse Noncoding Microarray chip from Life Technologies, which contains 10,802 lncRNAs and 25,178 protein-coding genes. Total RNA was isolated from mouse mammary epithelial NMuMG cells, which had been treated with TGFβ for 0, 12 and 24 hours, and was used to hybridize the microarray. The role of a top TGFβ-upregulated lncRNA, lncRNA-HIT, in EMT and metastasis was further characterized in cell culture and orthotopic breast cancer models
Results: Among 10,802 lnRNAs profiled, 680 were up-regulated and 633 were down-regulated during TGFβ-induced EMT, respectively. Further, we identify that lncRNA-HIT (HOXA antisense transcript induced by TGFβ) mediates TGFβ function, i.e., depletion of lncRNA-HIT inhibits TGFβ-induced migration, invasion, and EMT in NMuMG. LncRNA-HIT is also significantly elevated in the highly metastatic 4T1 cells. Knockdown of lncRNA-HIT in 4T1 results in decrease of cell migration, invasion, tumor growth and metastasis. Moreover, lncRNA-HIT is conserved in humans and elevated expression associates with more invasive human primary breast carcinoma.
Conclusions: These data suggest that a subset of lncRNAs such as lncRNA-HIT play a significant role in regulation of EMT and breast cancer invasion and metastasis, and could be potential therapeutic targets in breast cancers.
Citation Format: Edward Richards, Gu Zhang, Jennifer Permuth-Wey, Zhu-Peng Li, Sridevi Challa, William Kong, Dan Su, Domenico Coppola, Wei-min Mao, Thomas Sellers, Jin Q. Cheng. Identification of TGFβ-regulated long noncoding RNAs in mammary epithelia: lncRNA-HIT mediated TGFβ-induced EMT and breast cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 154. doi:10.1158/1538-7445.AM2015-154
Abstract 1542: Targeting KIF3a and primary cilia differentially affects sonic hedgehog sensitivity and the rate of glioblastoma progression
Authors: Hoang-Minh Lan , Siebzehnrubl Dorit , Deleyrolle Loic , Ugartemendia George , Futch Hunter , Griffith Benjamin , Breunig Joshua , Semple-Rowland Susan , Reynolds Brent , Sarkisian Matthew 
Published: August 2015

Abstract
Adults diagnosed with glioblastoma multiforme (GBM) typically have a median survival less than 15 months. GBM patient biopsies and derived cell lines contain subsets of cells extending primary cilia, microtubular antennae that mediate signaling events reported to influence cell proliferation and tumor cell growth. However, it remains unclear how cilia contribute to the phenotypic characteristics of GBM. To determine whether cilia influence GBM tumor progression, we generated several stable patient-derived cell lines devoid of cilia by expressing a dominant-negative form of Kif3a (dnKif3a), a protein normally essential for ciliogenesis. Depending on the line, mice receiving intracranial implants of dnKif3a-expressing cells survived shorter, as long as, or significantly longer than mice implanted with control cells. To determine if ciliated cells derived from different GBM tumors share similar sensitivities to sonic hedgehog (SHH), a mitogen present in adult brain that activates receptor signaling cascades within cilia, we exposed control and dnKif3a-expressing cells in vitro to vehicle or recombinant SHH. Interestingly, only the cell line that prolonged survival in vivo displayed significant increases in proliferation following exposure to SHH, an effect that was blocked by either dnKif3a or pretreatment of the cells with cyclopamine, an inhibitor of the SHH cascade. All cell lines tested appeared to respond to SHH as evidenced by activation of downstream SHH signaling components in their cilia. Collectively, our data suggest that strategies to disrupt primary cilia in GBM patients could lead to inhibition or enhancement of tumor growth potentially by altering cell sensitivity to the extracellular environment.
Citation Format: Lan Hoang-Minh, Dorit Siebzehnrubl, Loic Deleyrolle, George Ugartemendia, Hunter Futch, Benjamin Griffith, Joshua Breunig, Susan Semple-Rowland, Brent Reynolds, Matthew Sarkisian. Targeting KIF3a and primary cilia differentially affects sonic hedgehog sensitivity and the rate of glioblastoma progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1542. doi:10.1158/1538-7445.AM2015-1542
Abstract 1550: Significance of ectopic lymph node-like structures in neuroendocrine tumors of the small bowel
Authors: Cives Mauro , Strosberg Jonathan , Simons Stacey A. , Coppola Domenico 
Published: August 2015

Abstract
The formation of extranodal tertiary lymphoid follicles and lymphoid cell aggregates has been described in nonmalignant conditions including autoimmune diseases and chronic inflammation as well as in cancer. Tumor-induced lymph node-like structures (LLS) participate in the host's antitumor immune response by driving intratumoral immune cell priming. We evaluated the host immune response by immunohistochemistry in 60 well differentiated small bowel NETs. A miRNA microarray analysis was also performed to identify a molecular signature of LLS presence. In 13/60 samples the immune response was organized as ectopic LLS. When present, LLS were localized at the invasive edge of the tumors and contained germinal centers in different stages of maturation. CD21+ dendritic cells were present within the follicular germinal centers, while CD3+ T cells were dispersed in the parafollicular cortex zone surrounding the CD20+ B cell area of the follicles. Time to progression of metastatic tumors was compared in an exploratory cohort of 5 patients with strong evidence of LLS vs 5 patients with no evidence of LLS and was substantially longer in the former group (94 vs 28 months; p = 0.15). Updated survival and miRNA microarray analysis will be presented at the meeting.The understanding of the functional nature of LLS may provide new insights into the pathogenesis of the disease, possibly furnishing a new tool for prognostic stratification and prediction of response to immune-based treatments.
Citation Format: Mauro Cives, Jonathan Strosberg, Stacey A. Simons, Domenico Coppola. Significance of ectopic lymph node-like structures in neuroendocrine tumors of the small bowel. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1550. doi:10.1158/1538-7445.AM2015-1550
Abstract 1559: Progranulin A9D mutation functionally leads to the cytoplasm retardation of angiogenin
Authors: Sheng Jinghao , Chen Yongdui , Li Siqi , Dong Haojie , Chen Guangdi , Xu Zhengping 
Published: August 2015

Abstract
Neurodegenerative diseases are progressive neurological disorders with selective neuron loss in particular regions of brain, including frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and many others. Gene defects have been recognized as a prominent factor in the etiology and pathogenesis of neurodegenerative diseases. To date, hundreds of genetic variants that located in dozens of genes have been associated with susceptibility to various neurodegenerative diseases. Among them, more than 60 mutations in progranulin (PGRN) have been reported in FTLD, AD, ALS and PD. One of the mutations in PGRN gene exon 1 introduces a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (PGRN A9D), and results in cytoplasmic mis-sorting of this protein. However, the mechanism of actions of this mis-sorting remains elusive. To address this issue, we first examined the subcellular distribution of PGRN with A9D mutation in human neuronal-like cells (SH-SY5Y). The results have shown that PGRN A9D mutation failed to undergo maturation and accumulated in the stress granules. Interestingly, this mutation also induces redistribution of cellular angiogenin (ANG), a stress response factor and neurodegenerative diseases related protein, from nuclear to cytoplasm. PGRN was also directly interacted with ANG in stress granules. Furthermore, the cytoplasmic retardation of ANG by PGRN A9D mutation abolished ANG-enhanced rRNA transcription and cell survival. Taken together, these results indicate that PGRN with A9D mutation changed localization of ANG as well as cell growth and survival, suggesting that PGRN and ANG act in concert to regulate the progress of neurodegenerative diseases.
Citation Format: Jinghao Sheng, Yongdui Chen, Siqi Li, Haojie Dong, Guangdi Chen, Zhengping Xu. Progranulin A9D mutation functionally leads to the cytoplasm retardation of angiogenin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1559. doi:10.1158/1538-7445.AM2015-1559
Abstract 1576: Analysis of HSP10 as a putative biomarker of breast cancer
Authors: Shaheed Sadr-ul , Hadjisavvas Andreas , Sokratous Kleitos , Loadman Paul , Sutton Chris , Kyriacou Kyriacos 
Published: August 2015

Abstract
Introduction. Detection of the very earliest stages of breast cancer remain challenging and the differentiation of those carcinomas that develop into aggressive invasive forms from those that remain benign has not been achieved. Consequently, removal of the tumor by total mastectomy, local excision (LE) plus adjuvant radiotherapy (RT), or LE alone remain the main treatments, even if they prove unnecessary. Previously, using proteomics analysis, we identified proteins that were significantly changed in expression between matched normal and tumor tissues from Cypriot patients with different stages of the disease. Heat shock protein 10 (HSP10), which is responsible for the mitochondrial protein folding, was one of the proteins identified. A range of methods were used to verify HSP10 as a possible biomarker for breast cancer.
Materials and Methods. Protein extracts from breast cancer cell lines and breast tissue biopsies from Cypriot patients with different stages of the disease were analysed by (i) Western Blotting (WB) and (ii) multiple reaction monitoring mass spectrometry (MRM MS) using two proteotypic peptides unique to HSP10, in proteins extracted form fresh frozen as well as from FFPE breast tissues. Tissue microarray analysis (TMA) was carried out on core biopsies from the Leeds Breast Tissue Bank.
Results. WB indicated that HSP10 was ubiquitously and evenly expressed across breast cancer cell lines representative of different phenotypes. WB and MRM MS revealed that expression was significantly increased in invasive carcinoma compared to normal tissue, but was patient specific for fibroadenoma and DCIS cases. TMA of 360 samples indicated a strong correlation between staining and type of breast cancer (invasive ductal and lobular), grade and ER positive phenotype.
Discussion. Proteomics analysis using iTRAQ quantitation indicated an average of 1.6 fold increase in HSP10 in invasive carcinomas compared to matched normal tissue. By comparison, WB and MRM MS analysis indicated a significantly amplified discrimination in the expression of HSP10 as has been observed with other biomarker candidates. HSP10 protein levels were in agreement with mRNA results observed in breast cancer cell lines reported in the Cancer Cell Line Encyclopaedia. In conclusion, HSP10 represents an excellent biomarker candidate for further validation.
Citation Format: Sadr-ul Shaheed, Andreas Hadjisavvas, Kleitos Sokratous, Paul Loadman, Chris Sutton, Kyriacos Kyriacou. Analysis of HSP10 as a putative biomarker of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1576. doi:10.1158/1538-7445.AM2015-1576
Abstract 1583: Circulating tumor cells isolated from non-small cell lung cancer patients using the in vivo CellCollector Technology
Authors: Krahn Thomas , Gasiorowski Lukasz , Dyszkiewicz Wojciech , Dworacki Grzegorz , Zabel Maciej , Hoon Dave S. , Herold Stefanie , Nowack Bjoern , Tucholsky Johannes , Schumann Christian , Lücke Klaus 
Published: August 2015

Abstract
Access to tumor tissue is often limiting and archival samples may not be reflective of the current disease. Alternative approaches using liquid biopsies are being explored to support personalized treatment of cancer patients. Circulating tumor cells (CTCs) detached from primary tumors or metastases into the blood may reflect the current molecular tumor profile providing the opportunity to monitor molecular changes in the tumor. As CTCs are rare cells in the bloodstream and most in vitro approaches for capturing CTCs are based on small samples volumes (5 - 10 ml), accurate and reliable quantification of CTCs is difficult to achieve. We report on a comprehensive clinical study using a novel CellCollectorTM for in vivo isolation of CTCs.
Eighty four stage I - IIIB non-small cell lung cancer (NSCLC) patients and 7 healthy individuals were screened for CTCs using a CellCollectorTM (Gilupi, Germany) device. Molecular analysis of a patient with known mutation in the KRAS gene (G12D) was performed to confirm the predictive value of CTCs as “liquid biopsy”. CTCs were detected in 65 out of 84 NSCLC patients (77.4%) (median: 13 CTCs; range from 0 - 300). For comparison, using the U.S. Food and Drug Administration-cleared CellSearch® system only fifteen samples (17.8%) in this cohort were positive (median: 0 CTCs; range from 0-300). In all paired samples, the CellCollectorTM detected the same or higher numbers of CTCs. Healthy individuals were devoid of any cells classified as CTC. Investigating the KRAS status on CTCs captured by the CellCollectorTM, we were able to substantiate the G12D mutation that has earlier on been identified in the tissue of the primary lung tumor.Conclusions: The CellCollectorTM is a promising novel device for the in vivo isolation of CTCs and the device effectively isolated CTCs from NSCLC patients of all stages including the non-metastatic setting. The implementation of the CellColletorTM into clinical practice has the potential for early disease detection. Furthermore, this approach allows the molecular characterization of CTCs for possible therapeutic targets and early response to treatment which might be used in the setting of personalized cancer therapies and clinical development.
Citation Format: Thomas Krahn, Lukasz Gasiorowski, Wojciech Dyszkiewicz, Grzegorz Dworacki, Maciej Zabel, Dave S. Hoon, Stefanie Herold, Bjoern Nowack, Johannes Tucholsky, Christian Schumann, Klaus Lücke. Circulating tumor cells isolated from non-small cell lung cancer patients using the in vivo CellCollector Technology. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1583. doi:10.1158/1538-7445.AM2015-1583
Abstract 1592: CXCR4 pathways in CTCs: from bioinformatics to immunophenotype
Authors: Kallergi G. , Tsintari V. , Sfakianakis S. , Zervakis M. , Mavroudis D. , Georgoulias V. 
Published: August 2015

Abstract
Introduction: Bioinformatics’ analysis regarding gene expression in Normal tissue vs cancer tissue, Normal blood vs cancer patients’ blood and Normal blood vs cancer tissue revealed a subgroup of 24 genes which potentially could be overexpressed in CTCs. Among these genes are: CXCR4, a chemokine receptor which is involved in tumor metastasis and, JUNB a transcription factor participating in CXCR4 pathway. The objective of this study was to confirm the results of bioinformatics’ analysis in samples from breast cancer patients and therefore to evaluate the expression of CXCR4 and JUNB in CTCs.
Methods: Triple staining immunofluoresence with panytokeratin/CXCR4/JUNB antibodies were performed in SKBR3, MDA-MB231, MCF7 and Hela cell lines. The same experiments were performed in PBMCs from normal (n = 10.) subjects and in PBMCs (n = 55) from untreated metastatic breast cancer patients.
Results: Since CXCR4, as a chemokine receptor is also expressed on hematopoietic cells, its expression on CTCs was quantified using the ARIOL system. We used cell lines and both normal vs patients’ PBMCs in order to establish an expression pattern of both molecules. Quantification experiments among cell lines revealed that CXCR4 was overexpressed in SKBR3 following the subsequent hierarchy SKBR3&gt;MCF7&gt;MDA-MB231&gt;Hela. Accordingly, the expression pattern of JUNB in cell lines was SKBR3&gt;Hela&gt;MCF7&gt;MDA-MB231 with higher expression in SKBR3 and lower in MDA-MB 231. Statistical analysis revealed significant differences in the expression of both molecules between healthy donors’ PBMCs and patient's PBMCs.
Subsequently, CTCs were detected in 17 out of 55 screened patients (31%). Mean intensity of CTCs for CXCR4 was 34.38 and it was higher than Hela and lower than SKBR3. Patients with CXCR4-positive CTCs (with mean expression higher than 95% of normal PBMCs) were 53%. In addition 84% of the examined CTCs had expression profile higher than normal PBMCs.
JUNB expression in CTCs (above 95% of normal PBMCs) was identified in 76.92% of patients. JUNB mean expression in CTCs was 26.1 and it was lower than SKBR3 and higher than MCF7. Furthermore 64.3% of the total CTCs have expression higher than Normal PBMCs.
Conclusion: CXCR4 and JUNB are highly expressed in CTCs derived from breast cancer patients, in agreement to bioinformatics’ analysis. Quantification of immunofluoresence potentially delineates a subgroup of patients with high expression of CXCR4 and JUNB that could benefit from target therapies.
Citation Format: G. Kallergi, V. Tsintari, S. Sfakianakis, M. Zervakis, D. Mavroudis, V. Georgoulias. CXCR4 pathways in CTCs: from bioinformatics to immunophenotype. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1592. doi:10.1158/1538-7445.AM2015-1592
Abstract 1603: High purity isolation of circulating tumor cells for next-generation sequencing
Authors: Mohd Salleh Nur Lina , Lee Yi Fang , Tan Mei Hui , Rosario Michelle A. , Soo Ross A. , Bhagat Ali Asgar , Soong Richie Chuan Teck 
Published: August 2015

Abstract
Background: Being able to capture circulating tumor cells (CTCs) and characterize them at a molecular level promises novel insights into the mechanisms that drive metastasis, tumor recurrence and drug resistance. However, next generation sequencing (NGS) of CTCs has been challenged by antibody-enrichment bias, low CTC purity and nucleic acid yields commonly derived from existing technologies. Here, we describe the results of a new label-free protocol for CTC enrichment and NGS analysis.
Methods: The lung adenocarcinoma cell line, NCI-H1975, with EGFR T790M and L858R mutations, and colorectal cancer cell line HCT-116, with KRAS G13D mutation, were fluorescently labelled and spiked in concentrations of 250, 50, 10 and 0 cells per 7.5 mL healthy volunteer blood in duplicate. CTCs were enriched using a modified protocol of the label-free spiral microfluidics-based ClearCell® FX system. DNA was extracted by QIAamp Micro kit and sequenced using the Ion AmpliSeq Cancer Hotspot Panel and Ion Torrent PGM system.
Results: Imaging analysis indicated that CTCs were efficiently enriched (40-70% recovery) with extremely low leukocyte background (650-1300 cells). Despite a low DNA quantity (&lt;5ng), an average depth of 6897 reads and 97% coverage was achieved in NGS analysis. Expected mutations were detectable in samples down to 10 spiked tumor cells (0.5% CTC purity). Analysis of CTCs from clinical samples is currently on-going.
Conclusion: The new protocol generated sufficient label-free CTC purity for NGS analysis, overcoming current limitations in the field, and facilitating discovery and clinical application.
Citation Format: Nur Lina Mohd Salleh, Yi Fang Lee, Mei Hui Tan, Michelle A. Rosario, Ross A. Soo, Ali Asgar Bhagat, Richie Chuan Teck Soong. High purity isolation of circulating tumor cells for next-generation sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1603. doi:10.1158/1538-7445.AM2015-1603
Abstract 1613: β-lapachone: a novel targeted therapy for atypical teratoid rhabdoid tumors (ATRTs)
Authors: Moore Zachary R. , Stuart Sarai , Cholka Agnieszka , Venkataraman Ashwin , Xu Jingying , Erdreich-Epstein Anat , Rakheja Dinesh , Boothman David A. , Amatruda James F. , Laetsch Theodore W. 
Published: August 2015

Abstract
Atypical teratoid rhabdoid tumors (ATRTs) are aggressive malignant neoplasms that occur in the CNS, most commonly in children &lt;3 years of age. Despite intensive chemo-radiotherapy and surgery, the outcomes for patients with this disease remain dismal, with ∼75% of patients dying from their disease at a median of 10 months after diagnosis. Thus, it is critical to identify and validate novel ATRT targets for new therapies. We found that the pathognomonic genetic lesion of ATRTs, loss of the SWI/SNF chromatin remodeling complex member INI1/hSNF5/SMARCB1, leads to high expression of NAD(P)H:quinone oxidoreductase 1 (NQO1), a two-electron oxidoreductase. Thus, we hypothesized that ATRTs will be vulnerable to drugs, such as ß-lapachone (ß-lap, ARQ761 in clinical form), that selectively kill NQO1-expressing cells. A panel of ATRT cell lines exhibited overall high NQO1 expression and low micromolar sensitivity to ß-lap (IC50 1.6-4 uM), with the exception of cell lines that were homozygous for the C609T NQO1 (*2) polymorphism, which exhibited no NQO1 activity and were resistant to ß-lap treatment (IC50 &gt;15 uM). A two-hour pulse with ß-lap caused a burst of ROS-mediated DNA damage and PARP1 hyperactivation, resulting in NAD+ and ATP depletion and caspase-independent, mu-calpain-mediated apoptosis. Co-treatment with dicoumarol, a specific inhibitor of NQO1, prevented these effects by blocking the NQO1-dependent bioactivation of ß-lap. Low expression of NQO1 in normal brain and other pediatric tissues suggests a wide therapeutic window for ß-lap. These findings encourage the continued study of ß-lap and other NQO1 bioactivated therapeutics for the treatment of this recalcitrant disease. This work was supported by NIH/NCI R01 CA102972 to DAB and a REACH award from the Alex's Lemonade Stand Foundation to JFA and TWL.
Citation Format: Zachary R. Moore, Sarai Stuart, Agnieszka Cholka, Ashwin Venkataraman, Jingying Xu, Anat Erdreich-Epstein, Dinesh Rakheja, David A. Boothman, James F. Amatruda, Theodore W. Laetsch. β-lapachone: a novel targeted therapy for atypical teratoid rhabdoid tumors (ATRTs). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1613. doi:10.1158/1538-7445.AM2015-1613