tbuckley/cabot-search huggingface dataset:
Abstract 5499: The reprogramming of the steroid receptor binding landscape at active enhancers is associated with a fast DNA residence time through a mechanism termed dynamic assisted loading in breast cancer cells
Authors: Erin Swinstead, Tina Miranda, Ville Paakinaho, Songjoon Beak, Gordon Hager
Journal: Cancer Research (2017)

Abstract The transcription factor (TF), FoxA1 has been described as a pioneer factor, implicated in steroid receptor (SR) binding patterns. Classically it has been proposed that the pioneer factor model is a slow and static binding event. However, it has recently been described that the estrogen and glucocorticoid receptors (ER and GR), can regulate the binding patterns of each other in a mouse mammary cell line defined as dynamic assisted loading. Further, this phenomenon has been extending demonstrating that both ER and GR can recruit FoxA1 to specific binding sites associated with an increase in chromatin accessibility and fast DNA residence times. This was also associated with the absence of a DNaseI footprint for the initiating and secondary factor supporting the assisted loading model. To further investigate the molecular mechanism behind the dynamic assisted loading model we have characterized the binding and transcriptional landscape of ER and GR in a number of breast cancer cell line models. Genome wide analysis of ChIP and DNaseI hypersensitivity assays upon single and dual activation show that both SRs can recruit each other to a specific subset of binding sites associated with an increase in chromatin accessibility. Therefore, depending on the chromatin landscape, one factor functions as the initiating factor and the other the secondary factor. Further, RNA polymerase II (RNAP II), p300, and H3K27ac binding patterns are associated with the newly programed ER or GR binding sites. Together this suggests chromatin reorganization upon dual activation of either ER or GR (the initiating factors) and recruitment of the secondary factor (ER or GR) through an assisted loading mechanism. Further, we have demonstrated an association of the transcriptional machinery at these newly acquired binding sites at active enhancers. These results propose that many TFs in a given cell have the potential to affect the binding landscape of other TFs, depending on the chromatin context. In addition, this study has shifted our classical understanding of pioneer factors in breast cancer, demonstrating that not only can SRs alter the response of FoxA1 but also each other though highly dynamic and fast DNA interactions associated with active enhancers and transcription. Citation Format: Erin Swinstead, Tina Miranda, Ville Paakinaho, Songjoon Beak, Gordon Hager. The reprogramming of the steroid receptor binding landscape at active enhancers is associated with a fast DNA residence time through a mechanism termed dynamic assisted loading in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5499. doi:10.1158/1538-7445.AM2017-5499
Abstract 4457: Inverse relationship between exon 8 single nucleotide polymorphism (c.1293 C&amp;gt;T) of gigaxonin and human tumor cell growth
Authors: Eri S. Srivatsan, Kimberly J. Hwang, Albert Ko, Jenna R. Chatoff, Saroj K. Basak, Natarajan Venkatesan, Fernando Palma-Diaz, Michael S. Lewis, Pascale Bomont, Marilene B. Wang
Journal: Cancer Research (2017)

Abstract Gigaxonin, a product of the Giant Axonal Neuropathy (GAN) gene located on chromosome 16, is involved in intermediate filament processing of neural cells and vimentin fibers in fibroblasts. Previous studies have shown an interaction between p16 and gigaxonin in cisplatin mediated ubiquitination of NFkB. Genomic studies have indicated higher frequency (44.25%) of exon 8 single nucleotide polymorphism (SNP) (c.1293 C&amp;gt;T) of gigaxonin in the individuals of Caucasian population compared to normal population (22%). The polymorphism frequency is much lower in individuals of other ethnicities. To determine the relationship to tumors, we analyzed exon 8 polymorphism in HPV positive and negative cervical and head and tumors. Our studies showed a 47.25% polymorphic frequency in these tumors. There was no relationship between the presence of polypmorphism and HPV status. However, there was an inverse relationship between polymorphism and tumor recurrence. Our studies have further shown higher expression of gigaxonin protein in cancer cell lines containing the polymorphic T allele. Growth assays in vitro and in soft agar have shown a direct relationship between the presence of the T allele and slower cell line growth. Our results therefore indicate that in addition to p16 expression, exon 8 SNP could also serve as a diagnostic marker of chemo sensitivity in human tumors. Citation Format: Eri S. Srivatsan, Kimberly J. Hwang, Albert Ko, Jenna R. Chatoff, Saroj K. Basak, Natarajan Venkatesan, Fernando Palma-Diaz, Michael S. Lewis, Pascale Bomont, Marilene B. Wang. Inverse relationship between exon 8 single nucleotide polymorphism (c.1293 C&amp;gt;T) of gigaxonin and human tumor cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4457. doi:10.1158/1538-7445.AM2017-4457
Abstract 1874: First demonstration that hypoxia targeting with radiation improves tumor control in a mammal tumor model
Authors: Howard J. Halpern, Boris Epe;, Matthew C. Maggio, Martyna Krzykawska-Serda, Gage H. Redler, Richard C. Miller, Eugene D. Barth, Ralph R. Weichselbaum
Journal: Cancer Research (2017)

Abstract For over a century, resistance of radiation to living tissues has been associated with hypoxia, a local lack of molecular oxygen, or low pO2. The focus of this research has been to validate the hypothesis that has been assumed, but not proven over the past century, that radiation treatment focused specifically on hypoxic regions of tumors would improve tumor curability. This research used Electron Paramagnetic Resonance (EPR) imaging to provide absolute pO2 images in volume elements or voxels of murine tumors with 1 torr pO2 resolution and 0.7 mm spatial resolution in FSa fibrosarcomas in the legs of C3H mice. We define hypoxic regions of tumors as those whose image subvolumes or voxels have low pO2, voxels less than 10 torr. We have established EPR pO2 imaging as a reliable locator of relevant radiobiologically relevant hypoxia. To determine if pO2 based dose painting improves tumor cure, we implemented the XRAD225Cx system to deliver gantry based x-ray treatments to mouse tumors accurately registered with EPR pO2 images. All tumors were pretreated with a dose of radiation that had been determined in separate experiments to cure 30% of tumors, a TCD30. Conclusive failure to demonstrate a difference between treating crude spherical volumes including ~ 85% of hypoxic voxels with an additional curative dose compared with treatment with shells of radiation avoiding hypoxia (anti-boosts) proved tenets of radiation biology: a few surviving hypoxic clonogens cause radiation treatment failure. In response, we implemented rapid 3D printing Tungsten loaded, highly conformal plastic blocks to compare treating ~100% of hypoxic tumor voxels with hypoxia avoidance, treating similar volumes of well oxygenated tumor. Only then did we observe significant (p&amp;lt;0.01) tumor control differences between hypoxic boosts and anti-boosts. This is the first validation of the curative effectiveness of focusing hypoxia based dose painting in mammalian tumors. Citation Format: Howard J. Halpern, Boris Epe;, Matthew C. Maggio, Martyna Krzykawska-Serda, Gage H. Redler, Richard C. Miller, Eugene D. Barth, Ralph R. Weichselbaum. First demonstration that hypoxia targeting with radiation improves tumor control in a mammal tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1874. doi:10.1158/1538-7445.AM2017-1874
Abstract 5605: Frequencies of HLA-Class I and II alleles between German patients with renal cell carcinoma and healthy controls can be different
Authors: Steffen Göbel, Astrid Kehlen, Karen Bluemke, Wolfgang Altermann, Gerald Schlaf, Kersten Fischer, Paolo Fornara, Bernd Wullich, Sven Wach, Helge W. Taubert
Journal: Cancer Research (2017)

Abstract The human leukocyte antigen (HLA) system is a major part of the human immune system and has an impact on tumor initiation, tumor progression and immunosurveillance. Renal cell carcinoma tumors are considered to be immunogenic. Therefore, we studied the allele frequencies of four gene loci (HLA-A, -B, -C and HLA-DR) in a cohort of 106 German renal cell carcinoma (RCC) patients and in 201 healthy controls. HLA-A-C were determined using serological methods, whereas HLA-C12, C14, C16, C18 and HLA-DR were characterized through the use of standard molecular biological methods. The presence of HLA-A and HLA-B alleles did not differ significantly between RCC patients and healthy controls. However, the occurrence of the HLA-C*12 allele was significantly increased in German RCC patients compared with healthy controls (P &amp;lt; 0.005; RR=2.3; Fisher’s exact test), whereas the occurrence of the HLA-DRB1*04 allele was significantly reduced in RCC patients compared with healthy controls (P &amp;lt; 0.05; RR=0.7; Fisher’s exact test). But the presence of allele HLA-C*12 was not significantly associated with 10 years overall survival. We suggest that the frequency of HLA alleles can affect development of RCC and could add knowledge as predictive marker for future immunotherapies. Citation Format: Steffen Göbel, Astrid Kehlen, Karen Bluemke, Wolfgang Altermann, Gerald Schlaf, Kersten Fischer, Paolo Fornara, Bernd Wullich, Sven Wach, Helge W. Taubert. Frequencies of HLA-Class I and II alleles between German patients with renal cell carcinoma and healthy controls can be different [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5605. doi:10.1158/1538-7445.AM2017-5605
Abstract 900: Tumor Treating Fields (TTFields) affect human glioma cell migration, invasion and adherence properties in vitro
Authors: Dario Garcia-Carracedo, Rosa S. Schneiderman, Einav Zeevi, Anna Shteingauz2, Moshe Giladi, Tali Voloshin, Yaara Porat, Mijal Munster, Roni Blat, Eilon D. Kirson, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2017)

Abstract TTFields, an approved treatment modality for glioblastoma, are delivered via continuous, noninvasive application of low intensity, intermediate frequency alternating electric fields. The antimitotic effects of TTFields have been extensively investigated. We investigated other processes that may be affected by TTFields such as human glioma cell migration and cellular invasion properties. Four human glioma cell lines were treated with TTFields using the inovitro system. Cell migration rates were measured using wound healing assays. Invasion assays were performed using a modified Matrigel coated Boyden chamber. Cell adhesion assays were performed during TTFields treatment and compared to untreated controls. At the end of TTFields’ treatment, adhered cells were trypsinized and counted. A cells de-adhesion assay was performed following 24 and 72 hours of TTFields application with the outcome being the number of cells removed after varying times of trypsinization. Application of TTFields in-vitro led to a significant reduction in cell migration velocity compared with untreated control cells. Furthermore, comparison of the anti-migratory efficacy of TTFields applied from 2 directions vs. a single direction revealed that the single direction approach applied perpendicularly to the course of migration was more effective than TTFields applied in 2 directions or in a single parallel direction. Glioma cells invasion was significantly reduced compared to untreated cells in all tested cell lines. Cell adhesion to the substrate (fibronectin) was significantly reduced when exposed to TTFields. On the other hand, cell de-adherence following TTFields treatment took significantly longer time of trypsinization. Our results suggest that human glioma cell motility is impaired by exposure to TTFields. Both alterations in cells adherence and de-adherence during exposure to TTFields may contribute to reduction in cell motility. Further studies are needed to elucidate the mechanism by which TTFields disrupts cellular motility in glioma cancer cells. Citation Format: Dario Garcia-Carracedo, Rosa S. Schneiderman, Einav Zeevi, Anna Shteingauz2, Moshe Giladi, Tali Voloshin, Yaara Porat, Mijal Munster, Roni Blat, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Tumor Treating Fields (TTFields) affect human glioma cell migration, invasion and adherence properties in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 900. doi:10.1158/1538-7445.AM2017-900
Abstract 4737: A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells
Authors: Jiyoun Yeo, Erin Crawford, Xiaolu Zhang, Sadik Khuder, Tian Chen, Albert Levin, Thomas Blomquist, James Willey
Journal: Cancer Research (2017)

Abstract Background: Annual low dose CT (LDCT) screening of individuals at high demographic risk reduces lung cancer mortality by more than 20%. However, subjects selected for screening based on demographic criteria typically have less than a 10% lifetime risk for lung cancer. Thus, there is need for a biomarker that better stratifies subjects for LDCT screening. Toward this goal, we previously reported a lung cancer risk test (LCRT) biomarker comprising 14 genome-maintenance (GM) pathway genes measured in normal bronchial epithelial cells (NBEC) that accurately classified cancer (CA) from non-cancer (NC) subjects. The primary goal of the studies reported here was to optimize the LCRT biomarker for high specificity and ease of clinical implementation. Methods: Targeted competitive multiplex PCR amplicon libraries were prepared for next generation sequencing (NGS) analysis of transcript abundance at 68 sites among 33 GM target genes in NBEC specimens collected from a retrospective cohort of 120 subjects, including 60 CA cases and 60 NC controls. Genes were selected for analysis based on contribution to the previously reported LCRT biomarker and/or prior evidence for association with lung cancer risk. Linear discriminant analysis was used to identify the most accurate classifier suitable to stratify subjects for screening. Results: The best classifier comprised 11 features including age and 10 transcript abundance assays representing nine genes; specifically, CDKN1A, E2F1, ERCC5, GPX1, GSTP1, KEAP1, TP63, XPA, and XRCC1. After cross-validation, the Receiver Operator Characteristic area under the curve was 0.94 (95% CI: 0.92-0.96) and overall classification accuracy was 88.3% (95% CI 82.4%-94.1%). Using a threshold set at 95% sensitivity, specificity was &amp;gt; 70%. Conclusions: The LCRT biomarker reported here displayed high specificity and ease of implementation on a high throughput, quality-controlled targeted NGS platform. As such, it is optimized for clinical validation in specimens from the ongoing LCRT blinded prospective cohort study. Following validation, the biomarker is expected to have clinical utility by better stratifying subjects for annual lung cancer screening compared to current demographic criteria alone. Citation Format: Jiyoun Yeo, Erin Crawford, Xiaolu Zhang, Sadik Khuder, Tian Chen, Albert Levin, Thomas Blomquist, James Willey. A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4737. doi:10.1158/1538-7445.AM2017-4737
Cytogenetically cryptic ZMYM2-FLT3 and DIAPH1-PDGFRB gene fusions in myeloid neoplasms with eosinophilia
Authors: M Jawhar, N Naumann, M Knut, J Score, M Ghazzawi, B Schneider, K-A Kreuzer, M Hallek, H G Drexler, J Chacko, L Wallis, A Fabarius, G Metzgeroth, W-K Hofmann, A Chase, W Tapper, A Reiter, N C P Cross
Journal: Leukemia (2017)
Abstract 2380: Insertion mutations in the tyrosine kinase domain of FLT3 display a higher oncogenic potential than the D835Y mutation in acute myeloid leukemia
Authors: Alissa Marhäll, Thomas Fischer, Florian Heidel, Julhash U. Kazi, Lars Rönnstrand
Journal: Cancer Research (2017)

Abstract Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for a large number of deaths. Mutation in FMS-like tyrosine kinase 3 (FLT3) is one of the most prevalent factor in this heterogeneous disease. The major mutations in FLT3 can be categories as internal tandem duplications (ITD) and point mutations. Recent studies suggest that ITDs are subdivided in to two groups depending on their location: the juxtamembrane domain (ITD-JM) and the tyrosine kinase domain (ITD-TDK). Although, ITD-JM has been characterized well the ITD-TKD has not yet been studied well due to its recent discovery. For this reason, we compared ITD mutations in TKD and JM, as well as the most frequently occurring point mutation located in the TKD, D835Y. The purpose of this study was to understand whether it is the mutation’s nature or location that plays the driving role in leukemogenesis. We used a cytokine-dependent mouse pro-B cell line, BaF3, to overexpress different FLT3 mutants. We first examined the colony formation capacity in semisolid cytokine- and serum-free medium. The assay resulted in indistinguishable number and size of colonies for both ITD-JM and ITD-TKD, while D835Y-TKD transfected cells failed to form colonies suggesting that the ITD-TKD mutations have stronger transforming potential than other TKD mutations. In addition to colony formation assays, cell proliferation and survival was significantly higher in ITD-TKD expressing cells compared to cells expressing D835Y-TKD. Finally, we showed that phosphorylation of STAT5 and AKT is increased in ITD-TKD, while other FLT3 downstream signaling remained unaffected. All together, our data suggest that ITD-TKD displays higher oncogenic potential than other TKD mutants. Citation Format: Alissa Marhäll, Thomas Fischer, Florian Heidel, Julhash U. Kazi, Lars Rönnstrand. Insertion mutations in the tyrosine kinase domain of FLT3 display a higher oncogenic potential than the D835Y mutation in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2380. doi:10.1158/1538-7445.AM2017-2380
Abstract LB-271: SplashRNA, a sequential classification algorithm for ultra-potent RNAi
Authors: Raphael Pelossof, Lauren Fairchild, Christina S. Leslie, Christof Fellmann
Journal: Cancer Research (2017)

Abstract We present SplashRNA, a sequential classifier - analogous to face detection algorithms - to predict ultra-potent microRNA-based short hairpin RNAs (shRNAs) for virtually any gene. Trained on existing and novel large-scale datasets, SplashRNA outperforms previous algorithms and reliably predicts the most efficient shRNAs for a given gene. Combined with the optimized miR-E backbone, &amp;gt;90% of high-scoring SplashRNA predictions trigger &amp;gt;85% protein knockdown when expressed from a single genomic integration. SplashRNA can significantly improve the accuracy of loss-of-function genetics studies and facilitates the generation of compact shRNA libraries. The open source SplashRNA platform completes the RNAi toolkit to harness microRNA-based shRNAs for robust single-gene and multiplexed inducible and reversible target inhibition. Citation Format: Raphael Pelossof, Lauren Fairchild, Christina S. Leslie, Christof Fellmann. SplashRNA, a sequential classification algorithm for ultra-potent RNAi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-271. doi:10.1158/1538-7445.AM2017-LB-271
Abstract 3516: RUNX1 controls EGFR signaling pathway in non-small cell lung cancer cells
Authors: Akihiko Matsuo
Journal: Cancer Research (2017)

Abstract Epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy for non-small lung cancer (NSCLC). Mitogen-inducible gene 6 (Mig6) is known to be a negative feedback regulator of EGFR. Mig6 inhibits EGFR kinase activity and promote wild-type EGFR trafficking to the degradation pathway. Down-regulation of Mig6 is found in poor prognostic NSCLC. Previous gene array analysis results suggested that Mig6 is downregulated by runt-related transcription factor 1 (RUNX1), yet the detailed relationship between RUNX1 and Mig6 in NSCLC has not been elucidated. Herein we demonstrate that RUNX1 inhibition is effective for wild-type EGFR NSCLC. Tet-inducible shRNA mediated RUNX1 knockdown in wild-type EGFR cell line LU99A led to the increased expression of Mig6 and decreased expression of phosphorylated form of EGFR as well as deactivation of EGFR/ERK pathway. RUNX1 knockdown subsequently induced apoptosis in LU99A cells. Silencing of Mig6 in LU99A cells promoted the proliferation of these cancer cells and increased expression of phosphorylated form of EGFR, highlighting the importance of this EGFR signaling cascade in the maintenance of wild-type EGFR NSCLC. Indeed, RUNX1 overexpression promoted cell proliferation and decreased expression of Mig6 and increased phosphorylated form of EGFR. Notably Mig6 knockdown in RUNX1 knockdown LU99A cells increased their proliferation rates, indicating that Mig6 plays an important role in RUNX1-mediated pro-oncogenic pathway. We next examined the efficacy of a novel small molecule which specifically binds and inhibits the RUNX1 (We named it as CM). CM was drastically effective for wild-type EGFR NSCLC cell lines A549 and LU99A which are naturally resistant to EGFR Tyrosine kinase inhibitor: gefitinib. In addition, CM suppressed tumor growth of xeno-transplanted A549 cells in immune-deficient mice in vivo. Our study underscores the importance of RUNX1 inhibition therapy in the management of gefitinib-resistant NSCLC patients. Citation Format: Akihiko Matsuo. RUNX1 controls EGFR signaling pathway in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3516. doi:10.1158/1538-7445.AM2017-3516