tbuckley/cabot-search huggingface dataset:
Abstract 901: The mechanobiome of pancreatic cancer: a viable, targetable drug space
Authors: Alexandra Surcel, Eric S. Schiffhauer, Dustin Thomas, Qingfeng Zhu, Robert Anders, Douglas Robinson
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an annual mortality rate of 37,000 in the US alone. Its 5-year survival rate of ~6% remains relatively unchanged over the past 4 decades. Because PDAC has elevated rates of de novo and acquired resistance to traditional chemotherapies, we are exploring new drug spaces that target metastatic hepatic disease, the primary mortality factor for patients. Specifically, we have identified the cluster of proteins that sense and respond to mechanical stimuli - collectively known as the mechanobiome. This cytoskeletal machinery is responsible in large part for endowing metastatic cells with the ability to navigate through different tissue types. Based on their mechanoresponsiveness profile, we have predicted and identified via western blot and immunohistochemistry proteins in the mechanobiome that are upregulated in patient-derived pancreatic tissues. These proteins include non-muscle myosin IIA and IIC, alpha-actin-4, and filamin B. We are performing knockdown and overexpression studies of these isoforms on 2D and 3D behaviors - cell mechanics, migration, invasion, and tissue sphere formation and are poised to begin mouse studies on the metastatic sufficiency in altering the expression of these proteins. In addition, we are testing 4-HAP, a small molecule mechanics modulator that we previously identified that targets myosin IIC, thus affecting PDAC mechanics in PDAC murine models. Limited studies reveal that 4-HAP reduces metastasis. These data suggest that direct targeting of the mechanobiome may eventually expand treatment strategies for pancreatic cancer. Citation Format: Alexandra Surcel, Eric S. Schiffhauer, Dustin Thomas, Qingfeng Zhu, Robert Anders, Douglas Robinson. The mechanobiome of pancreatic cancer: a viable, targetable drug space [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 901. doi:10.1158/1538-7445.AM2017-901
Abstract 647: Bortezomib enhances CD8+T Lymphocyte antitumor effector function: Potential mechanism(s) via notch regulation
Authors: Ariana N. Renrick, Menaka C. Thounaojam, Portia Thomas, Samuel T. Pellom, Anil Shanker
Journal: Cancer Research (2017)

Abstract The immunosuppressive tumor microenvironment disturbs host antitumor immunity by multiple mechanisms including interference with the Notch system, which is important for various metazoan cell fate decisions and hematopoietic cell differentiation and function. We observed that treatment with the proteasome inhibitor bortezomib in mice bearing various solid tumors resulted in an upregulated expression of various Notch signaling components in lymphoid tissues, thereby increasing CD8+ T lymphocyte IFNγ secretion and expression of effector molecules, perforin and granzyme B, as well as the T-box transcription factor eomesodermin. Of note, bortezomib reversed tumor-induced downregulation of Notch receptors, Notch1 and Notch2, as well as increased the levels of cleaved Notch intracellular domain (NICD) and downstream targets Hes1 and Hey1 in tumor-draining CD8+ T cells. Moreover, bortezomib promoted CD8+ T cell nuclear factor-κB (NFκB) activity by increasing the total and phosphorylated levels of the IκB kinase and IκBα as well as the cytoplasmic and nuclear levels of phosphorylated p65. Even when we blocked NFκB activity by Bay-11-7082, or NICD cleavage by γ-secretase inhibitor, bortezomib significantly increased expression of Notch Hes1 and Hey1 genes as well as perforin, granzyme B and eomesodermin in activated CD8+ T cells. Data suggest that bortezomib can rescue tumor-induced dysfunction of CD8+ T cells by its intrinsic stimulatory effects promoting NICD-NFκB crosstalk. We are also elucidating components of microRNA regulation affecting NICD-NFκB crosstalk. Our preliminary data suggest that bortezomib is also able to positively regulate miR-155 expression in CD8+ T cells from mice bearing tumor. As well as, miR-155 suppression downregulates bortezomib-induced increase in Notch target genes in T cells. We are currently investigating alternative proteasome inhibitors in order to understand whether bortezomib’s effect on miR-155 expression in CD8+ T cells is specific to bortezomib or primarily conducive to a proteasome inhibition effect. These findings provide novel insights on using bortezomib not only as an agent to sensitize tumors to cell death, but also to provide lymphocyte-stimulatory effects, thereby overcoming immunosuppressive actions of tumor on antitumor T cell functions. Citation Format: Ariana N. Renrick, Menaka C. Thounaojam, Portia Thomas, Samuel T. Pellom, Anil Shanker. Bortezomib enhances CD8+ T Lymphocyte antitumor effector function: Potential mechanism(s) via notch regulation [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 647. doi:10.1158/1538-7445.AM2017-647
Abstract 4164: TRAIL resistance of glioblastoma cells is associated with DNA damage signalling network
Authors: Idot;lknur Sur, Kerem Muslu, Ahmet Cingöz, Tuğba Bağcı Önder
Journal: Cancer Research (2017)

Abstract To reduce the risk of ageing associated dysfunctions and maintain the genomic stability, cells need a complex DNA repair mechanisms. Defects in this pathway or accumulation of DNA damage lead to genome instability, tumorigenesis, and ageing. Chemotherapy and radiotherapy are designed to kill cancer cells by inducing DNA damage and triggering cellular ageing. Surgery followed by combined chemotherapy and radiotherapy is currently the standard therapy for glioblastoma multiforme (GBM) which is the most common primary brain tumor. TNF related apoptosis-inducing ligand (TRAIL) is promising anti-cancer agent for GBM therapy, as it induces apoptotic death in only cancerous cells, but not in normal cells. However, the mechanisms underlying TRAIL resistance in GBM have remained elusive. To understand the role of DNA damage response (DDR) mechanism and develop more effective therapeutic approaches, TRAIL resistant and sensitive T98G cells were generated. The effect of DDR proteins (H2AX (Ser319), ATM total, ATR total, CHK1 total, CHK2 total, ATM (Ser1981), ATR (Ser428), CHK1 (Ser345), CHK2 (Ser19) and 53BP1) on TRAIL resistance was detected in TRAIL resistant and sensitive T98G cells. These proteins showed different level of protein expressions in TRAIL resistance and sensitive T98G cells. Most remarkable difference was found in the level of phosphorylated kinase CHK2 (Ser19) with higher expression level in TRAIL resistant T98G cells than TRAIL sensitive T98G cells. Therapies that inhibit CHK2 (Ser19) levels in glioma may enhance the efficacy of TRAIL treatment. In immunofluorescence analysis, increased number of γH2AX foci was noted upon TRAIL treatment. These findings demonstrate that DNA damage signalling pathways contribute to TRAIL resistance and targeted inhibition of DNA repair factors can provide the most effective therapeutic strategies to overcome TRAIL resistance of GBMs. Moreover, the information from this study may hold answers for cancer research in future and serve as a potential suppressor for the treatment of cancer. Citation Format: İlknur Sur, Kerem Muslu, Ahmet Cingöz, Tuğba Bağcı Önder. TRAIL resistance of glioblastoma cells is associated with DNA damage signalling network [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 4164. doi:10.1158/1538-7445.AM2017-4164
Abstract 393: Predicting DNA accessibility in the pan-cancer tumor genome using RNA-Seq, WGS, and deep learning
Authors: Kamil Wnuk, Jeremi Sudol, Shahrooz Rabizadeh, Patrick Soon-Shiong, Christopher Szeto, Charles Vaske
Journal: Cancer Research (2017)

Abstract DNA accessibility, chromatin regulation, and genome methylation are key drivers of cancer transcription. However, there is much left to be understood about the functional implications of sequence-level data to the regulation of gene expression, especially when it comes to the noncoding genome. Recently [Kelley, D., Snoek, J., and Rinn, J., Genome Res. 2016] trained neural networks to effectively predict DNA accessibility in multiple cell types. These models make it possible to explore the impact of mutations on the predicted accessibility and thus directly link one aspect of the gene regulation puzzle all the way down to the sequence level. We present a model with improved performance on the original dataset of 164 ENCODE and Roadmap Epigenomics Consortium sample types, and then extend the method to provide predictions on any sample with RNA-Seq data without need of DNase-seq for the sample. We first demonstrate that with several model and algorithmic changes we improve performance across 164 cell types from a mean AUC of 0.895 to a mean AUC of 0.910. Unfortunately current accessibility models require DNase-seq for each new cell type. Models for detecting transcription factor binding sites, which rely on ChIP-seq for training data, also share this issue. In order to generalize sequence-based predictive models to apply to unseen cell types without requiring re-training we investigate using RNA-Seq as a proxy signature of cell type. The model aims to capture the interdependence of gene expression levels that characterize a cell with the regulatory logic in which sequence-level signatures are combined to determine accessibility without restriction to cell type. We explore the model’s performance when applied to held-out cell types in the ENCODE and Roadmap Epigenomics Consortium data as well as data from the TCGA Pan-Cancer initiative. We look for the impact of non-coding changes in whole-genome sequencing data in TCGA samples, and report on predicted differences in DNA accessibility across cancer subtypes. Citation Format: Kamil Wnuk, Jeremi Sudol, Shahrooz Rabizadeh, Patrick Soon-Shiong, Christopher Szeto, Charles Vaske. Predicting DNA accessibility in the pan-cancer tumor genome using RNA-Seq, WGS, and deep learning [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 393. doi:10.1158/1538-7445.AM2017-393
Abstract 1711: Detection of circulating tumor cells for use as prognostic, predictive and pharmacodynamic biomarkers in neuroblastoma
Authors: Swathi Merugu, Deborah Tweddle
Journal: Cancer Research (2017)

Abstract Introduction: Neuroblastoma (NB) is the commonest extracranial childhood solid tumour. New treatments and a better understanding of drug resistance are needed to improve survival. Circulating tumour cells (CTCs) may provide a source of tumour cells for genetic biomarkers, give insights into tumour load and serve as pharmacodynamic (PD) biomarkers for new treatments. In clinical diagnostics, slide based FISH is used to detect MYCN amplification in neuroblastoma tumours. As it is not possible to conduct slide based FISH on an entire blood sample due to the infrequency of CTCs in peripheral blood (1 in 106 leucocytes), an alternative method FISH-IS (in suspension) was used in the present study to detect MYCN gene amplification using the Imagestream imaging flow cytometer (ISx). Aims: 1) To detect CTCs from blood and disseminated tumour cells (DTC) from bone marrow (BM) from NB patients using the (ISx) 2) To use these cells for genetic and PD biomarker studies for novel targeted therapies. Methods: A panel of NB cell lines (n=6) cloned into neuronal (N) and substrate-adherent (S) types were used to determine expression of NB cell surface markers (GD2 and NCAM) using the ISx. Western blotting and fluorescence activated cell sorting (FACS) were used to validate NCAM and GD2 expression respectively. 25 paired NB patient blood and BM samples were analysed for CTCs and DTCs, 4 unpaired blood samples were analysed for CTCs and one unpaired BM sample was for DTCs using the ISx to detect GD2 +ve and CD45-ve cells. Results: Using the ISx 80-90% of N-type cells immunostained positive for GD2 compared to 0.8 -10% of S-type cells confirmed by FACS. CTCs were detected in 21/29 patient samples and DTCs in 19/26 cases. The numbers of CTCs ranged from 10-522/ml blood and DTCs from 57-35,515/ml of bone marrow. After validating FISH-IS protocol on ISx using NGP and SHSY5Y cell lines, 4 NB patient DTC samples were analysed for MYCN amplification. 2/4 cases showed MYCN gene amplification consistent with results obtained on the primary tumour. Conclusion: This the first study to show that DTCs and CTCs are detectable in NB patient samples using the ISx. Future work will involve further genetic characterisation and development of PD biomarkers for Phase I clinical trials. Citation Format: Swathi Merugu, Deborah Tweddle. Detection of circulating tumor cells for use as prognostic, predictive and pharmacodynamic biomarkers in neuroblastoma [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 1711. doi:10.1158/1538-7445.AM2017-1711
Abstract 4497: Single-cell protein-mRNA co-detection to reveals subpopulation-specific correlation patterns
Authors: Haibiao Gong, Xiaohui Wang, Benjamin Liu, Ilona Holcomb, Gajalakshmi Dakshinamoorthy, Aik Ooi, Gang Sun, Ramesh Ramakrishnan
Journal: Cancer Research (2017)

Abstract We have developed a streamlined workflow for multiplexed co-detection of proteins and mRNAs in single reactions at single-cell resolution. This workflow couples OER for protein detection with reverse transcription (RT) for mRNA detection. In this study, we examined 31 overlapping targets, from a panel of 84 protein and 40 mRNA assays, across three different cell lines (A549, SKBR3 and K562). Unsupervised gene expression profiling analysis, including principal component analysis and hierarchical clustering revealed different aspects of the protein-mRNA relationship. The top 10 genes contributing to cell differentiation were identified for both proteins and mRNAs, and eight of them overlap. This result implies an overall concordance of certain protein and mRNA expression in different cell lines. Our results also demonstrate that cells can be classified into subpopulations based on protein-mRNA expression profiles, and different subpopulations have distinct correlation coefficient values. The correlation between CCNB1 protein and mRNA was low (R = 0.2884) in the whole population. However, there was a subpopulation in which CCNB1 protein correlated strongly with its mRNA. When this subpopulation was analyzed, the R value was 0.8350, while therest of the cells had an R value of 0.0233. More interestingly, in subpopulation I CCNB1 protein level correlated positively with CCNA2 protein (R = 0.9102) but negatively with CCNE1 protein(R = - 0.5249). The observed correlation patterns of these genes match their known expression profiling at cell-cycle phases of S, G2 and M, suggesting that this subpopulation may represent actively dividing cells. This study further indicated that systematic comparisons of protein and mRNA expression data in single cells can reveal additional layers of complexity which are not attainable at bulk levels. Citation Format: Haibiao Gong, Xiaohui Wang, Benjamin Liu, Ilona Holcomb, Gajalakshmi Dakshinamoorthy, Aik Ooi, Gang Sun, Ramesh Ramakrishnan. Single-cell protein-mRNA co-detection to reveals subpopulation-specific correlation patterns [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 4497. doi:10.1158/1538-7445.AM2017-4497
Abstract 495: Somatic copy number variants detection using the NEBNext Direct target enrichment method
Authors: Kruti M. Patel, Sarah K. Bowman, Noa Henig, Amy B. Emerman, Andrew Barry, Charles Elfe, Scott Adams, Salvatore Russello, Ted Davis, Cynthia L. Hendrickson
Journal: Cancer Research (2017)

Abstract Variations in copy number are the most common type of DNA structural variations. Many of these alterations are associated with disease or indicate disease susceptibility. Detection of copy number variants (CNVs) for clinical applications requires efficient, fast and cost effective methods. Here we describe the use of the NEBNext Direct® hybridization-based target enrichment method to identify somatic CNVs with high sensitivity. This approach begins with target enrichment followed by enzymatic digestion of off-target sequences and ligation of adapters that contain unique molecular identifiers (UMIs). The UMIs enhance the identification of duplicate reads and further increase the final number of on-target reads used for variant detection. We used a cell line known to contain a deletion in the CDKN2A gene and spiked DNA isolated from the cell line into a HapMap DNA sample that contains full diploid copies of CDKN2A. We were able to detect the gene deletion as a somatic CNV in a dose dependent manner with high sensitivity. Thus, we demonstrate that the NEBNext Direct approach is an efficient technique to detect somatic CNVs of high and low frequencies. Citation Format: Kruti M. Patel, Sarah K. Bowman, Noa Henig, Amy B. Emerman, Andrew Barry, Charles Elfe, Scott Adams, Salvatore Russello, Ted Davis, Cynthia L. Hendrickson. Somatic copy number variants detection using the NEBNext Direct target enrichment method [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 495. doi:10.1158/1538-7445.AM2017-495
Impact of Early Salvage Radiation Therapy in Patients with Persistently Elevated or Rising Prostate-specific Antigen After Radical Prostatectomy
Authors: Nicola Fossati, R. Jeffrey Karnes, Michele Colicchia, Stephen A. Boorjian, Alberto Bossi, Thomas Seisen, Nadia Di Muzio, Cesare Cozzarini, Barbara Noris Chiorda, Claudio Fiorino, Giorgio Gandaglia, Paolo Dell’Oglio, Shahrokh F. Shariat, Gregor Goldner, Steven Joniau, Antonino Battaglia, Karin Haustermans, Gert De Meerleer, Valérie Fonteyne, Piet Ost, Hendrik Van Poppel, Thomas Wiegel, Francesco Montorsi, Alberto Briganti
Journal: European Urology (2017)
Abstract 5465: Persistent oxidative stress in mouse intestinal and colonic epithelial cells after exposure to 12C-ion radiation
Authors: Shubhankar Suman, Santosh Kumar, Albert J. Fornace, Kamal Datta
Journal: Cancer Research (2017)

Abstract Purpose: 12C-ion radiotherapy is demonstrating favorable results compared to photon radiotherapy for select cancers. While normal tissue exposure is lower with 12C-ions relative to γ-rays, it cannot be completely eliminated and therefore, late tissue toxicity, inflammation and secondary carcinogenesis cannot be ruled out. The goal of this study was to assess the extent of persistent oxidative stress (POS) after 12C radiation exposure and compare the results to that after γ radiation exposure. Methods and Materials: Mice (C57BL/6J; 6 to 8 weeks; male) were irradiated with 0.5 or 1.3 Gy of γ or 12C-ion, and intestinal (IEC), colonic (CEC) epithelial cells and tissues were collected 2 months after radiation exposure. In epithelial cells, intracellular ROS, mitochondrial superoxide, mitochondrial membrane potential (MMP), and cardiolipin oxidation were studied by flow-cytometry. Superoxide dismutase (SOD), catalase, and NADPH oxidase activity along with lipid oxidation were also assessed in epithelial cells using biochemical assays. Results: Our results clearly showed radiation quality and dose-dependent induction of POS. Both intestine and colon showed a higher elevation of intracellular ROS, mitochondrial superoxide, NADPH oxidase activity, and mitochondrial cardiolipin oxidation after 12C relative to γ radiation. Moreover, antioxidant enzyme activity in intestine and colon was also significantly reduced in 12C-irradiated mice. Compared to γ radiation, membrane lipid damage was remarkably higher in both intestine and colon of 12C-ion irradiated mice. At 0.5 Gy, persistent oxidative damage indicated by 4-hydroxynonenal was 3-fold in colon and 1.6 fold in intestine after 12C relative γ radiation. Conclusions: Mitochondrial deregulation, increased NADPH oxidase activity and loss of SOD and catalase activities were the major contributory events in 12C-ion-induced POS in mouse GI-tissues. Compared to intestine, colon was more susceptible to POS induction that might be due to progressive cell turnover in intestine resulting in faster elimination of initial damage signal in a given time than colon. Taken together, our data suggest that normal tissue exposure to 12C radiation carries higher long-term risk relative to γ-rays at comparable doses and further detail evaluation is warranted. Citation Format: Shubhankar Suman, Santosh Kumar, Albert J. Fornace, Kamal Datta. Persistent oxidative stress in mouse intestinal and colonic epithelial cells after exposure to 12C-ion radiation [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 5465. doi:10.1158/1538-7445.AM2017-5465